Afleveringen
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Dr. Shaalan Beg and Dr. David Wang discuss key abstracts in GI cancers from the 2025 ASCO Gastrointestinal Cancers Symposium, including major advances in CRC, neoadjuvant approaches in esophageal cancer, and innovative studies on ctDNA.
TRANSCRIPT
Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Today, we're bringing you some key highlights from the 2025 ASCO Gastrointestinal Cancers Symposium, and I'm delighted to be joined by the chair of GI25, Dr. David Wang. Dr. Wang is a GI medical oncologist at the University of Michigan.
Our full disclosures are available in the transcript of this episode.
Dr. Wang, thanks for coming on the podcast today.
Dr. David Wang: Well, thank you. It's a pleasure to be here.
Dr. Shaalan Beg: GI25 featured major therapeutic advances across the spectrum of GI malignancies, and it was exciting to hear about innovations and novel approaches that are shaping the future of our field. Before we start talking about specific abstracts, could you share some of your key highlights from the meeting?
Dr. David Wang: Sure. Our theme this year was “Breaking Boundaries to Enhance Patient Centered Care.” Past years’ themes have focused more on precision oncology, but we wanted to broaden our focus on patients and to be more holistic, which kind of led us into some of the Intersection [sessions] that we had. Each day started with a different Intersection. The first one was “Emerging Therapies in GI Cancers”, where invited speakers talked about bispecific antibody drug conjugates, theranostics, CAR T and other cell-based therapies. The second day was on “Personalized Risk Assessment for GI Cancers,” and this included looking at polygenic risk scores for colorectal cancer, microRNAs and liquid biopsies such as exosomes and pancreatic cancer and non-endoscopic screening modalities in esophageal cancer. And on our final day, we wanted to talk about “Integrative Oncology and Integrative Medicine,” looking at evidence-based uses of acupuncture and supplements in patients who are receiving treatment for cancer, mindfulness-based practices and exercise. And of course, we had a fantastic keynote talk by Dr. Pamela Kunz from the Yale School of Medicine titled, “Disrupting Gastrointestinal Oncology: Shattering Barriers with Inclusive Science.” She highlighted the intersection of science, patient care, and health and gender equity. And I would encourage your podcast listeners to access the lecture in ASCO's Meeting Library if they haven't yet had a chance to hear Dr. Kunz’s wonderful lecture.
We were really happy this year because the attendance hit a new record. We had over 5,000 people attend either in person or virtually from their home or office, and we had almost 1,000 abstracts submitted to the meeting, so these were either record or near record numbers. We offered a lot of different networking opportunities throughout the meeting, and attending found these to be incredibly rewarding and important and this will continue to be an area of emphasis in future meetings.
Dr. Shaalan Beg: Let's take a deeper dive into the exciting studies presented at GI25. The late breaking abstract LBA143 was CheckMate-8HW. This was the first results of NIVO + IPI versus NIVO monotherapy for MSI-high metastatic colorectal cancer. What are your thoughts about this study?
Dr. David Wang: Yeah, so we know that colorectal cancer patients with MSI-high tumors don't necessarily respond well to chemotherapy. And we were fortunate because last year CheckMate-8HW actually looked at two different arms – so this was NIVO + IPI compared to standard of care chemotherapy and showed its very significant improvement in median progression-free survival. And that was actually published in the New England Journal of Medicine back in November of 2024.
This year's presentation actually focused now on NIVO + IPI versus NIVO monotherapy. And as you know IPI+NIVO can be quite toxic. So this was an important analysis to be done. So we know that NIVO is definitely more easily tolerated. So what was interesting was that the 2-year and 3-year progression-free survival not surprisingly favored IPI+NIVO and this was statistically significant. And the overall response rate was also better with IPI+NIVO versus NIVO alone. I know we're always concerned about toxicities and there were higher grade 3 and 4 toxicity incidences in the combination arm versus the monotherapy arm, but overall, only about 28 additional events in several hundred patients treated. So I think that's well-tolerated. Our discussant Dr. Wells Messersmith actually said that, with this new data, he would consider doing combination immunotherapy in any patient that presented in the front line with MSI-high or deficient mismatch repair colorectal cancer that was metastatic.
Dr. Shaalan Beg: One of the focuses for directing first-line therapy for colorectal cancer has been right and left sided colon cancer because we know these are two different cancers with their own unique molecular subtypes. We heard on Abstract 17, the DEEPER trial, the final analysis of modified FOLFOXIRI plus cetuximab versus bevacizumab for RAS wild-type and left sided metastatic colorectal cancer. How do you summarize the findings of this study and what should our readers be aware of?
Dr. David Wang: Interestingly, this was a phase 2 study and the emphasis of the abstract was actually a subgroup analysis of those patients with RAS wild-type and BRAF wild-type as well as left sided cancers. So, I think the entire study enrolled 359 patients, but the analysis that was discussed at the meeting really focused on 178 patients that fit that characteristic. Very similar to what we've seen in prior studies, left-sided tumors have better response to cetuximab versus bevacizumab. And if you flip it so that you now are looking at right sided tumors, targeting EGFR is actually detrimental. The depth of response was better with cetuximab in these left sided RAS and BRAF mutant tumors. And so the lead author actually suggested that this could be a new first-line standard of care.
And the question is, is there a benefit of doing this triple agent regimen with modified FOLFIRINOX? We know there's a lot more toxicity with that. Not clear that there's a benefit for that over FOLFOX, maybe in younger patients that could tolerate it. When our discussant, again Dr. Wells Messersmith, spoke about this, he said that, in his practice he would, again, favor cetuximab over bevacizumab in combination with chemo, these left-sided RAS and BRAF wild-type tumors, but that he would actually prefer a doublet versus a triplet chemo regimen, and that is consistent with the current NCCN guidelines.
Dr. Shaalan Beg: Another area where colorectal cancer has been a wonderful model to study new technology has been in the area of circulating tumor DNA (ctDNA). And the BESPOKE CRC trial is looking to see if ctDNA can inform adjuvant treatment decisions for stage II and III colorectal cancer. And in Abstract 15, we heard final results of the BESPOKE CRC sub-cohort. What were the findings there?
Dr. David Wang: BESPOKE CRC is another one of these important ctDNA studies. It was an observational study, not a randomized trial, but it did provide a lot of different insights to us. We know that there were over 1,700 patients enrolled, and so it was reported that this is the largest ctDNA study in colorectal cancer performed in the United States. And they were able to analyze over 1,100 patients.
Some of the key findings were that postoperative adjuvant therapy management decisions actually changed in 1 out of 6 patients, so that's pretty significant. In terms of surveillance, we know that patients who have ctDNA positivity, this is prognostic of recurrence. In terms of patients who have positive ctDNA post-surgery, it looked like, at least in this observational study, the majority of patients who received any benefit were those who had positive ctDNA. So adjuvant therapy, even in stage II and stage III patients seemed to only benefit those patients who have positive ctDNA. I think that does raise the question, and this also was brought up in the discussion, which is “Can we de-escalate adjuvant therapy in terms of patients who are ctDNA-negative post-op?” And Dr. Richard Kim from Moffitt felt that we are not yet there. Obviously, we need randomized control trials where we are taking ctDNA results and then randomizing patients to receive adjuvant or non-adjuvant to really know the difference.
Other questions that come up with use of ctDNA include: What do you do with these patients who turn positive? This study for BESPOKE actually followed patients out to two years after surgery. So what you do with a positive ctDNA result wasn't really clear. It seems to suggest that once you turn positive, patients go on to more intensive surveillance. You know, again as an observation, patients who did turn positive were able to go to metastasis-directed therapy much more quickly. And again, this was supposedly to improve their curative intent therapy. And I think the other question that has been brought up all the time is, is this really cost effective? Patients want to know, and we want to give patients that information, but I think we're still stuck with what to do with a positive ctDNA level in a patient that's on surveillance because no randomized control studies have actually suggested that we need to start systemic therapy right away.
Dr. Shaalan Beg: Yeah. And I guess in terms of practice informing or practice changing, these results may not give us a clear answer. But because a lot of patients are asking for these tests, it does give us some real world experiences on what to expect in terms of conversion of these positive into negative and the outcome so we can have a shared decision making with our patients in the clinic and then come up with a determination on whether ctDNA for molecular residual disease is something which would be worthwhile for the care of our patient. But more to come, I guess, in coming years to answer different problems around this challenge.
Dr. David Wang: Yes, I agree.
Dr. Shaalan Beg: The BREAKWATER trial looked at the use of encorafenib, cetuximab and chemotherapy for BRAF V600E-mutant metastatic colorectal cancer. We've covered this combination for a second- third-line treatment in metastatic colorectal cancer previously. Abstract 16 from GI25 was evaluating the use of this regimen in the first-line space. Everyone was looking forward to these results, and what did the investigators present?
Dr. David Wang: I think this is, as you mentioned, a nice follow up to later lines of therapy where Dr. Kopetz from MD Anderson pioneered use of encorafenib, cetuximab and binimetinib in the BEACON trial. Everybody was kind of curious what would happen now if you use encorafenib plus cetuximab plus chemotherapy in the first-line setting. And so this is an interim analysis that was pre-planned in the phase 3 open label BREAKWATER trial. And even though there were three arms, and so the three arms were encorafenib plus cetuximab, encorafenib plus cetuximab plus FOLFOX, or standard of care chemo, only two arms were presented in the abstract. So basically looking at encorafenib plus cetuximab and FOLFOX-6 versus standard of care therapy, and the overall response rate was statistically significant with a 60.9% overall response rate encorafenib plus cetuximab plus chemo arm versus standard of care chemo was only 40%. The interim overall survival also was different. It was 92% versus 87% at 6 months and 79% versus 66% at 12 months, again favoring the chemotherapy plus encorafenib plus cetuximab. In terms of the statistics, the p was 0.0004. However, the pre-plan analysis required the p-value to be 1x10 to the -8. And so even though this looks really good, it hasn't quite met its pre-specified significance level. The good thing is that this is only interim analysis and the study is ongoing with future analysis planned.
So the real question is: Does it matter when we actually use this regimen? We know that the regimen's approved in the second third-line setting. What about in the first line? And there was some preclinical data that the discussant reviewed that shows that patients actually benefit if this is done in the first-line setting. For example, there was some preclinical data showing that even FOLFIRI, for example, can upregulate RAS, which would make tumors more resistant to this combination. This was thought to be practice-changing in a patient that has B600E showing up treatment naive that we should probably consider this regimen. And actually this did receive accelerated FDA approval about a month ago.
Dr. Shaalan Beg: Yeah, and for what it's worth, I put up a Twitter poll asking my Twitter followers on how the BREAKWATER trial results will change their approach for newly diagnosed BRAF mutated colorectal cancer. We got 112 responses; 72% said that they will incorporate encorafenib, cetuximab, FOLFOX for their frontline BRAF mutated patients. But 23% said that they would like to wait for overall survival results.
Dr. David Wang: Wow, that's interesting. They really want that 1x10 to the -8.
Dr. Shaalan Beg: I guess so. All right. Let's change gears and talk about esophageal cancer. LBA329 was the SCIENCE study which presented preliminary results from a randomized phase 3 trial comparing sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant resectable locally advanced squamous esophageal cancer. Where are we in this space?
Dr. David Wang: Okay. So, yeah, this was an interesting trial. Again, just to set the context, esophageal squamous cell carcinoma is more prevalent in Asia. And the study sites as well as the patients were mostly from Asia. So this was again a phase 3 trial with interim results. They only rolled 146 out of the planned 420 for this interim analysis. And yeah, they're using immune checkpoint inhibitor that we don't use in the United States, sintilimab, combined with their two standards of neoadjuvant therapy, either chemotherapy, which is more common in Asia, or or chemoradiation, which is more common in the US and Western Europe, versus chemoradiation. And so they actually had two primary endpoints, but only were reporting one. So their two primary endpoints were pathCR and the other one was event-free survival. The event-free survival, again, was not reported at the meeting.
What they found was that in terms of pathCR rate, if you take the two arms that are really informative about that, chemoradiation plus sintilimab versus chemoradiation alone, the pathCR rate was 60% versus 47%. We know that chemo alone doesn't induce as much of a pathCR rate, and that was 13%. So it was found that the delta in terms of pathCR between the chemoradiation arms, one with sintilimab and one without, was significant. And this actually confirms data again from Asia, like for the ESCORT-NEO trial where it used another immune checkpoint inhibitor pembrolizumab in addition to neoadjuvant chemo.
So as our discussant for this abstract said, yes, we know that radiation combined with chemotherapy improves pathCR rates, but we have recent data from the ESOPEC trial, we don't know that that necessarily will translate to overall survival. So again, waiting for additional enrollments and longer term follow up before incorporating this into clinical care here.
Dr. Shaalan Beg: So David, how do the results of the SCIENCE trial compare with our practice in the United States and ongoing studies asking questions for neoadjuvant therapy for esophageal carcinoma in the United States?
Dr. David Wang: I think obviously immune checkpoint inhibitor in the new adjuvant setting is important. Jennifer Eads at UPenn is running that EA2174 which is looking at chemoradiation plus or minus nivolumab, and then in non-pathCR responders randomized to adjuvant nivolumab per CheckMate 577 or nivolumab with intensification adding ipilimumab. We know that the ESOPEC trial just came out, and was published actually during the meeting, and that really focuses on adenocarcinomas. So adenocarcinomas of the GE junction, distal esophagus, now, we would probably treat very similarly to gastric using perioperative FLOT. However, the standard in the US for esophageal squamous cell carcinoma remains neoadjuvant chemoradiation. We know that squamous cell carcinomas are more exquisitely sensitive to radiotherapy. And then obviously in those patients who don't achieve a pathologic complete response, the expectation would be that they would go on to receive nivolumab per CheckMate 577. Again, the thought is that these tumors are more sensitive to immunotherapy given their higher incidences of mutational changes. And so again, this kind of goes along with the positive results seen in the SCIENCE trial that we just discussed with sintilimab but also EFFECT-neo with pembrolizumab. Obviously, we await the results of Jennifer's trial.
Dr. Shaalan Beg: And the last abstract I was hoping we could get your perspective on was Abstract 652, which is a Phase 3 study of everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumors, the STARTER-NET trial. What were the results of this study?
Dr. David Wang: So, I just want to give a shout out because we did have a session at this year's GI ASCO that looked at more rare tumors. So appendiceal tumors, neuroendocrine tumors, those kinds of things. So again, I would encourage your listeners to listen to that session if they have interest in that. Another type of rare tumor was adenosquamous tumors.
But in terms of the STARTER-NET trial, this was again an interim analysis of his phase 3trial and it was looking at combining everolimus plus lanreotide versus everolimus. So we know that in pancreatic-gastric neuroendocrine tumors, if you have low Ki-67, a well differentiated tumor, that the standard of care really is a somatostatin analog, and sometimes if they're more aggressive, we kind of consider molecular targeted therapy with everolimus. This was asking the question of whether we should do the combination on the frontline. And what was interesting is in this study, the patients were actually more of a poor prognostic set. So they had Ki-67 up to 20% or these were patients that actually had multiple liver lesions. And what they found was a median for progression free survival was improved with a combination out to 29.7 months versus 11.5 months with the somatostatin analog alone, and that the overall response rate was 23% versus 8.3%, again, favoring the combination.
If you looked at subgroup analysis, it was actually those patients who had Ki-67 greater than 10%, so the more aggressive tumors, or those with diffuse liver lesions that had the most benefit. So I think that would be the patient population I would consider this new combination with using would be those patients again with poorer prognosis neuroendocrine tumor phenotype.
Dr. Shaalan Beg: Thank you very much, Dr. Wang, for sharing your insights with us today and your great work to build a robust GI Cancers Symposium this year.
Dr. David Wang: Well, thank you. I mean that really is a cooperative effort. We appreciate all the members of the GI25 Program Committee as well as the ASCO staff that just made it an outstanding meeting.
Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode.
Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Shaalan Beg
@ShaalanBeg
Dr. David Wang
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Disclosures:
Dr. Shaalan Beg:
Employment: Science 37
Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine
Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals
Dr. David Wang:
Honoraria: Novartis
Consulting or Advisory Role: Novartis, Cardinal Health, Bristol-Myers Squibb, BeiGene, Eisai
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Dr. Jasmine Sukumar and Dr. Dionisia Quiroga discuss advances in adjuvant therapy for patients with early breast cancer and BRCA1/2 mutations, including how to identify patients who should receive genetic testing and the significant survival benefits of olaparib that emerged from the OlympiA trial.
TRANSCRIPT
Dr. Jasmine Sukumar: Hello, I'm Dr. Jasmine Sukumar, your guest host of the ASCO Daily News Podcast today. I'm an assistant professor and breast medical oncologist at the University of Texas MD Anderson Cancer Center. On today's episode, we'll be exploring advances in adjuvant therapy for high-risk early breast cancer in people with BRCA1/2 germline mutations. Joining me for this discussion is Dr. Dionisa Quiroga, an assistant professor and breast medical oncologist at the Ohio State University Comprehensive Cancer Center.
Our full disclosures are available in the transcript of this episode.
Dr. Quiroga, it's great to have you on the podcast. Thanks for being here.
Dr. Dionisia Quiroga: Thank you. Looking forward to discussing this important topic.
Dr. Jasmine Sukumar: Let's start by going over who should be tested for BRCA1/2 genetic mutations. How do you identify patients with breast cancer in your clinic who should be offered BRCA1/2 genetic testing?
Dr. Dionisia Quiroga: So, guidelines on who to offer testing to somewhat differ between organizations at this point. I would say, generally, I do follow our current ASCO-Society of Surgical Oncology (SSO) Guidelines, though. Those guidelines recommend that BRCA1/2 mutation testing be offered to all patients who are diagnosed with breast cancer and are 65 years old or younger. For those that are older than 65 years old, there are additional factors to really take into account to decide on who to recommend testing for. Some of this has to do with personal and family history as well as ancestry. The NCCN also has their own specific guidelines for who to offer testing to. For example, people assigned male at birth; those who are found to have a second breast primary; those who are diagnosed at a young age; and those with significant family history should also be offered BRCA1/2 testing.
I think, very important for our discussion today, ASCO and SSO also made a very important point that all patients who may be eligible for PARP inhibitor therapy should be offered testing. So clearly this includes a large amount of our patient population. In my practice, we often refer to our Cancer Genetics Program. We're fortunate to have many experienced genetic counselors who can complete pre-test and post-test counseling with our patients. However, in settings where this may not be accessible to patients, it can also be appropriate for oncology providers to order the testing and ideally perform some of this counseling as well.
Dr. Jasmine Sukumar: Thank you Dr. Quiroga. Let's next review where we are in current clinical practice guidelines. What current options do we have for adjuvant therapy specific to people with high-risk early breast cancer and BRCA1/2 genetic mutations?
Dr. Dionisia Quiroga: Our current guidelines recommend adjuvant olaparib for one year for individuals with HER2-negative high risk breast cancer. This approval largely came from the data and the results of the OlympiA trial. This was a prospective phase 3, double blind, randomized clinical trial. It enrolled patients who had been diagnosed with HER2-negative early-stage breast cancer who also carried germline pathogenic or likely pathogenic variants of either the BRCA1 and/or BRCA2 genes. The disease also had to be considered high-risk and there were several criteria that had to be evaluated to deem whether or not these patients were high-risk. For example, those who are treated with neoadjuvant chemotherapy, if they had disease that was triple-negative, they needed to have some level of invasive residual disease at time of surgery. Alternatively, if the disease was hormone receptor-positive, they needed to have residual disease and a calculated CPS + EG score of 3 or higher. This scoring system is something that estimates relapse probability on the basis of clinical and pathologic stage, ER status, and histologic grade, and this will give you a score ranging from 0 to 6. In general, the higher the score, the worse the prognosis. This calculator though is available to the public online to allow providers to calculate this risk.
For the subset of patients who received adjuvant chemotherapy, for them to qualify for the OlympiA trial, if they had triple-negative disease, they needed to have a tumor of at least 2 cm or greater and/or have positive lymph nodes for disease. For hormone receptor-positive disease that was treated with adjuvant chemotherapy, they were required to have four or more pathologically confirmed positive lymph nodes at time of surgery. From this specified pool, patients were then randomized 1:1 to get either adjuvant olaparib starting at 300 mg twice a day or a matching placebo twice a day after they had completed surgery, chemotherapy and radiation treatment if needed.
Dr. Jasmine Sukumar: And what were the outcomes of this study?
Dr. Dionisia Quiroga: The study ended up enrolling over 1,800 patients and from these 1,800 patients, 70% had a BRCA1 mutation while 30% had a BRCA2 mutation. About 80% of the patients had triple-negative disease compared to hormone receptor-positive disease. Interestingly, about half of all patients enrolled had received neoadjuvant chemotherapy while the other half received adjuvant chemotherapy.
Looking at the outcomes, this was overall a very positive study. We actually now have outcomes data from a median of about 6 years out. This was just reported in December at the 2024 San Antonio Breast Cancer Symposium. There was found to be a 9.4% absolute difference in six-year invasive disease-free survival favoring the olaparib arm over the placebo arm. What was also interesting is that this was consistent across multiple subgroups of patients and the benefit was really seen whether or not they had hormone receptor-positive or triple-negative disease. The absolute difference in distant disease-free survival was also high at 7.8% and additionally favored olaparib. Most importantly, there was found to be a significant overall survival benefit. The six-year overall survival was 87.5% in the olaparib group compared to 83.2% in the placebo group. This translates to about a 4.4% difference and a relative 28% overall survival benefit in using olaparib.
Now, future follow up is going to be very important. Follow up for this study is actually planned to continue out until June 2029 so we can continue to observe if these survival curves will continue to branch apart as they have so far at each follow up. And I think this is especially important for those patients diagnosed with hormone receptor-positive cancers because we know those patients are at particular risk for later recurrences.
As an additional side note, the researchers also noted that there were fewer primary malignancies in the olaparib group, not just of the breast but also primary ovarian or fallopian tube cancers as well, which is not completely surprising knowing that this drug is also heavily used and beneficial in different types of gynecologic cancers. Ultimately, the amount of adverse events reported have been low with only about 9.9% of patients receiving olaparib needing to discontinue drug due to adverse events, and this is compared to 4.2% reported in the placebo group.
Dr. Jasmine Sukumar: You mentioned that the OlympiA trial showed an overall survival benefit, but interestingly the OlympiAD trial looking at olaparib versus chemotherapy in patients with advanced metastatic HER2-negative breast cancer did not show a significant overall survival benefit. Could you discuss those differences?
Dr. Dionisia Quiroga: I agree, that's a very good point. So OlympiA’s comparator arm was, of course, a placebo. So while this isn't the same as comparing to chemotherapy, it does still potentially suggest that there is a degree of benefit that olaparib can provide when it's introduced in the early local disease setting compared to advanced metastatic disease. I think we need more future trials looking at potential other combinations to see if we can improve the efficacy of PARP inhibitors in the metastatic setting.
Dr. Jasmine Sukumar: For patients who do choose to proceed with use of adjuvant olaparib due to the promising efficacy, what side effects should oncologists counsel their patients about?
Dr. Dionisia Quiroga: The most common notable side effects, I would say with olaparib and other PARP inhibitors are really cytopenias. Gastrointestinal side effects such as nausea and vomiting can occur as well as fatigue. There are some less common but potentially more serious side effects that we should counsel our patients on. This includes pneumonitis. So counseling patients on if they're short of breath or experiencing cough to let their provider know. Venous thromboembolism can also be increased rates of occurrence. And then of course myelodysplastic syndromes or acute myeloid leukemia is something that we often are concerned about. That being said, I think it should be noted that interestingly in the OlympiA trial so far, there have been less new cases of MDS and AML in the olaparib group than actually what's been reported in the placebo group at this median follow up of over six years out. So we'll need to continue to monitor this endpoint over time, but I do think this provides some reassurance.
Dr. Jasmine Sukumar: Since the initiation of the OlympiA trial, other adjuvant treatments have also been studied and FDA approved for non-metastatic HER2-negative breast cancer. So for example, the CREATE-X trial established adjuvant capecitabine as an FDA approved treatment option in patients with triple-negative breast cancer who had residual disease following neoadjuvant chemotherapy. So if a patient with triple-negative breast cancer with residual disease is eligible for both adjuvant olaparib and adjuvant capecitabine treatments, how do you decide amongst the two?
Dr. Dionisia Quiroga: If a patient's eligible for both, I honestly often favor olaparib, and I do this because I find the data for adjuvant olaparib a little bit more compelling. There are also differences in toxicity profile and treatment duration between the two that I think we should discuss with patients. For example, olaparib is supposed to be taken for a year total, whereas with capecitabine we typically treat for six to eight cycles with each cycle taking three weeks. There are some who may also sequence the two drugs in very high-risk disease. However, this is very much a data free zone. We don't have any current clinical trials really comparing these two or if sequencing of these agents is appropriate. So I don't currently do this in my own clinical practice.
Dr. Jasmine Sukumar: Nowadays, almost all patients with stage 2 to 3 triple-negative breast cancer will be offered neoadjuvant chemotherapy plus immune checkpoint inhibitor therapy pembrolizumab per our KEYNOTE-522 trial data. With our current approach, pembrolizumab is continued into the adjuvant setting regardless of surgical outcome, so that patients receive a year total of immunotherapy. So in patients with residual disease and a BRCA germline mutation, do you suggest using adjuvant olaparib concurrently with pembrolizumab? Do we have any data to support that approach?
Dr. Dionisia Quiroga: I do. I do use them concurrently. If a patient is eligible for adjuvant olaparib, I would use it the same way as if they were not on pembrolizumab. That being said, there are no large studies currently that have shown what the benefit or the toxicity of pembrolizumab plus olaparib are for early-stage disease. However, we do have some safety data of this combinatorial approach from other studies. For example, the phase 2/3 KEYLYNK-009 study showed that patients with advanced metastatic triple-negative breast cancer who were receiving concurrent pembrolizumab and olaparib had a manageable safety profile, particularly as the toxicities of these drugs alone don't tend to overlap.
Dr. Jasmine Sukumar: And what about endocrine therapy for those that also have hormone receptor-positive disease?
Dr. Dionisia Quiroga: Adjuvant endocrine therapy should definitely be continued while patients are on olaparib if they're hormone receptor-positive. An important component of this will also likely be ovarian suppression, which should include recommendation of risk reducing bilateral salpingo oophorectomy due to the risk of ovarian cancer development in patients who carry BRCA1/2 gene mutations. In most cases, this should happen at age 40 or before for those that carry a BRCA1 mutation, and at age 45 or prior for those with BRCA2 mutations.
Dr. Jasmine Sukumar: And do you also consider adjuvant bisphosphonates in this context?
Dr. Dionisia Quiroga: Yes. Like adjuvant endocrine therapy, adjuvant bisphosphonates were also instructed to be given according to standard guidelines in the OlympiA trial, so I would recommend use of bisphosphonates when indicated. You can refer to the ASCO Ontario Health Guidelines on Adjuvant Bone-Modifying Therapy Breast Cancer to guide that decision in order to utilize this due to multiple clinical benefits. It doesn't just help in terms of adjuvant breast cancer treatment but also reduction of fracture rate and down the line, improved breast cancer mortality.
Dr. Jasmine Sukumar: Particularly in hormone receptor-positive breast cancer, another adjuvant therapy option that was not available when the OlympiA trial started are the CDK4/6 inhibitors, ribociclib and abemaciclib, based on the NATALEE and monarchE studies. So how do you consider the use of these adjuvant therapy drugs in the context of olaparib and BRCA mutations?
Dr. Dionisia Quiroga: Yeah, so we are definitely in a data-free zone here. And that's in part because the NATALEE and the monarchE studies are still ongoing and reporting data out at the same time that we're getting updated OlympiA data. So unlike some of our other adjuvant treatments that we discussed, where olaparib could be safely given concurrently, the risk of myelosuppression and using both a CDK4/6 inhibitor and a PARP inhibitor at the same time would be too high. In some cases, even if a patient has a BRCA1/2 mutation, they may not meet that specified inclusion criteria that OlympiA set for what they consider to be high-risk disease. And we know from the NATALEE and the monarchE trial there are also different markers that they use to denote high-risk disease. So it's possible, for example, in the NATALEE trial that looks specifically at adjuvant ribociclib, they included a much larger pool of hormone receptor-positive early-stage breast cancers, including a subset that did not have positive axillary lymph nodes.
In cases where patients would qualify for both olaparib and a CDK4/6 inhibitor, I think this is worth a nuanced discussion with our patients about the potential benefits, risks and administration of these drugs. I think another point to bring up is the cost associated with these drugs and the length of time patients will be on for, because financial toxicity is always something that we should bring up with patients as well. When sequencing these in high-risk disease, my practice is to generally favor olaparib first due to the overall survival data. There is also some data to support that patients with BRCA1/2 germline mutations may not respond quite as well to CDK4/6 inhibitors compared to those without. But again, this is still outside of the purview of current guidelines. Fortunately, we have more potential choices for patients, and that's a good thing, but shared decision making also needs to be key.
Dr. Jasmine Sukumar: And while our focus today is on adjuvant treatment for people who carry germline BRCA mutations, what about other related gene mutations such as PALB2 pathogenic variant?
Dr. Dionisia Quiroga: That's a great question. Clinical trials in the advanced metastatic setting have shown that there is efficacy of olaparib in the setting for PALB2 mutations. This is largely based on the TBCRC 048 phase 2 trial and that provided a Category 2B NCCN recommendation for patients with these PALB2 gene mutations. However, we're really still lacking enough clinical data for use in early-stage disease, so I don't currently use adjuvant olaparib in this case. I am definitely eager for more data in this area as the efficacy of PARP inhibitors in PALB2 gene mutations is very compelling. I think also, in the same line, there's been some data for somatic BRCA1/2 mutations in the metastatic setting, but we still have a lack of data for the early stage setting here as well.
Dr. Jasmine Sukumar: Thank you Dr. Quiroga, for sharing your valuable insights with us today on the ASCO Daily News Podcast.
Dr. Dionisia Quiroga: Thank you, Dr. Sukumar.
Dr. Jasmine Sukumar: And thank you to our listeners for your time today. You'll find links to the studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Follow today’s speakers:
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@quirogad.bsky.social
Dr. Jasmine Sukumar
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Disclosures:
Dr. Dionisia Quiroga: No relationships to disclose
Dr. Jasmine Sukumar:
Honoraria: Sanofi (Immediate Family Member)
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Zijn er afleveringen die ontbreken?
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Native American oncologist Dr. Amanda Bruegl and Dr. Noelle LoConte discuss culturally tailored interventions and the importance of community engagement to advance cancer prevention, diagnosis, and treatment for Native communities.
TRANSCRIPT
ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. On today's episode, we'll be discussing cancer care for Native American communities who face unique challenges and disparities in accessing and receiving cancer care. I'm delighted to be joined by two oncologists who will be sharing their insights on ways to advance cancer prevention, diagnosis, and treatment through culturally tailored interventions and community-based programs for high-risk Native Americans whose issues are chronically overlooked in the healthcare system, according to experts.
Dr. Amanda Bruegl is an associate professor of obstetrics and gynecology at the Oregon Health and Science University School of Medicine. She is a gynecologic oncologist at the OHSU Knight Cancer Institute and a citizen of the Oneida Nation and descendant of Stockbridge-Munsee. Dr. Noelle LoConte is an associate professor of medicine at the University of Wisconsin Madison Carbone Cancer Center where she also serves as a GI medical oncologist, geriatrician and leads community outreach.
Full disclosures are available in the transcript of this episode.
Dr. LoConte and Dr. Bruegl, it's great to have you on the podcast today.
Dr. Noelle LoConte: Thanks so much for having me.
Dr. Amanda Bruegl: Thank you for having us.
ASCO Daily News: Dr. Bruegl, I'd like to start by asking you to tell us a bit about your background and how it has influenced your career and interests as a gynecologic oncologist.
Dr. Amanda Bruegl: I grew up in Wisconsin and I have a Native parent and a non-Native parent. And so having an awareness of both cultural influences in my life has really shaped my interest in cancer prevention. Seeing the high rates of preventable death in cancer among Native populations in gynecologic cancers, in particular, has really driven me to dedicate my research career toward decreasing the morbidity and mortality of cervical cancer among Native women.
ASCO Daily News: Well, can you tell us about your work in cancer prevention, specifically cervical cancer? The data shows that Native Americans in Oregon get cervical cancer one and a half times more than the general state population and die from it two times more often. What are the factors, the barriers, that are contributing to these high rates of cervical cancer?
Dr. Amanda Bruegl: The data in Oregon is actually not just limited to Oregon. Our group did some work in collaboration with the Northwest Portland Area Indian Health Board Tribal Epidemiology Center, and we found that, as you stated, the rates of cervical cancer are one and a half times that of non-Hispanic Whites and the rate of death is about twice. And that's true for the Pacific Northwest. And if you dig deeper into the literature, you see that these rates are true across Indian Country, sometimes worse. When we looked at the age groups, we found that older women had three times the rate of mortality. So looking at like 45 to 65. As I was looking through the literature to figure out, well, why is this, we found that there are very, very few funded studies that even look at this. We have a known persistent disparity that is chronically understudied and underfunded. And so I'm trying to do work in this arena to explore this further.
A follow up study that we did was looking at whether we are using the prevention tools. So it's common across the United States that we have two very powerful prevention tools. So participation in cervical cancer screening doesn't necessarily prevent cervical cancer, but you can have early detection of pre-invasive disease or detection of early-stage disease, which is highly curable. And then we also have HPV vaccination, something geared towards the youth in our communities across the U.S. HPV vaccination starting at age 9 with a goal of complete vaccination by the age of 12. So we looked at: Are we using these two tools in Indian Country? And what we found was that participation in cervical cancer screening, looking at who is up-to- date among Natives, and we found that overall the population had about 60% rates of up-to- date on cervical cancer screening compared to general US rates, which are in like the high 70s or low 80s. And then when we looked at that age group that has higher rates of mortality, we actually found that there's only about a 50% rate of up-to-date screening. So we know in one arena people aren't participating in screening. And there's a variety of different contributors to that. There's access to care. How far do you have to travel to get to a provider who will provide cervical cancer screening? Among Native women, there's an over 50% rate of history of sexual trauma, sexual violence, pelvic exam trauma. It's a huge barrier to coming in for this very sensitive exam. There is also mistrust with the medical system in general. There's high turnover of providers at Indian Health Service Clinics.
The clinic that I'm currently working at now, so I do outreach at a clinic one day a month and I'm the longest standing doc at that clinic and I'm a consultant who comes one day a month. I've been there since 2016. And so when you can't develop a relationship with a provider and develop trust and there's just this churn of new people every three to six months, developing a relationship to allow someone to feel comfortable with a very personal and private examination can be a huge barrier.
On the HPV vaccination side, we found that the numbers for HPV vaccination were pretty optimistic. So the numbers have been going up since our study period started in 2015. The clinics in the Pacific Northwest that are serving Native populations are doing a great job with education, outreach and increasing the numbers. The group with the greatest rates of HPV vaccination are for people assigned female at birth in the 13-18 age group. They are the only group that is approaching the Healthy People 2030 goal. But there's still work to be done in this arena. Those are some big drivers of why this persistent disparity continues.
ASCO Daily News: Absolutely. You mentioned some very serious barriers. Sexual trauma, mistrust, long distance to travel to clinics. Looking ahead, can you tell us about potential screening tools that could improve screening? And I also wanted to ask you about innovations you're excited about that could be potentially incorporated into practice to increase the ability and comfort of your patients to screening and access to HPV vaccination.
Dr. Amanda Bruegl: So, in terms of cervical cancer screening and how to increase the rates, there are a number of different things in the literature broadly across populations that really show that knowledge and awareness of cervical cancer and cervical cancer screening guidelines is associated with guideline concordant care. And so ensuring that our patients in our communities know and understand what the recommendations are is very important. Efforts to provide education to women in the community, community stakeholders, and culturally tailored content can all be important for increasing the rates of cervical cancer participation.
Another thing that has the potential to really help improve screening rates is HPV self-collection. The FDA just recently approved HPV self-collection which can help empower an individual to do their own testing on their own body and not have someone else place a speculum in a private personal area where they're not comfortable. Some of the tribes in our region are starting to adopt this practice. And I just gave a talk to the regional Indian Health Service medical directors and have had really positive feedback about clinics working towards bringing this into their practice. I hope that the FDA can move forward with allowing patients to do this in the comfort of their own home. Sadly, the FDA in their evaluations decided it had to be a clinic administered test. So someone still has to go through the barrier of finding time to, if they have caregiver responsibilities or work, to have these responsibilities taken care of for someone else so they can drive to a clinic. So these barriers of transportation and caregiving are not addressed by this. It addresses some of the trauma, that barrier. And so I think in the US, we can do better about bringing this like FIT testing to our patients. I really hope and challenge our country to move forward with that a bit more.
Geraldine Carroll: Thanks, Dr. Bruegl. I'll come back to you in a moment, but first I'd like to switch gears and address some of the challenges faced by Native communities in Wisconsin that were featured in a fascinating study presented by our guest, Dr. Noelle LoConte, at the recent ASCO Quality Care Symposium. The study found that radon levels in Native lands in Wisconsin were much higher than anticipated and may explain higher rates of lung cancer among Native communities in the state. Radon is the second leading cause of lung cancer in the U.S. So, Dr. LoConte, can you tell us more about this study and your incredible partnership with the Stockbridge-Munsee Band of the Mohican Nation Health Center in this work?
Dr. Noelle LoConte: You bet. Thanks for the interest. First of all, I think it's just an incredible privilege to work with all of these communities. So, I wanted to say at the jump that this was a joint project led by the cancer center that I'm affiliated with, but also with the Stockbridge-Munsee community. They approved the project and they designed it with us, and they retain ownership of the data. Data sovereignty is an important issue when you're doing this work. But we came to them wanting to work on something around cancer. I actually thought maybe colorectal cancer screening. But in meeting with the health center and the tribal community members, it became clear that they were more concerned that they had intergenerational rates of cancer, and they felt that they were being poisoned by their land. And that brought me to the state Environmental Health Program. And we looked at some data and realized, one, their lung cancer rates were quite high, but two, their radon testing rates were quite low. And that that was a place where we thought we couldn't make some forward momentum.
So, we designed a program to educate around radon and radon testing and mitigation and then tested all the homes on the reservation. And we successfully tested all homes for radon and then successfully mitigated all the homes that tested over four picocuries per liter, which is the recommended level at which you should mitigate per the EPA, the Environmental Protection Agency. The statewide average for Wisconsin is 10% positive. And amongst homes that had a basement, which is thought to be the highest risk kind of dwelling in the Stockbridge-Munsee Reservation community, the positive rate was 77%. And when you take all the homes together because we had some homes with crawl spaces or slab foundation, it was around, I believe, 55% positive, so much higher than 10%.
ASCO Daily News: Well, that data is just striking. Your study certainly illustrates the vital role that cancer centers can play in mitigating structural determinants of health among Native communities, such as with housing quality. Do you think this will inspire a similar approach in other regions of the country?
Dr. Noelle LoConte: Yeah, I think this work was possible because of philanthropy. It is very, very hard to get grant funding for mitigation, in particular. Mitigation is usually done once in the life of the dwelling, but it is very, very expensive. A cheap mitigation is $750, and many are many thousands of dollars especially when you're looking at very rural communities where there's not really a mitigator within hundreds of miles and you have to really negotiate to get somebody to come out there. Every cancer center that's designated by the National Cancer Institute has to have a community outreach and engagement unit or program. I would argue that rather than us generating reports describing disparities, that this kind of work to actually dismantle these determinants of health and move power back into the community is an ideal role for a cancer center. But the funding was definitely a tricky piece of it. And I would hope that we could either envision funding mechanisms that allow for this kind of direct service to communities, or we can continue to work with philanthropic agencies to fund this.
ASCO Daily News: Well, looking through a wider lens at the experience of Native communities navigating cancer care, I'd like to ask each of you to comment on how you think the oncology community can better support and serve high-risk Native populations. What message would you like oncologists to take away from this discussion today? Dr. Bruegl, would you like to respond first?
Dr. Amanda Bruegl: There's so many layers to needs in our communities. First and foremost, it's important to understand that American Indians and Alaska Natives are sovereign people, sovereign nations. We've been written into the US Constitution as citizens of our own tribes. And it's important to remember that when working with our populations. I think it's also really important to remember that there's treaty law that promised healthcare to our communities. And you see that we are underfunded in all aspects of healthcare, and it's a driver. And people on the healthcare side of things need to remember we represent the failures of the healthcare system to care for our Native communities. Whether or not you wake up in the morning with a goal to help, you have to remember that you represent the institution and the history of this country and are going to be asked to prove yourself in a genuine fashion. And that takes time.
I think for people who are in research, it's really important to think about how do you engage and partner with tribal communities so that we're not chronically left behind and left out of study? We seldom show up in the data, and we have to find our own data. Tribal epidemiology centers have been really paramount in helping tribes get access to their data and analyze their data. But you can see in trial after trial after trial, we're sort of shoved into the other box. And so it's so difficult to understand how the cancer story relates to us and how do we improve it?
ASCO Daily News: Thank you, Dr. Bruegl. Dr. LoConte, would you like to comment on this as well?
Dr. Noelle LoConte: Yeah. I had jotted down a few points. Many are going to be a little bit of a repetition here, but I think the overarching theme is that the goals for academic medicine often are not the goals of the community that you may be seeking to work in, and so being able to pivot was key to the success of my project, I think. Can't underestimate the importance of trust. And trust takes a lot of time and a lot of showing up and a lot of being consistent and delivering on what you say you're going to do. And there's a lot of turnover in academic medicine. People leave institutions, move on for promotions. None of that is going to help strengthen these relationships. So I think institutions would be wise to invest in people that stay. I think there should be things like retention bonuses for those of us that stay in places and do community work. It's certainly not the sexy stuff. It's not what gets you in the Plenary at the ASCO Annual Meeting, for example, but I was beyond delighted that I was on the podium for the ASCO Quality Care Symposium. And I think continuing to elevate this work as meaningful and important work, just as important as clinical trials and new drugs, is really important.
I would like to second the motion or the thought that we need to support full funding for the Indian Health Services. It is a promise we made that we continue to underdeliver on that continues to harm patients every day, particularly in the latter half of the year when they run out of funding pretty consistently. For those of us that are non-Native doing this work, to know the history of the community that you're working in and be really mindful of that but also know the role that your institution played in propagating some of these harms. And I think we need more Native physicians that really will help to have concordance with patients and physicians. And so as much as we can support getting more Native folks starting really early – high school, middle school, interested in medicine and biomedical research, all the way through medical school residency fellowship would be really, really impactful. We have a program here founded by Amanda's husband called the Native American Center for Health Professions, or NACHP. It's really a feather in our cap here and I would love to see all medical schools have some sort of pathway program like that. We won't get out of this hole until we start to really take that seriously.
ASCO Daily News: Well, thank you so much, Dr. LoConte and Dr. Bruegl for taking the time and showing up for Native communities, and all your work to advance cancer care. We are certainly very grateful for your time today and we will embed links to all of the studies discussed in the transcript of this episode. So thank you again, Dr. LoConte and Dr. Bruegl.
Dr. Noelle LoConte: You're welcome.
Dr. Amanda Bruegl: Thank you for having us.
ASCO Daily News: And thank you to our listeners for your time today. Again, you'll find links to the studies we discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Follow today’s speakers:
Dr. Amanda Bruegl
Dr. Noelle LoConte
@noelleloconte.bsky.social
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Amanda Bruegl – No relationships to disclose
Dr. Noelle LoConte:
Consulting or Advisory Role: Abbvie, PDGx
Research Funding: Exact Sciences
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Dr. Nathan Pennell and Dr. John Sweetenham discuss the evolving landscape of oncology in 2025 and the challenges oncologists will be facing, including the impact of Medicare drug price negotiations, ongoing drug shortages, and the promising role of AI and telehealth in improving patient outcomes and access to clinical trials.
TRANSCRIPT
Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. 2025 promises to be a year of continued progress in drug development, patient care, and technological innovations that will shape the future of cancer care. Oncologists will also be grappling with some familiar challenges in oncology practice and probably face a few new ones as well. I'm delighted to be joined today by Dr. Nathan Pennell to discuss some of these challenges. Dr. Pennell is the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. He also serves as the editor-in-chief of the ASCO Educational Book.
You'll find our full disclosures in the transcript of this episode.
Nate, it's great to have you on the podcast today.
Dr. Nathan Pennell: Thanks for inviting me, John. I'm excited to be here.
Dr. John Sweetenham: Thanks. So, Nate, we've been hearing a lot recently about implementation science in oncology particularly. This has been the case, I would say, over the past decade and of course the goal is to how do we figure out the best way to integrate evidence-based practice into oncology care? There's been a lot of very good guidance from organizations like ASCO and every year we're reminded of the need for clinical decision support for practicing oncologists at the point of care. Although I think we all agree it is the right thing to do, and this has been a matter of discussion for probably more than 10 years, for the most part, I don't think we've really got there. Some big practices probably have a truly well-integrated clinical decision support tool, but for many of us this is still lacking in the field. I wonder whether we do need some kind of global clinical decision support tool. What do you think about the future of clinical decision support at the point of care? And do you think this is going to continue to be a need?
Dr. Nathan Pennell: I think that's a fantastic question and it absolutely is something we're going to continue to work towards. We're in an incredibly exciting time in oncology. We've got all these exciting predictive biomarkers, effective treatments that are working better than anything we've had in our careers up to this point. But when we actually look to see who is benefiting from them, what we find is that outside of clinical trial populations, many of our patients aren't actually accessing these.
And so publications that look at real-world use of these, one that jumps to mind for me is a publication looking at biomarker testing for driver oncogenes in lung cancer showed that while everyone who treats lung cancer says, “Absolutely, we need to test for biomarkers such as EGFR mutations,” in the real world, probably only slightly over a third of people ever access these drugs because there are so many different gaps in care that fall through the cracks. And so decision support is absolutely critical.
You mentioned this has been going on for a decade. Actually, the Institute of Medicine in 2013 recommended that with the uptake of electronic medical records, that we move forward with building these true learning health care systems that would improve quality and use every patient's information to help inform their care. And in 2023, as a representative of ASCO, I was able to look back at the last decade, and the uniform conclusion was that we had failed to build this learning health care system. So, what can we do going forward? The good news is there are improvements in technology. There are, for better or for worse, some consolidation of electronic medical records that has allowed larger numbers of patients to sort of have data sets shared. ASCO started CancerLinQ to try to improve quality, which is now part of OpenAI, and is still working on technology solutions to help provide decision support as we are better able to access patient data. And I think we're going to talk a little bit later about some of the technological advances that are going on in artificial intelligence that are really going to help improve this. So I think this is very close to impacting patient care and improving quality of care. I think for, as you'd mentioned, large health care systems and users of the major EMRs, this is going to be extremely close.
Dr. John Sweetenham: Thanks, Nate. And just to extend the conversation into another area, one of the constant, I think, pain points for practicing oncologists has been the issue of prior authorization and the amount of time and energy it takes to deal with insurance denials in cancer care. And I think in a way, these two things are linked in as much as if we had clinical decision support tools at the point of care which were truly functional, then hopefully there would be a more facile way for an oncologist to be able to determine whether the patient in front of him or her is actually covered for the treatment that the oncologist wants to prescribe. But nevertheless, we're really not there yet, although, I think we're on the way to being there. But it does remain, like I said, a real pain point for oncologists.
I wonder if you have any thoughts on the issue of prior authorization and whether you see in the coming year anything which is going to help practicing oncologists to overcome the time and effort that they spend in this space.
Dr. Nathan Pennell: I think many oncologists would have to list this among, if not the least favorite aspects of our job these days is dealing with insurance, dealing with prior authorizations. We understand that health care is incredibly expensive. We understand that oncology drugs and tests are even more expensive, probably among, if not the most rapidly growing costs to the health care system in the U.S., which is already at about 20% of our GDP every year. And so I understand the concern that costs are potentially unsustainable in the long term. Unfortunately, the major efforts to contain these costs seem to have fallen on the group that we would least like to be in charge of that, which are the payers and insurance companies, through use of prior authorization. And this is good in concept, utilization review, making sure that things are appropriate, not overutilizing our expensive treatments, that makes perfect sense. Unfortunately, it's moved beyond expensive treatments that have limited utility to more or less everything, no matter how inexpensive or standard. And there's now multiple publications suggesting that this is taking on massive amounts of time. Some even estimated that for each physician it's a full 40-hour work week per physician from someone to manage prior authorizations, which costs billions of dollars for practices every year. And so this is definitely a major pain point.
It is, however, an area where I'm kind of optimistic, maybe not necessarily in 2025, but in the coming several years with some of the technology solutions that are coming out, as we've talked about, with things like clinical pathways and whatnot, where the insurance company approvals can be tied directly to some of these guideline concordance pathway tools. So the recent publication at the ASCO Quality [Care] Symposium looking at a radiation oncology practice that had a guideline concordant prior auth tool that showed there was massive decrease in denials by using this. And as this gets rolled out more broadly, I think that this can increase the concept of gold carding, where if practices follow these clinical guidelines to a certain extent, they may be even exempt from prior authorization. I think I can envision that this is very close to potentially removing this as a major problem. I know that ASCO certainly has advocated on the national level for changes to this through, for example, advocating for the Improving Seniors Timely Access to Care Act. But I think, unfortunately, the recent election, I'm not sure how much progress will be made on the national level for progress in this. So I think that the market solutions with some of the technology interventions may be the best hope.
Dr. John Sweetenham: Yeah, thanks. You raised a couple of other important points in that answer, Nate, which I'll pick up on now. You mentioned drug prices, and of course, during 2025, we're going to see Medicare negotiating drug prices. And we've already seen, I think, early effects from that. But I think it's going to be really interesting to see how this rolls out for our cancer patients in 2025. And of course, the thing that we can't really tell at the moment that you've alluded to is how all this is going to evolve with the new administration of President Trump. I understand, of course, that none of us really knows at this point; it's too early to know what the new administration will do. But would you care to comment on this in any way and about your concerns and hopes for Medicare specifically and what the administration will do to cancer care in general?
Dr. Nathan Pennell: I think all of us are naturally a little bit anxious about what's going to happen under the new administration. The good news, if there's good news, is that under the first Trump administration, the National Cancer Institute and cancer care in general was pretty broadly supported both in Congress and by the administration. And if we look at specifically negotiating drug prices by Medicare, you can envision that having a businessman president who prides himself in negotiations might be something that would be supported and perhaps even expanded under the incoming Trump administration. So I think that's not too hard to imagine, although we don't really know. On the other hand, there are very valid concerns about what's going to happen with the Affordable Care Act, with Medicaid expansion, with protections for preexisting conditions, which impact our patients with cancer. And obviously there are potential people in the new administration who perhaps lack trust in traditional evidence-based medicine, vaccines, things like that, which we're not sure where they're going to fall in terms of the health care landscape, but certainly something we'll have to watch out for.
Dr. John Sweetenham: Yeah. Certainly, when we regroup to record next year's podcast, we may have a clearer picture of how that's going to play out.
Dr. Nathan Pennell: I mean, if there's anything good from this, it's that cancer has always been a bipartisan issue that people support. And so I don't want to be too negative about this. I do think that public support for cancer is likely to continue. And so overall, I think we'll probably be okay.
Dr. John Sweetenham: Yeah, I agree with that. And I think one of the things that's important to remember, I do remember that one of the institutions I've worked at previously that there from time to time was some discussion about politics and cancer care. And the quote that I always remember is “We all belong to the cancer party,” and that's what's really important. So let's just keep our eye on the board. I hope that we can do that.
I'm going to switch gears just a little bit now because another issue which has been quite prominent in 2024 and in a few years before that has been supply chain issues and drug shortages. We've seen this over many years now, but obviously the problems have apparently been exacerbated in recent years, particularly by climate events. But certainly ASCO has published some recommendations in terms of quality care delivery for patients with cancer. Can you tell us a little bit about how you think this will go in the coming year and what we can do to address some of the concerns that are there over drug shortages?
Dr. Nathan Pennell: Yeah. This continues to be, I think, a surprising issue for many oncologists because it has been going on for a long time, but really hasn't been in the public eye. The general problem is that once drugs go off patent and become generic, they often have limited manufacturers that are often outside the U.S. sometimes even a single manufacturer, which leaves them extremely vulnerable to supply chain disruption issues or regulatory issues. So situations where the FDA inspects and decides that they're not manufacturing things up to snuff and suddenly the only manufacturer is temporarily shut down. And then as you mentioned, things like extreme weather events where we had Hurricane Maria hit Puerto Rico and suddenly we have no bags of saline for several months. And so these are major issues which I think have benefited from being in the public eye.
ASCO, on the one hand, has, I think, done an excellent job leading on what to do in scenarios where there are shortages. But I think more importantly, we need more attention on a national level to policy changes that would help prevent this in the future. Some suggestions have been to increase some of the oversight of the FDA into supply chain issues and generic drugs, perhaps forming more of an early warning system to anticipate shortages so that we can find workarounds, find alternative suppliers that perhaps aren't currently being widely utilized. We can advocate for our legislators to pass legislation to support drug production for vital agents through things like long term contracts or even guaranteed pricing that might also even encourage U.S. manufacturers to take back up generic drugs if they were able to make it profitable. And then finally, I think just more of a national coordinated approach rather than the piecemeal approach we've done in the past. I remember when we had a platinum [drug] shortage last year. Our institution, with massive resources in our pharmacy, really did an excellent job of making sure that we always had enough supply. We never actually saw that shortage in real time, but I know a lot of places did not have those resources and therefore were really struggling. And so I think more of a coordinated approach with communication and awareness so that we can try to prevent this from happening.
Dr. John Sweetenham: Thanks, Nate. And you raised the issue of major weather events, and I'd like to pick up on that for just a moment to talk about climate change. We now know that there is a growing body of evidence showing that climate change impacts cancer care. And it does it in a lot of ways. I mean, the most obvious is disrupting care delivery during one of these major events. But there are also issues about increased exposure to carcinogens, reduced access to food, reduced access to cancer screenings during these major disasters. And the recent hurricanes, of course, have highlighted the need for cancer centers to have robust disaster preparedness plans. In addition to that, obviously there are questions about greenhouse gas emissions and how cancer centers and health care organizations handle that.
But what do you see for 2025 in this regard? And what's your thinking about how well we're prepared as deliverers of cancer care to deal with these climate change issues?
Dr. Nathan Pennell: Yeah, that is sobering to look at some of the things that have happened with climate change in recent years. I would love to say that I think that from a national level, we will see these changes and proactively work to reduce greenhouse emissions so that we can reduce these issues in the future. I'm not sure what we're going to see from the incoming administration and current government in terms of national policy on changes for fossil fuel use and climate change. I worry that there's a chance that we may see less done on the national level. I know the NCI certainly has policies in place to try to study climate change impact on cancer. It's possible that even that policy could be impacted by the incoming administration. So we'll have to see.
So, unfortunately, I worry that we may be still dealing in a reactive way to the impacts of this. So, obviously, wildfires causing carcinogens, pollution leading to increased cancer incidence, obviously, major weather events leading to physical disruptions, where cancer centers definitely have to have plans in place to help people maintain their treatment during those periods. As an individual, we can certainly make our impact on climate change. There are certainly organizations like Oncologists United for Climate and Health, or so-called OUCH, led by Dr. Joan Schiller, a friend of mine in the lung cancer world, where oncologists are advocating for policies to reduce use of fossil fuels. But I don't know, John, I don't know if I'm hopeful that there's going to be major policy changes on this in the coming year.
Dr. John Sweetenham: I suspect you're right about that, although I think on the positive side, I think the issue as a whole is getting a lot more attention than it was maybe even two or three years ago. So that has to be a good thing that there's more advocacy and more attention out there now.
Nate, before we go on to the last question, because I do want to finish on a positive note, I just wanted to mention briefly that there are a couple of ongoing issues which, when we do this podcast each year, we normally address, and they certainly haven't gone away. But we know that burnout and workforce issues in oncology will continue to be a big challenge. The workforce issues may or may not be exacerbated by whatever the new administration's approach to immigration is going to be, because that could easily significantly affect the workforce in oncology. So that's one issue around workforce and burnout that we are not addressing in detail this year. But I wanted to raise it just because it certainly hasn't gone away and is going to continue to challenge us in 2025.
And then the other one, which I kind of put in the same category, is that of disparities. We continue to see ethnic and racial disparities of care. We continue to see disparities in rural areas. And I certainly wouldn't want to minimize the challenges that these are likely to continue to present in 2025. I wonder if you just have any brief comments you'd like to make and whether you think we're headed in the right direction with those issues.
Dr. Nathan Pennell: Well, I'm somewhat optimistic in some ways about burnout. And I think when we get to our final topic, I think some of that may help. There may be some technology changes that may help reduce some of the influences of burnout. Disparities in care, obviously, I think similarly to some of the other issues we talked about have really benefited from just a lot of attention being cast on that. But again, I actually am optimistic that there are some technology changes that are going to help reduce some disparities in care.
Dr. John Sweetenham: It's always great to finish one of these conversations on a positive note, and I think there is a lot to be very positive about. As you mentioned right at the beginning of the podcast, we continue to see quite extraordinary advances, remarkable advances in all fields of oncology in the therapeutic area, with just a massive expansion in not only our understanding, but also resulting from that improved understanding of the biology of the disease, the treatment advances that have come along. And so I think undoubtedly, we're going to see continued progress during 2025. And I know that there are technology solutions that you've mentioned already that you're very excited about. So, I'd really like to finish today by asking you if you could tell us a little about those and in particular what you're excited about for 2025.
Dr. Nathan Pennell: Yeah. It's always dangerous to ask me to nerd out a little bit about some of these technology things, but I don't think that we can end any conversation about technology and not discuss the potential for artificial intelligence (AI) in health care and oncology. AI is sort of everywhere in the media and sort of already worked its way into our lives in our phones and apps that we're using and whatnot. But some of what I am seeing in tools that are probably going to be here very soon and, in some cases, already arriving, are pretty remarkable.
So some of the advances in natural language processing, or NLP, which in the past has been a barrier to really mining the vast amounts of patient information in the electronic medical record, is so much better now. So now, we can actually use technology to read doctor's notes, to read through scanned PDFs in our EMRs. And we can imagine that it's going to become very soon, much harder to miss abnormal labs, going to be much harder to miss findings on scans such as pulmonary nodules that get picked up incidentally. It's going to be much easier to keep up with new developments as clinical guidelines get worked in and decision support tools start reminding patients and physicians about evidence-based, high-quality recommendations. Being able to identify patients who are eligible for clinical trials is going to become much more easy.
And that leads me to the second thing, which is, throughout the pandemic we have greatly increased our use of telehealth, and this really has the potential to reduce disparities in care by reaching patients basically wherever they are. This is going to disproportionately allow us to access rural patients, patients that are currently underrepresented in clinical trials and whatnot, being able to present patients for clinical trials. In the recent “State of Cancer Care in America” report from ASCO, more than 60% of patients in the U.S. did not have access to clinical trials. And now we have the technology to screen them, identify them and reach out to and potentially enroll them in trials through use of decentralized elements for clinical trials. And so I'm very optimistic that not just good quality standard cancer care, but also clinical research is going to be greatly expanded with the use of AI and telehealth.
Dr. John Sweetenham: Really encouraging to hear that. Nate, it's been a real pleasure speaking with you today and I want to thank you for taking the time to share your insights with us on the ASCO Daily News Podcast.
Dr. Nathan Pennell: Thanks, John.
Dr. John Sweetenham: I also want to say thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Nathan Pennell
@n8pennell
Dr. John Sweetenham
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
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Disclosures:
Dr. John Sweetenham:
Consulting or Advisory Role: EMA Wellness
Dr. Nathan Pennell:
Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron
Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi
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Dr. Linda Duska and Dr. Domenica Lorusso discuss the practice-changing results of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, which evaluated pembrolizumab plus chemoradiotherapy as treatment for previously untreated, high-risk, locally advanced cervical cancer.
TRANSCRIPT
Dr. Linda Duska: Hello, I'm Linda Duska, your guest host of the ASCO Daily News Podcast today. I'm a professor of obstetrics and gynecology and serve as the associate dean for clinical research at the University of Virginia School of Medicine.
On today's episode, we'll be discussing a new standard of care for previously untreated, high- risk locally advanced cervical cancer. This follows the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, which I will be referring to as KEYNOTE-A18 for the rest of this podcast, which demonstrated that pembrolizumab plus chemoradiotherapy improved both progression-free and overall survival compared to chemoradiotherapy alone. I was a co-author of this study, and I'm delighted to be joined today by the study's lead investigator, Dr. Domenica Lorusso, for today's discussion. She is also a professor of obstetrics and gynecology. She's at Humanitas University Rosano and the director of the Gynecologic Oncology Unit at the Humanitas Hospital San Pio in Milan, Italy.
Our full disclosures are available in the transcript of this episode.
Dr. Lorusso, it's great to be speaking with you today.
Dr. Domenica Lorusso: Thank you, Linda. It's a great pleasure to be here. Thank you.
Dr. Linda Duska: So I was hoping you could start us out with some context on the challenges associated with treating patients with high-risk, locally advanced cervical cancer.
Dr. Domenica Lorusso: Yes. I have to make a disclosure because in my experience as a gynecologist, cervical cancer patients are the most difficult patients to treat. This is a tumor that involves young patients [who often have] small kids. This is a very symptomatic tumor. More than 50% of patients report pain. Sometimes the pain is difficult to control because there is an infiltration of the pelvic nerves and also a kind of vaginal discharge, so it's very difficult to treat the tumor. Since more than 25 years, we have the publication of 5 randomized trials that demonstrate that when we combine platinum chemotherapy to radiation treatment, we increase overall survival by 6%. This is the new standard of care – concurrent chemoradiation plus brachytherapy. This is a good standard of care because particularly modern, image-guided radiotherapy has reported to increase local control. And local control in cervical cancer translates to better overall survival. So modern radiotherapy actually is able to cure about 75% of patients. This is what we expect with chemoradiation right now.
Dr. Linda Duska: So what are the key takeaways of A18? This is a really exciting trial, and you've presented it a couple of times. Tell us what are the key takeaways that you want our listeners to know.
Dr. Domenica Lorusso: Linda, this is our trial. This is a trial that we did together. And you gave me the inspiration because you were running a randomized phase 2 trial exploring if the combination of pembrolizumab to concurrent chemoradiation was able to give signals of efficacy, but also was feasible in terms of toxicity. There were several clinical data suggesting that when we combine immunotherapy to radiotherapy, we can potentially increase the benefit of radiotherapy because there is a kind of synergistic effect between the two strategies. Radiotherapy works as a primer and immunotherapy works better. And you demonstrated that it was feasible to combine immunotherapy to concurrent chemoradiation.
And KEYNOTE-A18 was based on this preliminary data. We randomized about 1,060 patients to receive concurrent chemoradiation and brachytherapy or concurrent chemoradiation and brachytherapy in combination with pembrolizumab followed by pembrolizumab for about two years. Why two years? Because in more than 80% of cases, recurrence in this patient population occurred during the first two years. So the duration of treatment was based on the idea to provide protection to the patient during the maximum time of risk.
And the trial had the two primary endpoints, progression free and overall survival, and met both the endpoints, a significant 30% reduction in the risk of progression that was confirmed. At the 3-year follow up, the observation was even better, 0.68. So 32% reduction in the risk of progression. And more importantly, because this is a curative setting, 33% reduction in the risk of death was reported in the experimental arm when pembro was combined with chemoradiation.
Dr. Linda Duska: That's amazing. I wanted to ask you, a prior similar study called CALLA was negative. Why do you think A18 was positive?
Dr. Domenica Lorusso: Linda, there are several discussions about that. I had the possibility to discuss several times with the PI of CALLA, Brad Monk. The idea of Brad is that CALLA was negative because of using durvalumab instead of PD-1 inhibitor, which is pembrolizumab. I do not have exactly the same impression. My idea is that it's the kind of patient population enrolled. The patient population enrolled in KEYNOTE-A18 was really a high-risk population; 85% of that patient were node positive, where the definition of node positivity was at least 2 lymph nodes in the pelvis with a short diameter of 1.5. So, we are very confident this patient was node-positive, 55% at the grade 3 and 4 diseases. So this is really a high-risk population. I remember at the first presentation of CALLA, I was honored to discuss the CALLA trial when it was first presented at IGCS a few years ago. And when I received the forest plot of Calla, it was evident to me that in patients with stage III and node positive there was a signal of efficacy. And we have a huge number of patients with node positive. So in my opinion this is the reason why KEYNOTE-A18 is positive.
Dr. Linda Duska: Yeah, I agree with you. I've thought about it a lot and I think you're right about that. The INTERLACE trial results were recently published. How should we interpret these results in the context of A18?
Dr. Domenica Lorusso: So it's very difficult to compare the 2 trials. First of all, in terms of population. The population enrolled in INTERLACE is a low-risk, locally advanced but low risk population; 76% were stage II, 10% were stage I, 60% were node-negative patients. So, first of all, the population is completely different. Second is the type of radiotherapy that was provided. INTERLACE is a 10-year long trial, but in 10 years the quality and the technique of radiotherapy completely changed. Only 30% of patients in INTERLACE received what we call the modern image-guided brachytherapy, which is important because it provides local control and local control increases overall survival. And third, we read the paper. I'm not a methodologist, but there are some methodological biases in the paper. All the statistical design of the trial was based on PFS, but PFS was evaluated at physician description. And honestly, I never saw a trial that had no pre-specified timeline for radiological evaluation. It's very difficult to evaluate progression in cervical cancer because the fibrosis related to radiotherapy changes the anatomy in the pelvis. And I think that the radiological evaluation is important to address if the patient is progressing or not. Particularly, because the conclusion of CALLA is that the PFS was mainly in favor of distant metastasis. So really, it's difficult for me to understand how distant metastasis may be evaluated with the vagina visit.
So really, it's very difficult to compare the two trials, but I have some concerns. And also because of toxicity in the study, unfortunately 30% of patients did not complete concurrent chemoradiation because of residual toxicity due to induction chemotherapy. So I wanted to be sure in the context of modern radiotherapy, if really induction chemo adds something to modern radiotherapy.
Dr. Linda Duska: Well, I have two more questions for you. As we move immunotherapy into the front line, at least for these high risk locally advanced cervical cancer patients that were eligible for A18, what does that mean then for hopefully those few that develop recurrence in terms of second line therapy?
Dr. Domenica Lorusso: Well, Linda, this is a very important question. We do not have data about immuno after immuno, but I would not completely exclude this hypothesis because in KEYNOTE-A18, the patient received treatment for a well-defined time period. And for those patients not progressing during immunotherapy, I really guess if there is a space for the reintroduction of immunotherapy at the time of recurrence. In this moment we have 30% of patients in KEYNOTE-A18 in the control arm that receive immunotherapy after progression, but still we have 11% of patients that receive immunotherapy in combination with concurrent chemoradiation and then receive, again, immunotherapy in later line of therapy. I think we need to collect these data to capture some signals and for sure we have the new drug. We have antibody drug conjugate. The trials are ongoing exploring the role of antibody drug conjugate, particularly in immune pretreated patients. So I think this is a very interesting strategy.
Dr. Linda Duska: I was going to ask you, “What are the next steps,” but I think you already answered that question.
You talked about the second line. If you were going to redesign a study in the frontline, what would it look like?
Dr. Domenica Lorusso: Probably one question that I would like to answer – there are two questions in my opinion in KEYNOTE-A18 – one is induction immunotherapy. Linda, correct me if I'm wrong, you reported very interesting data about the immune landscape change when you use induction immunotherapy. And I think this is something that we need to explore in the future. And the second question is the duration of maintenance. Because, again, we decided for two years based only on the epidemiology of recurrence, but I guess if one year may be enough.
Dr. Linda Duska: I think this sequencing question is really important, that the induction immunotherapy was actually GY017. I can't take credit for that, but I think you're right. I think the sequencing question is really important. Whether you need the concurrent IO or not is an important question. And then to your point about the 2 years, the length of the need for maintenance therapy is a question that we don't know the answer to. So there are lots of really important questions we can continue to ask.
I want to thank you so much for sharing your valuable insights with us on the podcast today. You're always so thoughtful about this particular study and cervix cancer in general and also for your great work to advance the care for patients with GYN cancers.
Dr. Domenica Lorusso: Thank you, Linda. It's our work - we progress together.
Dr. Linda Duska: Yes. And we thank the patients as well. The over 1,000 patients that went on this trial during a pandemic. Right?
Dr. Domenica Lorusso: Absolutely. Without their generosity and their trust, we would not be able to do this trial.
Dr. Linda Duska: So we're very grateful to them and we thank our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you all.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Follow today’s speakers:
Dr. Linda Duska
@Lduska
Dr. Domenica Lorusso
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Linda Duska:
Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma
Research Funding (Inst.): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Ludwig Institute for Cancer Research, Leap Therapeutics
Patents, Royalties, Other Intellectual Property: UptToDate, Editor, British Journal of Ob/Gyn
Dr. Domenica Lorusso:
Consulting or Advisory Role: PharmaMar, AstraZeneca, Clovis Oncology, GSK, MSD, Genmab, Seagen, Immunogen, Oncoinvest, Corcept, Sutro Biopharma, Novartis, Novocure, Daiichi Sankyo/Lilly
Speakers’ Bureau: AstraZeneca, Clovis, GSK, MSD, ImmunoGen, Seagen
Research Funding (Inst.): PharmMar, Clovis, GSK, MSD, AstraZeneca, Clovis Oncology, Genmab, Seagen, Immunogen, Incyte, Roche, Pharma&, Corcept Therapeutics, Alkermes
Travel, Accommodations, Expenses: AstraZeneca, Clovis, GSK, Menarini
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Dr. Ryan Augustin and Dr. Jason Luke discuss neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, promising new TIL therapy for advanced melanoma, and the emerging role of CD3 engagers in treatment strategies.
TRANSCRIPT
Dr. Ryan Augustin: Hello, I'm Dr. Ryan Augustin, your guest host of the ASCO Daily News Podcast today. I'm a medical oncology fellow at Mayo Clinic in Rochester, Minnesota. Joining me today is Dr. Jason Luke, an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center. I had the privilege of working as a postdoc in Jason's translational bioinformatics lab, where we investigated mechanisms of resistance to immunotherapy in melanoma and other cancers.
Today, we'll be discussing 3 important topics, including neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, the impact and practical considerations for incorporating TIL therapy into melanoma, and the current and future use of CD3 engagers in both uveal and cutaneous melanoma.
You'll find our full disclosures in the transcript of this episode.
Jason, it's great to have this opportunity to speak with you today.
Dr. Jason Luke: Absolutely. Thanks, Ryan. It's great to see you.
Dr. Ryan Augustin: So, to kick things off, Jason, we, of course, have seen tremendous advances in cancer immunotherapy, not only in metastatic disease but also the perioperative setting. Recent data have shown that the use of neoadjuvant therapy can provide not only critical prognostic information but can also help individualize post-resection treatment strategies and potentially even eliminate adjuvant therapy altogether in patients who achieve a pathologic, complete response. This signifies a conceptual shift in oncology with the goal of curing patients with immunotherapy. In triple-negative breast cancer, the KEYNOTE-522 regimen with pembrolizumab is standard of care. In non-small cell lung cancer, there are now four FDA approved chemo-IO regimens in both the neoadjuvant and perioperative settings. And, of course, in melanoma, starting with SWOG S1801 utilizing pembro mono therapy, and now with combined CTLA-4 PD-1 blockade based on results from the NADINA trial, neoadjuvant IO is the new standard of care in high-risk, resectable melanoma. It's important to highlight this because whereas other tumor types have more mature multidisciplinary care, for example, patients with breast cancer are reviewed by the whole team in every center, and every patient with lung cancer certainly benefits from multidisciplinary care conferences, that's not always the case with melanoma, given the relative frequency of cases compared to other tumor types.
Jason, would you say that we have now moved into an era where the integration of a multidisciplinary team and melanoma needs to be prioritized. And why is it important to have multidisciplinary team coordination from the onset of a patient's diagnosis?
Dr. Jason Luke: Well, I think those are great questions, Ryan, and I think they really speak to the movement in our field and the great success that we've had integrating systemic therapy, particularly immunotherapy, into our treatment paradigms. And so, before answering your question directly, I would add even a little bit more color, which is to note that over the last few years, we've additionally seen the development of adjuvant therapy into stages of melanoma that, historically speaking, were considered low-risk, and medical oncologists might not even see the patient. To that, I'm speaking specifically about the stage 2B and 2C approvals for adjuvant anti-PD-1 with pembrolizumab or nivolumab. So this has been an emerging complication.
Classically, patients are diagnosed with melanoma by either their primary care doctor or a dermatologist. Again, classically, the next step was referral to a surgeon who had removed the primary lesion, with discussion around nodal evaluation as well. And that paradigm has really changed now, where I think integration of medical oncology input early on in the evaluation of the appropriate treatment plan for patients with melanoma is quite a pressing issue now, both because we have FDA approvals for therapeutics that can reduce risk of recurrence, and whether or not to pursue those makes a big difference to the patient for discussion early on.
And, moreover, the use of systemic therapies now, prior to surgery, of course, then, of course, requires the involvement of medical oncology. And just for an emphasis point on this, it's classically the case, for good reason, that surgeons complete their surgery and then feel confident to tell the patient, “Well, we got it all, and you're just in really good shape.” And while I understand where that's coming from, that often leaves aside the risk of recurrence. So you can have the most perfect surgery in the world and yet still be at very high risk of recurrence. And so it's commonly the case that we get patients referred to us after surgery who think they're just in totally good shape, quite surprised to find out that, in fact, they might have a 20% to 50% risk of recurrence. And so that's where this multidisciplinary integration for patient management really does make a big difference.
And so I would really emphasize the point you were making before, which is that we need multidisciplinary teams of med onc with derm, with surgery early on, to discuss “What are the treatment plans going to be for patients?” And that's true for neoadjuvant therapy, so, for palpable stage 3, where we might give checkpoint inhibitors or combinations before surgery. But it's true even in any reasonably high-risk melanoma, and I would argue in that state, anything more than stage 1 should be discussed as a group, because that communication strategy with the patient is so important from first principles, so that they have an expectation of what it's going to look like as they are followed out over time. And so we're emphasizing this point because I think it's mostly the case at most hospitals that there isn't a cutaneous oncology disease management meeting, and I think there needs to be.
It's important to point out that usually the surgeons that do this kind of surgery are actually either the GI surgeons who do colon cancer or the breast surgeons. And so, given that melanoma, it's not the most common kind of cancer, it could easily be integrated into the existing disease review groups to review these cases. And I think that's the point we really want to emphasize now. I think we're not going to belabor the data so much, but there are enormous advantages to either perioperative or adjuvant systemic therapy in melanoma. We're talking about risk reduction of more than 50%, 50-75% risk reduction. It's essential that we make sure we optimally offer that to patients. And, of course, patients will choose what they think is best for their care. But we need to message to them in a way that they can understand what the risks and benefits of those treatments are and then are well set up to understand what that treatment might look like and what their expectations would be out over time.
So I think this is a great art of medicine place to start. Instead of belaboring just the details of the trial to say, let's think about how we take care of our patients and how we communicate with them on first principles so that we can make the most out of the treatments that we do have available.
Dr. Ryan Augustin: That's great, Jason. Very insightful points. Thank you.
So, shifting gears now, I'd also like to ask you a little bit about TIL therapy in melanoma. So our listeners will be aware that TIL is a promising new approach for treating advanced melanoma and leverages the power of a patient's cytotoxic T cells to attack cancer cells. While we've known about the potential of this therapy for some time, based on pioneering work at the NCI, this therapy is now FDA approved under the brand AMTAGVI (Lifileucel) from Iovance Biotherapeutics, making it the first cellular therapy to be approved for a solid tumor. Now, I know TIL therapy has been administered at your institution, Jason, for several years now, under trial status primarily for uveal melanoma using an in-house processing. But for many cancer centers, the only experience with cellular therapy has come under the domain of malignant hematology with CAR T administration. At our institution, for example, we have only recently started administering TIL therapy for melanoma, which has required a tremendous multidisciplinary effort among outpatient oncology, critical care, and an inpatient hematology service that has expertise in cytokine release syndrome.
Jason, where do you see TIL therapy fitting into the metastatic space? Which patients do you think are truly candidates for this intensive therapy? And what other practical or logistical considerations do you think we should keep in mind moving forward?
Dr. Jason Luke: Well, thanks for raising this. I think the approval of lifileucel, which is the scientific name for the TIL product that's on the market now. It really is a shift, a landscape shift in oncology, and we're starting in melanoma again, as seems to be commonly the case in drug development. But it's really important to understand that this is a conceptually different kind of treatment, and therefore, it does require different considerations. Starting first with data and then actualization, maybe secondarily, when we see across the accelerated approval package that led to this being available, we quote patients that the response rate is likely in the range of 30%, maybe slightly lower than that, but a meaningful 25% to 30% response rate, and that most of those patients that do have response, it seems to be quite durable, meaning patients have been followed up to four years, and almost all the responders are still in response. And that's a really powerful thing to be able to tell a patient, particularly if the patient has already proceeded through multiple lines of prior standard therapy. So this is a very, very promising therapy.
Now, it is a complicated therapy as well. And so you highlighted that to do this, you have to have a tumor that's amenable for resection, a multidisciplinary team that has done a surgery to remove the tumor, sent it off to the company. They then need to process the TIL out of the tumor and then build them up into a personalized cell product, bring it back, you have to lympho-deplete the patient, re-introduce this TIL. So this is a process that, in the standard of care setting under best circumstances, takes roughly six weeks. So how to get that done in a timely fashion, I think, is evolving within our paradigms. But I think it is very important for people who practice in settings where this isn't already available to realize that referring patients for this should be a strong consideration. And thinking about how you could build your multidisciplinary team in a way to be able to facilitate this process, I think is going to be important, because this concept of TIL is relevant to other solid tumors as well. It's not approved yet in others, but we kind of assume eventually it probably will be. And so I think, thinking through this, how could it work, how do you refer patients is very important.
Now, coming back to the science, who should we treat with this? Well, of course, it's now an air quotes “standard of care option”, so really it ought to be available to anybody. I will note that currently, the capacity across the country to make these products is not really adequate to treat all the patients that we’d want. But who would we optimally want to treat, of course, would be people who have retained a good performance status after first line therapy, people who have tumors that are easily removable and who have not manifested a really rapid disease progression course, because then, of course, that six-week timeline probably doesn't make sense. The other really interesting data point out of the clinical trials so far is it has looked like the patients who got the least amount of benefit from anti-PD-1 immunotherapy, in other words, who progressed immediately without any kind of sustained response, those patients seem to have the best response to TILs, and that's actually sort of a great biomarker. So, this drug works the best for the population of patients where checkpoint inhibitors were not effective. And so as you think about who those patients might be in your practice, as you're listening, I think prioritizing it for primary progression on anti PD-1, again and giving it ahead thought about how would you get the patient through this process or referred to this process very quickly is really important because that lag time is a problem. Patients who have melanoma tend to progress reasonably quickly, and six weeks can be a long time in melanoma land. So, thinking ahead and building those processes is going to be important moving into the future
Dr. Ryan Augustin: Definitely appreciate those practical considerations. Jason, thank you.
Moving on to our final topic, I was hoping to discuss the use of immune cell engagers in melanoma. So, similar to CAR T therapy, bispecific T-cell engagers, or BiTEs, as they're commonly known, are standard of care in refractory myeloma and lymphoma. But these antibodies engaging CD-3 on T cells and a tumor specific antigen on cancer cells are relatively new in the solid tumor space. Tarlatamab, which is a DLL-3 and CD-3 bispecific antibody, was recently approved in refractory small cell lung cancer, and, of course, tebentafusp, an HLA-directed CD-3 T cell engager was approved in uveal melanoma in 2022. Both T and NK cell engaging therapies are now offering hope in cancers where there has historically been little to offer. However, similar to our discussion with TIL therapy, bispecifics can lead to CRS and neurotoxicity, which require considerable logistical support and care coordination.
Jason, I was wondering if you could briefly discuss the current landscape of immune cell engagers in melanoma and how soon we may see these therapies enter the treatment paradigm for cutaneous disease.
Dr. Jason Luke: I think it is an exciting, novel treatment strategy that I think we will only see emerge more and more. You alluded to the approval of tebentafusp in uveal melanoma, and those trials were, over the course of a decade, where those of us in solid tumor land learned how to manage cytokine release syndrome or the impact of these C3 bispecifics, in a way that we weren't used to. And what I'll caution people is that CRS, as this term, it sounds very scary because people have heard of patients that, of course, had difficult outcomes and hematological malignancies, but it's a spectrum of side effects. And so, when we think about tebentafusp, which is the approved molecule, really what we see is a lot of rash because GP100, the other tumor antigen target, is in the skin. So, patients get a rash, and then people do get fevers, but it's pretty rare to get more than that. So really what you have to have is the capacity to monitor patients for 12 hours, but it's really not more scary than that. So it really just requires treating a few people to kind of get used to these kinds of symptoms, because they're not the full-on ICU level CRS that we see with, say, CAR T-cells.
But where is the field going? Well, there's a second CD3 bispecific called brenetafusp that targets the molecule PRAME, that's in a phase 3 clinical trial now for frontline cutaneous melanoma. And tebentafusp is also being evaluated in cutaneous melanoma for refractory disease. So, it's very possible that these could be very commonly used for cutaneous melanoma, moving into, say, a two-to-four-year time horizon. And so therefore, getting used to what are these side effects, how do you manage them in an ambulatory practice for solid tumor, etc., is going to be something everyone's going to have to learn how to deal with, but I don't think it should be something that people should be afraid of.
One thing that we've seen with these molecules so far is that their kinetics of treatment effect do look slightly different than what we see with more classic oncology therapies. These drugs have a long-term benefit but doesn't always manifest as disease regression. So, we commonly see patients will have stable disease, meaning their tumor stops growing, but we don't see that it shrank a lot, but that can turn into a very meaningful long-term benefit. So that's something that we're also, as a community, going to have to get used to. It may not be the case we see tumors shrink dramatically upfront, but rather we can actually follow people with good quality- of-life over a longer period of time.
Where is the field going? You mentioned tarlatamab in small cell lung cancer, and I think we're only going to see more of these as appropriate tumor antigens are identified in different tumors. And then the other piece is these CD3 engagers generally rely upon some kind of engagement with a T cell, whether CD3 engagers, and so they can be TCR or T-cell receptor-based therapies, although they can be also SCFV-based. But that then requires new biomarkers, because TCR therapy requires HLA restriction. So, understanding that now we're going to need to profile patients based on their germline in addition to the genomics of the tumor. And those two things are separate. But I would argue at this point, basically everybody with cutaneous melanoma should be being profiled for HLA-A(*)0201, which is the major T-cell receptor HLA haplotype that we would be looking for, because whether or not you can get access immediately to tebentafusp, but therefore clinical trials will become more and more important.
Finally, in that T-cell receptor vein, there are also T cell receptor-transduced T cells, which are also becoming of relevance in the oncology community and people listening will be aware in synovial sarcoma of the first approval for a TCR-transduced T cell with afamitresgene autoleucel. And in melanoma, we similarly have TCR-transduced T cells that are coming forward in clinical trials into phase 3, the IMA203 PRAME-directed molecule particularly. And leveraging our prior conversation about TILs, we're going to have more and more cellular based therapies coming forward, which is going to make it important to understand what are the biomarkers that go with those, what are the side effect profiles of these, and how do you build your practice in a way that you can optimally get your patients access to all of these different treatments, because it will become more logistically complicated, kind of as more of these therapies come online over the next, like we said, two to four years kind of time horizon. So, it's very exciting, but there is more to do, both logistically and scientifically.
Dr. Ryan Augustin: That's excellent. Thanks, Jason, and thank you so much for sharing your great insight with us today on the ASCO Daily News Podcast.
Dr. Jason Luke: Thanks so much for the opportunity.
Dr. Ryan Augustin: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode, and you can follow Dr. Luke on X, formerly known as Twitter, @jasonlukemd. And you can find me, @RyanAugustinMD. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Follow today’s speakers:
@ryanaugustinmd
Dr. Jason Luke
@jasonlukemd
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Ryan Augustin: No relationships to disclose
Dr. Jason Luke:
Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX
Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine
Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure
Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio
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Dr. Dionisia Quiroga discusses emerging approaches to personalizing locoregional treatment for breast cancer with Drs. Walter Paul Weber and Charlote Coles, who share insights on tailoring axillary surgery, escalating lymphatic surgery, and implementing hypofractionated radiotherapy.
TRANSCRIPT
Dr. Dionisia Quiroga: Hello, I'm Dr. Dionisia Quiroga, your guest host of the ASCO Daily News Podcast today. I'm a breast medical oncologist and assistant professor in the Division of Medical Oncology at the Ohio State University Comprehensive Cancer Center. On today's episode, we'll be discussing emerging approaches to personalize locoregional treatment for patients with breast cancer, including many of the latest updates on axillary surgical staging, lymphatic surgery, and evidence-based radiotherapy in the treatment of breast cancer.
We're very fortunate to have joining me today for this discussion Dr. Walter Paul Weber, a professor and head at the Division of Breast Surgery at the University Hospital Basel in Switzerland, and Dr. Charlotte Coles, a professor of cancer clinical oncology and the deputy head of the Department of Oncology at the University of Cambridge in the United Kingdom.
Our full disclosures are available in the transcript of this episode. Dr. Weber and Dr. Coles, it's very wonderful to have you on the podcast and thank you so much for being here.
Dr. Walter Paul Weber: Thank you very much for having us.
Dr. Charlotte Coles: Thank you.
Dr. Dionisia Quiroga: Now, for many decades prior, axillary lymph node dissection has very much been our standard of care. But recently, axillary surgeries have been able to be gradually deescalated to spare some of our patients from relative and relevant long-term morbidity. There are still some indications in which axillary lymph node dissection still remain. And therefore, we still see breast cancer-related lymphedema, a well-known sequela of the axillary surgery to continue to be prevalent. And I think it's important also to acknowledge that today there's about an estimated 1.5 million cancer survivors who deal with breast cancer-related lymphedema. Now, Dr. Weber, at the recent ASCO Annual Meeting, you and your co-presenters discussed tailoring axillary surgery, escalating lymphatic surgery and implementing evidence-based hypofractionated radiotherapy to really personalize locoregional treatment for people who've been diagnosed with breast cancer. And in addition to that, you and Dr. Coles have also published this work in the 2024 ASCO Educational Book. Can you tell us about some of the recent advances in axillary surgery and what are really the current indications for axillary dissection?
Dr. Walter Paul Weber: Yes, I'm happy to do so. So as you've said, we've known for a while that we can omit axillary dissection in patients with clinically known negative breast cancer and negative sentinel nodes. We've known for about 10-15 years that we can omit axillary dissection in patients with one or two positive sentinel nodes in many patients. But what we've learned recently is that we can omit axillary dissection also in patients with one or two positive sentinel nodes who have larger primary tumors who undergo mastectomy or who have extranodal extension. This is a landmark trial that was published just a few months ago, the SENOMAC trial that established this. The remaining indications for axillary dissection are situations where you expect a heavy tumor load in the axilla. For example, when you have more than two positive sentinel nodes or you have a patient with clinically node-positive breast cancer who undergoes upfront surgery and has palpable disease or significant disease on imaging. Patients with locally advanced breast cancer, who are considered by some to be not eligible for nodal downstaging, such as patients with CN2, CN3 disease or CT4 breast cancer. And then the big group of patients who have residual disease after neoadjuvant chemotherapy in the nodes, standard of care is still axillary dissection.
But we now have some real-world evidence that it's safe for selected patients with low volume nodal disease left in the nodes, mostly isolated tumor cells, to not undergo axillary dissection. So these are the remaining indications today.
Dr. Dionisia Quiroga: Can you speak to situations where maybe even sentinel lymph node biopsies might be omitted? I know you spoke a little bit about the use of imaging in your work.
Dr. Walter Paul Weber: Yes, this is correct. So, we started about maybe 7 or 8 years ago to omit sentinel lymph node biopsy in older patients above 70 years of age who have luminal disease, according to recommendations from the Choosing Wisely initiative. And now indeed there are several ongoing randomized trials that investigate if axillary imaging can replace surgical staging of the axilla.
And the first of these trials was published recently, the SOUND trial with almost 1,500 patients, who underwent breast conserving surgery and had small tumors and all had a negative ultrasound of the axilla. And then they were randomized into a sentinel lymph node biopsy versus no axillary surgery. And that trial showed non-inferiority of the omission of sentinel lymph node biopsy in these patients.
Now, it's a bit early to roll out the Choosing Wisely recommendation to all patients who have a negative ultrasound. The SOUND trial showed that about 14% had a false-negative ultrasound. So, in the control arm, they actually did have a positive sentinel node. And in patients where that one missed sentinel node makes a big difference in terms of systemic therapy, most experts would still recommend sentinel biopsy, and these are patients mainly with HER2-positive or triple-negative breast cancer or premenopausal patients or those who have G3 biology.
Dr. Dionisia Quiroga: I think you bring up a very important point. Coming from the side of a breast medical oncologist, we're also very interested to see what these studies show because many of our practices are based on what we find out from our lymph node biopsies. So, I think a lot of interesting prospective studies to look at in the future.
Dr. Walter Paul Weber: Absolutely.
Dr. Dionisia Quiroga: One other topic we wanted to discuss was local regional management of stage four disease and particularly oligometastatic disease. And this is not a new topic of interest. We've been speaking about this for a long time in breast cancer management, but can you address some of the axillary management strategies that you currently use for stage 4 disease?
Dr. Walter Paul Weber: Yes, it depends on your intention. If your intention is to cure the patient, then you would apply all the locoregional standards that apply in the curative setting, which means lymph node biopsy with or without axillary dissection. Now in a palliative situation, it's individualized. Very often you don't touch the axilla and sometimes you open it and just remove palpable disease, trying to minimize morbidity. The question of which intent you should follow is controversial; three out of the four randomized trials did not show a benefit for locoregional surgery in patients with de novo stage 4 disease. However, experts seem to disagree. The last St. Gallen consensus recommendation was in favor of the curative intent in such a patient with oligometastatic disease; 85% favored the curative intent. So there's a bit of discrepancy there, but everybody would agree, and this is what has been done in all of these trials, that if you try to cure the patient, then you should apply the curative standards of sentinel and axillary dissection that you use also in early-stage breast cancer.
Dr. Dionisia Quiroga: Thank you. Now, moving on from surgical axillary management and more into lymphedema prevention and treatment. Can you speak to some of the promising advances that have happened in this field?
Dr. Walter Paul Weber: Yes, so the best way to prevent lymphedema still is not to perform axillary dissection, which is the number 1 risk factor, which is all the axillary surgery de-escalation research that we've just discussed is all about. Prevention of lymphedema is one major aim of this. Now, once you indicate axillary dissection and you expect the patient to be at high risk – for example, if there are other risk factors such as obesity or neoadjuvant chemotherapy or extended regional nodal radiotherapy, then indeed there are emerging techniques that really seem to work. There is some evidence supporting it, which is categorizable as immediate lymphatic repair basically or bypass. And that is usually in a patient who undergoes axillary dissection, and also undergoes axillary reverse mapping. That allows the identification of the lymph nodes that are probably most relevant to the drainage of the lymphatic fluid from the arm. And then you can try to spare these. But if you decide, and this is effective, there is a consistent body of evidence, not phase 3 trials, but pretty consistent evidence that axillary reverse mapping works just by sparing the identified nodes.
But if you decide that you have to remove these nodes as part of the radical concept of axillary dissection, then immediate lymphatic repair is also increasingly being done and is also supported by consistent evidence, even some single center randomized trials, low volume, but all consistently showing quite a striking benefit of this immediate lymphatic repair technique.
There are different ways you can do it. You can either use it the microscope, and it's being done by the plastic surgeons, but it's also a simplified technique described that can be used by specialized general and breast surgeons. Both techniques seem to really work based on what we know from the studies, but also based on our common sense.
Dr. Dionisia Quiroga: You talked about the procedures that can be offered to patients at time of breast surgery. And unfortunately, many of our patients maybe did not have the availability of those techniques when they undergo their initial breast cancer treatment. Once lymphedema is developed in a limb following breast cancer diagnosis, can you speak to other interventions that can be done to potentially help mitigate lymphedema?
Dr. Walter Paul Weber: Right, so for patients who no longer benefit from or wish to further undergo conservative treatment of lymphedema, there are emerging procedures that are now out of my personal comfort zone because they're being performed by plastic surgeons; they use the microscope. There are two groups, the lymphovenous anastomosis and then the real vascular lymph node transfer as a free flap. And both of these procedures (there are no randomized trials yet published), but some really good ones are on the way and currently recruiting based on the evidence we have, which is over 20 observational studies all consistently again showing a benefit in terms of what you can measure in terms of centimeters or with a bioimpedance spectroscopy, or also when you ask the patients, you see quite some dramatic improvements by both of these techniques. And it's increasingly being done. Personally, I strongly believe that it works based on everything we know and understand from lymphedema development, but also prevention and treatment. So I am quite sure that in 5-10 years, we will see much more surgical treatment of patients with lymphedema by highly specialized plastic surgeons.
Dr. Dionisia Quiroga: That's my hope as well. Now, another important component of local regional treatment we know is of course radiotherapy. And there have been many incredible advances in breast radiotherapy over the past decades, which has really improved cancer control and decreased side effects in our patients. Dr. Coles, you've led practice changing radiotherapy trials in the past and your research has really influenced international hypofractionation policy.
Can you expand upon the emergence of hypofractionated radiation for breast cancer and the effects that it can have on our patient care?
Dr. Charlotte Coles: Yes, so thank you very much, Dr. Quiroga. So I think the first thing to say is that radiotherapy hypofractionation isn't a new concept. And in fact, the breast radiotherapy hypofractionation trial started around three decades ago. And the rationale for this was the hypothesis that breast cancer is as sensitive to fraction, which is the treatments that we give, we split it into fractions, is sensitive as late responding tissue. So what does this mean? It means that the small traditional 2 Gy fraction spare tumor and normal tissues equally, so there's no advantage. So therefore, fewer fractions with a larger dose per fraction are worth testing.
The problem is there's a concern that hypofractionation might increase the risk of side effects, and that includes the really important one we've been talking about, lymphedema. But we can reduce this risk by reducing the total radiotherapy dose over the whole course. But the question was by how much. So that's why randomized trials were needed. And there's been really high-quality trials with robust radiotherapy quality assurance, and they've been designed in partnership with patients. So just a very quick run through: A landmark trial was the UK START B trial. And this was a pragmatic design that compared 50 Gy in 25 fractions, which was commonly used in the south of the country with 40 Gy in 15 fractions, which was used at that time in the north [of the UK]. And this recruitment was around in the late 1990s and early 2000s. What we knew was that the three-week regimen was actually radiobiologically lower dose. And therefore the results that we got, it wasn't surprising that the 40 Gy was actually gentler on the normal tissue. So that's an advantage for patients.
But what was surprising was it wasn't gentler on the tumor and non-inferiority was proven. So this suggests that overall treatment time is important for local control. So this fits with hypofractionation. Way back in 2009, 40 Gy in 15 fractions to both the breast and regional nodes became standard of care in the UK. But five-week nodal and actually breast as well remained standard of care in many countries for many years after that, a little bit to do with the fact that there were few patients treated in the START trial in terms of treating the node. So more recently we've had more randomized trials, particularly for nodal radiotherapy. And this includes the recently reported Danish SKAGEN 1 trial and also the French HypoG-01 trial, which was actually presented at ESMO in Barcelona a couple of weeks ago. So we've now got data for over 5,800 participants in really high-quality randomized trials testing three weeks and five weeks of nodal radiotherapy. And there's no statistically significant difference in late normal tissues for any of these, including lymphedema. So certainly, in my opinion and reflecting in many of the European guidelines, five-week radiotherapy is no longer indicated and three-week nodal radiotherapy is the international standard of care. So, in conclusion, the question is can we hypofractionate even further?
So the UK FAST-Forward trial tested three weeks with two different dose levels of one week for the whole breast. Primary endpoint was ipsilateral breast tumor response. More than 4,000 patients participated and this was reported in 2020 with a median follow -up of six years and this was very timely because this is a time of COVID and the results showed non-inferiority for local control with similar late normal tissue side effects and we've also had other results from the UK IMPORT HIGH trial which shows that we can safely deliver a small, highly targeted team of boost simultaneously with the whole breast in all in three weeks.
Finally, these two landmark trials have come together for the design of the UK FAST-Forward Boost Study led by my colleague Dr. Anna Kirby. And this is going to test three-week simultaneous integrated boost with two levels of one-week simultaneous integrated boost. And it's also going to test the safety of 5 fraction nodal radiotherapy, including the internal mammary node. Primary endpoint is ipsilateral breast tumor response, multiple normal tissue endpoints, including patient-reported outcomes of course, and the target recall is large with 4,800 participants. So, in summary, I would say that hypofractionation is efficacious, has similarly reduced toxicity. Importantly, it reduces patient burden and that's incredibly important because it means that people can get back on with their life quicker. It reduces health system costs, and also increases equity of access. So we really do need to continue to recruit and design high quality trials in this area.
Dr. Dionisia Quiroga: Thank you, Dr. Coles. I think you highlight that there really aren't any downsides to looking into hypofractionated radiotherapy at this point. So excited to see what those future trials yield.
And I want to thank you so much, Dr. Weber and Dr. Coles for sharing your valuable insights with us today on the ASCO Daily News Podcast.
Dr. Walter Paul Weber: Thank you very much.
Dr. Charlotte Coles: Thank you.
Dr. Dionisia Quiroga: And thank you to our listeners for joining us today. Our listeners will find a link to our guests’ article from the ASCO Educational Book in the transcript of this episode, as well as a link to their presentation from the most recent ASCO Annual Meeting. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Dionisia Quiroga
@quirogad
Dr. Walter Paul Weber
Dr. Charlotte Coles
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Dionisia Quiroga:
No relationships to disclose
Dr. Walter Weber:
Honoraria: MSD
Dr. Charlotte Coles:
No relationships to disclose
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Dr. Merry Jennifer Markham and ASCO CMO Dr. Julie Gralow discuss the shortage of IV fluids and other challenges that have emerged from Hurricane Helene as high-risk areas brace for impact from another storm, Hurricane Milton. In a conversation with Dr. John Sweetenham, they highlight resources for oncologists and patients and stress the importance of crisis preparedness at cancer centers.
TRANSCRIPT
Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast. Hurricane Helene made landfall on September 26th in Florida and raged over parts of Georgia, North Carolina, Tennessee, and Virginia. The disaster has claimed over 230 lives. Many people are still missing, and many thousands are homeless.
The hurricane has exacerbated the nation's IV fluid shortage, and some health care facilities have begun implementing conservation strategies. Meanwhile, Hurricane Milton, another powerful hurricane, is expected to wreak havoc as Florida braces for back-to-back hurricanes in parts of the state.
On today's episode, we'll be discussing the impact of these events on cancer care, including the shortage of IV fluids. Joining me for this discussion is Dr. Merry Jennifer Markham, a professor and research lead for the University of Florida Health Cancer Center's Gynecologic Cancer Disease Site Group. I'm also delighted to welcome Dr. Julie Gralow, the chief medical officer at ASCO. Our full disclosures are available in the transcript of this episode.
Merry Jennifer and Julie, many thanks for joining us for the podcast today.
Dr. Julie Gralow: Thanks for having us, John.
Dr. Merry Jennifer Markham: Yes, thank you.
Dr. John Sweetenham: Merry Jennifer, can you tell us your exact location today and how your patients and institution have been impacted by Hurricane Helene so far?
Dr. Merry Jennifer Markham: I am in the north-central part of Florida. I'm in Gainesville, Florida, which is the home of the University of Florida, where I practice medicine. And we are physically about two hours north of Tampa, two hours north of Orlando, and about an hour and a half southwest of Jacksonville. So right in the middle. And we are currently in the track for the next storm.
Helene was a really a devastating storm and what our area felt was primarily what we tend to get in most storms here in the center part of the state, which is a lot of rain, a high risk for tornadoes and a lot of power outages. And one of the challenges that my center in particular faces, and some of the local cancer centers and cancer care providers around in our region, is our patients live in a very rural population. So for those patients who are not in downtown Tampa, downtown Orlando, for example, the rest of the state, especially in the northern part, tends to be quite rural. And so many of our patients had loss of power and a lot also in those regions are on well water. And so when the power goes out, it's not just a matter of losing air conditioning and losing access to Wi-Fi, but it's also losing access to fresh, clean water.
Dr. John Sweetenham: Wow, it sounds very challenging. And of course, there are growing concerns at the moment about the IV fluid shortage that's being caused by Hurricane Helene and some hospitals have already begun conserving IV fluid supplies. Can you tell us a little bit about your experience with IV fluid shortages so far and whether you are anticipating other medical supplies to be affected by these shortages in the days or weeks ahead?
Dr. Merry Jennifer Markham: Well, the IV fluid shortage has definitely impacted us. I happened to be on service last week and this week, and, working in the inpatient setting right now on our oncology inpatient service, we are having to conserve all IV fluid, and the entire hospital has been directed to find workarounds. And it's not always easy to find workarounds. It has definitely impacted our ability to safely discharge patients and to sometimes adequately give people the hydration, for example, that they need. A lot of the cancer therapies, we also use intravenous fluids to pre-hydrate or post-hydrate, and it's a challenge when we also need to conserve those IV fluids for other critical needs in the hospital setting. And for me, the shortage is really being felt in that inpatient setting right now. I think that other centers are still going through. And what we learned from the pandemic is that when there is a shortage, and it's not just actually the pandemic that we learned this from, but from any of the supply chain issues that we've had is then centers start buying it up, right? And so there's a bit of a panic in the healthcare field where if we're short on IV fluids, then well, now everybody is buying up the remaining IV fluids. And I think that does impact, unfortunately, everyone in a negative way.
Dr. John Sweetenham: Yeah, I was reading some news reports earlier today actually about stockpiling and the efforts that some of the companies are going to control their outward going supplies to hopefully prevent some of that stockpiling. As if life for you and your patients wasn't difficult enough, you now have the prospect of another major storm, Hurricane Milton, which is headed your way and predicted to be among the most destructive hurricanes ever on record in central Florida. What are your major concerns in the days ahead and for what this might mean for the longer-term impact on cancer care?
Dr. Merry Jennifer Markham: It's concerning. We are definitely in the path and the hospital is currently in sort of crisis preparedness mode. My concerns are always for the patients and for the teams caring for them, especially in my current work in the inpatient setting, these last two weeks. Our patients, because they come from such rural areas, are going to lose power. We will probably lose power, but we have generators at the hospital system, so we're a bit protected. But in many of these areas around us, there will be high winds, there will be flooding for those along the coast, and just the access to a clean, safe living environment is going be in jeopardy during and after the storm.
What concerns me about our patients in particular with cancer are the ones who are undergoing treatments and who may have complications and may not be able to reach the help that they need during the storm or in the days following. I have patients that I have been caring for in the last week who still haven't recuperated, still haven't recovered their power from Helene. And so this is just adding insult to injury. I think that the impact on medical supplies is still to be seen. The challenge is always when a storm wipes out the major manufacturer of a particular product, I think we'll probably continue to have the IV fluid shortages. And I think it's just going to be a matter of preparing for a worst-case scenario but being prepared.
Dr. John Sweetenham: Absolutely, yes. I think you've already alluded to the fact that as each of these successive disasters affect the country, we sort of learn a little bit more each time. And ASCO has provided resources on its website for disaster assistance. We'll share a link in the transcript of this episode to connect providers and patients to the Hurricane Helene-specific resources, government agencies, and also to patient and caregiver groups.
Julie, as ASCO's chief medical officer, you've been speaking to stakeholders across the oncology community, as well as many groups that are responding to the crisis. What's your message to ASCO members and patients and caregivers today?
Dr. Julie Gralow: Our main message at ASCO to our members, our immediate outreach was, ‘We're thinking of you, we're here for you, let us know how we can help you.’ As you've already said, we've learned from past natural disasters. We had Katrina way back when, specifically for the IV drug shortages. We had a shortage back in 2014 due to a problem in Norway, but in 2017 we had another hurricane, Maria, which impacted Puerto Rico and majorly impacted IV fluids. So we have knowledge that we've gained, we as the whole medical community have gained on how to adapt and where we can hydrate orally or, you know, give electrolytes and where we can reserve things. I think one of our main messages at ASCO is that while our members are those who treat patients with cancer, we use IV fluid everywhere in the hospital, the operating room, the emergency room, the ICUs. We are all in this together, and so, while we have some specific things related to oncology where we can probably save fluid and conserve, etc., we need to work as a whole team, a whole body to protect each other. So, if you're developing an incident management team at your institution or whatever, it needs to be multidisciplinary. We all need to be protecting each other's patients as well.
Dr. John Sweetenham: Yeah, absolutely. Just briefly on the subject of IV fluids, do you think it will be necessary to mitigate the IV fluid issue by bringing IV fluids in from other countries?
Dr. Julie Gralow: I think the full impact, how long this is going to be, how much we can ramp up domestically, is really yet to be seen. all looking at this. So Baxter, which supplies about 60% of hospital IV fluids and peritoneal dialysis solutions, it was flooded essentially at their big plant in North Carolina. They have several other plants in the US and some internationally too. So the question will be, did those other plants also make IV fluids? Can they be ramped up? There are another at least two companies in the U.S. that make IV fluid. What will be their ability to ramp up? we already do. Baxter says they've already; I think Merry Jennifer alluded to this, they've already instituted a mitigation strategy where they're placing products on a protective allocation. So they are really trying to protect against stockpiling, et cetera.
The FDA has come out and said it will consider reviewing potential temporary imports. It also is looking at expediting reviews once the manufacturing lines are up and going again, it will expedite those as well. And they're looking at alternative providers. IV drugs are officially on the FDA's drug shortages list, and that allows certain flexibilities, I am told, in terms of, for example, being able to make sterile IV fluids at a local site if it's on the FDA drug shortage list. And there are some other things that go along with it. It's really hard to find on the FDA drug shortage site. You have to use the right keyword. You have to look it up under sodium chloride for injection. You can't look up saline on it. But it is now there. I think it just got placed in the last 24 hours or so. And so that does allow some additional flexibilities.
Dr. John Sweetenham: Okay, great. Thank you. So a question for both of you. A couple of years ago, we covered the consequences of Hurricane Ian on this podcast. And Helene and Milton will presumably not be the last storms which are going to disrupt cancer care and undoubtedly cause a great deal of hardship to many people, both our patients and our caregivers, those who are giving care. Climate change probably predicts that this is going to be an ongoing event. You know, these events have undoubtedly tested the disaster preparedness plans of cancer centers in the region. I wonder how you would assess the readiness of cancer centers to respond to these big disasters, which are undoubtedly in our future, and what areas of care do you think would need more attention? Merry Jennifer, maybe I'll start with you for that question.
Dr. Merry Jennifer Markham: I think cancer centers, working within their health system, really should have a disaster preparedness plan in place. Here in Florida, I am very used to the preparedness plans that my system has developed really for every hurricane season. And because hurricane season is from June to the end of November, we are fully aware of this plan and can start taking action. And a lot of that deals with when do we close particular clinics? What areas do we need to prioritize? How do we make sure we've got proper staffing? I think that is the type of thing that cancer centers should have really in a written protocol – here's what we do when this news is coming out of the weather center or something along those lines.
One of the challenges that we face, and I think probably this is, I guess I'm going to speak for all of the Southeast who is in the, you know, a hurricane, you know, risk area is disaster fatigue. And I think that is a problem. I don't know if it's unrecognized. I fully recognize it because I feel it. think earlier when we were talking, you mentioned Hurricane Ian and I don't even remember, Ian, because we have so many of these hurricanes. Every year there's a new one or multiple, and they all seem to bring the same kind of disasters. Usually on a local scale; I think what we've seen with Helene has just been so massive across multiple states. But the fatigue, that disaster fatigue, I think can lead people to become a little lax.
And there is a risk. If we think of all of us as caregivers for all of our patients and for the physicians and teams practicing, it's easy to become numb and tired and worn out of preparing for these disasters. So, I think it's very important that this stays top of mind and that centers are preparing and also cognizant of the fact that fatigue is also a real potential issue.
Dr. John Sweetenham: Right, thanks. Julie.
Dr. Julie Gralow: We learn from each event and the events have come closer and closer, at least the hurricanes have. I totally agree with Merry Jennifer that we can't have disaster fatigue. Each one does have its unique component. For example, Helene, while we could see the path and it didn't stray that far from its path, did we really expect that this region, this Appalachian region would be the one most impacted? They're nowhere near a coast, you know, it was a bunch of flooding and dams breaking, so each one is different. From ASCO's perspective, we've learned and we've developed both a domestic crisis response team and plan, as well as an international one.
And it's, besides hurricanes and major storms, you know, we've had fires and earthquakes and for our international crisis response team, we've been dealing with conflict and getting cancer care delivery in regions of conflict. So by having a team formed, by learning from each event, and then quickly communicating with members when we can get ahold of them on the ground as to what the real situation is and how we can help, I think we've gotten stronger over the years. It's still, with each one, it's horrible for the people on the ground and our job really is to best support our members and their patients as they're trying to get their lives back together.
Dr. John Sweetenham: Thank you. So, I think that winds up most of the issues we wanted to cover today. And I wanted to thank you both Dr. Markham and Dr. Gralow for being on the podcast today and sharing your insights on what is, of course, an extremely challenging situation.
I should remind listeners that they will find links to disaster resources for providers and patients on the ASCO website at asco.org. You can also follow Dr. Markham on X. Her tag is at @DrMarkham, where she has been sharing key information and resources. And Dr. Julie Gralow will continue to share resources on X. You can find her @jrgralow.
We want to wish you, Merry Jennifer, and our many colleagues in the affected regions, all the best during what we know are very challenging times.
Dr. Merry Jennifer Markham: Thank you.
And thanks to you, Dr. Gralow, for sharing your insights and thoughts with us today as well.
Dr. Julie Gralow: Thanks for having us, John.
Dr. John Sweetenham: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. The guests on this podcast express their own opinions, experience, and conclusions. Guest statements do not necessarily reflect the opinions of ASCO. Mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Find out more about today’s guests:
Dr. Merry Jennifer Markham
@DrMarkham
Dr. Julie Gralow
@jrgralow
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. John Sweetenham
No relationships to disclose
Dr. Merry Jennifer Markham:
Stock and Other Ownership Interests (Immediate Family Member): Pfizer
Research Funding (Inst.): AstraZeneca, Merck
Dr. Julie Gralow:
No relationships to disclose
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Dr. Fumiko Chino and Dr. Raymond Osarogiagbon share highlights from the 2024 ASCO Quality Care Symposium, including patient perspectives and compelling research on topics like equity, supportive care, survivorship, and technology and innovation.
TRANSCRIPT
Dr. Fumiko Chino: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Fumiko Chino, an assistant professor in radiation oncology at the MD Anderson Cancer Center. On today's episode, we'll be highlighting key research and compelling perspectives that were featured at the 2024 ASCO Quality Care Symposium. I was delighted to serve as the chair-elect of this meeting's program committee, and I'm overjoyed to welcome its chair, Dr. Raymond Osarogiagbon, to the podcast today. He is the chief scientist at the Baptist Memorial Health Care Corporation and the director of the Multidisciplinary Thoracic Oncology Program at the Baptist Cancer Center in Memphis, Tennessee.
Our full disclosures are available in the transcript of this episode, and we've already agreed to go by our first names for this podcast today. Ray, it's so great to speak with you today.
Dr. Raymond Osarogiagbon: Thank you, Dr. Chino, and thank you for letting me call you by your first name.
Dr. Fumiko Chino: I think both of our names are complicated enough and so I appreciate the level of familiarity that we've had with each other during the planning process for this fantastic meeting. Now, the Quality Care Symposium featured some really compelling research on very timely topics that address a wide range of issues in cancer care, including quality, safety, equity, supportive care, survivorship, and technology and innovation. Wow, what a lot to cover. Ray, do you mind sharing with me some of the key sessions that really stood out for you?
Dr. Raymond Osarogiagbon: Yes, Fumiko, this was such a great conference. Our tagline this year was ‘Driving Solutions, Implementing Change.’ We had more than 700 attendees in person and virtually. The Symposium featured many fantastic speakers, oral abstracts, posters, and we had networking opportunities for junior colleagues to interact with leaders in the space. We had conversations that will surely inspire future collaborations to improve quality cancer care. We had patients, advocates. I was inspired by the patient perspectives that were presented, learned a lot. And I really felt like this enhanced our understanding of some of the key issues that we see in our clinics.
I was honored to be able to introduce my dear friend, Dr. Ethan Basch from the University of North Carolina, Chapel Hill, who received the Joseph Simone Quality Care Award this year. Dr. Basch gave a talk titled, “On the Verge of a Golden Age in Quality Cancer Care.” In his talk, which received a standing ovation, Dr. Basch tracked his personal development from fellowship training at Memorial Sloan Kettering through a junior faculty position at the same institution under the mentorship of Dr. Deborah Schrag, and ultimately to his current position as chair of oncology at the University of North Carolina and as physician-in-chief at the North Carolina Cancer Hospital. In parallel, with the evolution of the patient-reported outcomes movement that he has been right at the heart of, and also the evolution of cancer care delivery research into its current position of prominence in oncology. That was a spectacular talk, and it rightly received a standing ovation. We also had presentations and panel discussions that addressed patient navigation and cancer care moving from theory to practice, which provided wonderful, diverse perspectives on the evidence-based approaches to patient navigation and cancer care. And a wonderful session on the complexities of the pharmaceutical supply chain and what everyone in oncology should know that looks at the current challenges in the pharmaceutical supply chain.
Leveraging technology to support patient-centered multidisciplinary care [was also covered], and we talked about health-related social needs and the impact of diversity, equity and inclusion on the oncology workforce. Patient care perspectives were just incredible. So, Fumiko, as an equity researcher, I really want to hear your key takeaways from some of these discussions.
Dr. Fumiko Chino: I have to say, I was so impressed with not just the science that was presented, but also the passion from some of our educational speakers who are really speaking from their expertise and their commitment to try to continue to advance equity in the field of cancer care. And as someone who is still a relatively junior researcher, I feel that the work that I've done over the last decade has really been built on the shoulders of these giants. Just harkening back to you had mentioned that Dr. Basch essentially gave an overview of his career and as a young health services researcher, I've been really impressed about how generous the leaders in the field have been with their time not only to discuss their research at this conference, but also to talk to trainees and fellows and junior researchers and really share the wealth of their knowledge.
In terms of equity research presented at the conference though, I was really struck by the overview we were able to provide about the best care to provide to LGBTQ patients. Dr. Mandy Pratt-Chapman actually gave a really lovely overview that was always centered in the patient. It really taught me a lot about what the best practice is to not just collect SOGI data to improve research, but also that there's billing codes that can actually help decrease the chance that a patient may be misbilled based on anatomical misunderstanding of their gender identity. I was very impressed about the capacity for some of our researchers to really think outside of the classic box for DEI research. So not just race as a social construct, ethnicity, but also health literacy barriers. There was a fantastic analysis looking at a randomized control trial (Abstract 385) that actually showed that patients with low health literacy actually got the most benefit from a digital intervention that involved text reminders to increase adherence.
And the flip side of health literacy is that we know that the specific interventions that we do really need to be explicitly designed for the populations that they will be implemented on. Dr. LoConte actually had the results from her intervention looking at a radon mitigation indigenous communities (Abstract 44). And I was so impressed about her commitment to the process of listening to the communities and what their needs were, what their concerns were, and then implementing this community led intervention that helped mitigate the radon risk from many households where the actual radon levels were surprisingly high, beyond what they were that what they were anticipating. And so, it's all of these manifestations of how do we actually improve research, how do we advance the field and further the conversation in an era when it seems like DEI is really under attack.
Well, I know you've long been an advocate for equity for lung cancer. And I know that you were actually involved in one of the amazing abstracts being presented that was essentially a decade- long QI (quality improvement) project to try to improve standards of care for lung cancer in a high-risk community in the Mississippi Delta (Abstract 278). And it actually showed over time that this surgical pathology intervention actually was able to improve overall survival for lung cancer.
I know that this is part of the work that you've been doing for years. Can you talk a little bit about what was presented within the Symposium specifically for lung cancer, including your study?
Dr. Raymond Osarogiagbon: Yes, Fumiko. The member of my team, Olawale Akinbobola, who has an MPH that he actually acquired within my research team I'm proud to say, had the wonderful opportunity to present this work on implementing surgical quality improvement, and in parallel, pathology quality improvement in a well-defined population involving 14 hospitals in seven health care systems across five contiguous hospital referral regions in Mississippi, Arkansas, and Tennessee, at the heart of the Mississippi Delta region. So Olawale showed that over the course of four consecutive 5-year time spans, the quality of surgery has improved from a time when using current objective benchmarks of surgical quality, anywhere from 0-5% of resections met these current standards. So basically, applying today's standards, but retrospectively, to where, as the interventions took hold, we now got to a point where about 67% of the sections in this population now attain surgical quality. And we saw in sequential lockstep with that, that the hazard of death among these patients has significantly decreased. All the way, I think using the first 5 years as the reference, the hazard reduced about 64%. Really amazing to see.
But you know, there were other fascinating abstracts. There was a randomized controlled trial, Abstract 185, that demonstrated that olanzapine therapy was actually way more effective than prochlorperazine for patients with intractable chemotherapy-induced nausea and vomiting. I found that very compelling abstract.
And then there was Elyse Richelle Parks who reported on the effectiveness of a virtual sustained tobacco treatment, Abstract 376 [a clinical trial conducted by ECOG-ACRIN within the NCI Community Oncology Research Program]. This tobacco control intervention is remotely administered using technology that was presented in today's session on leveraging technology to enhance multidisciplinary care delivery. That too was amazing to behold.
Dr. Fumiko Chino: I've been so impressed within my, at least my interactions with the Quality Care Symposium for the last several years about how this meeting really creates the perfect space for this type of science, which can be frankly underappreciated at other meetings. You know, something like a QI project, a quality improvement project leading to an overall survival benefit or a trial like you mentioned, the randomized control trial for olanzapine, which specifically had a quality-of-life endpoint, meaning that patient quality-of-life was a compelling justification for optimal nausea control. These things are really underappreciated sometimes at the larger scientific meetings, and the ASCO Quality Care Symposium is really where these types of studies and this type of research really shines; it's very patient-centered.
You mentioned the patient voice being a really integral part, and I certainly agree with that. The entire meeting started with a session featuring a phenomenal patient advocate, Jamil Rivers, who was diagnosed with de novo stage 4 metastatic breast cancer. And her experience with her primary treatment really highlighted some of the care gaps that Black women experience in their journey with breast cancer. And it really charged her to actually create a patient navigation organization to help Black women with breast cancer get more evidence-based care to make sure that they were actually asking the questions that needed to be asked, getting the resources that they qualified for, and making sure they were getting evidence-based care.
Now shifting gears a little bit, in oncology and across medicine, there's actually been some major challenges with drug shortages. I'd like to ask you about the session that was featured to inform oncologists about what we need to know about navigating the complexities of the pharmaceutical supply chain. Do you mind sharing highlights from that discussion, Ray?
Dr. Raymond Osarogiagbon: I will, Fumiko, but before I do that, I have to follow up on what you said about Jamil Rivers, the breast cancer survivor and advocate who leads the Chrysalis Initiative. She made the statement of the meeting [in my opinion] when she said, “A hospital encounter for a Black woman is like a Black man being pulled over by the police.” Wow. I mean, that's a direct quote. It suddenly helped me understand my wife's many years-long anxiety whenever she has to deal with encounters with clinicians and health care systems.
But about that wonderful session on the challenges with the pharmaceutical supply chain. For me, there were two key highlights. One was Dr. Deborah Patt’s discussion on the growing influence of pharmacy benefit managers, PBMs, on the cost and delivery of cancer care.
And then there is Jason Weston's discussion of how U.S. generic oncology drug manufacturing has moved almost entirely out of the U.S. with this incredible unrealistic price focus, almost so focused on price competition, almost totally ignoring quality and safety. And paradoxically, that fierce competition has inhibited competition, right?
So as the margins have shrunk and all these generic drug manufacturers have moved overseas with little oversight, the supply chain gets disrupted because these companies are not able to invest in processes, in their manufacturing facilities and so on. So, when something goes wrong, all of us become vulnerable. And the other striking thing I learned from Jason was this problem is not new. It is not new. It's been with us for decades. And without comprehensive solutions, unfortunately, it's not going to go away. So, these are some of the examples of things that I would really love the podcast audience to go and check out for themselves.
Dr. Fumiko Chino: I will just highlight one additional aspect of that session, which was actually the oral abstract (Abstract 1) that was embedded into the session that was specifically about how when during the cisplatin shortage of last year, when that drug was out of stock, which is honestly a very widely available, typically cheap medication, Dr. Jody Garey actually presented on the fact that the things that were substituted were actually far more expensive, and that actually led to not just people not getting the standard of care due to the drug shortages, but also increased costs. So, the bizarre side effect of the race to the bottom in terms of price competition is the fact that during these shortage periods, there's actually a sharp increase in the overall cost, not just to the administration, but also in terms of payer costs and patient cost sharing. So, it is sort of a lose-lose situation. And that was really highlighted to me by that abstract. And I'm so grateful for the research that really puts these experiences that we see in our clinic, things like drug shortages, in a larger perspective of how things like health policy and reimbursement and some of the nitty-gritty that goes on beyond the scenes in terms of oncology practice really is ending up impacting patient care.
Now Ray, is there anything else you'd like to highlight before we wrap up the podcast?
Dr. Raymond Osarogiagbon: One I maybe should highlight was the discussion about DEI, which is obviously a contentious topic. And we had Dr. Tawana Thomas Johnson with the American Cancer Society tell us how DEI has evolved from something that everybody seemed like they were eager to support and champion in 2020 to a kind of backlash...how we moved from $5 billion in pledges by corporations to support DEI initiatives in 2020 after the George Floyd murder to now where everybody is wanting to roll things back. And yet in the face of this, wanting to roll things back, wanting to respond to the inevitable backlash, there is this commitment still that some companies have had to DEI and workforce development ideas, so nevertheless, ongoing support. For me, that was a bright spot.
Dr. Fumiko Chino: I have to say, as someone who started going to the ASCO Quality Care Symposium as a trainee, I've been really encouraged myself in terms of bright spots for this meeting about the engagement from trainees, from medical students to residents and fellows to early faculty. We even had someone who had just graduated high school ask us one of the questions in a session. And that really highlighted for me that this meeting is a very young meeting. It really is the next generation of health services researchers. And that has always been one of the joys about some of the discussions because I feel like the science presented, the education presented is sparking new collaborations, new research paradigms, new mission driven research for another generation. And it's been just simply phenomenal.
Dr. Raymond Osarogiagbon: Yeah, the networking opportunities. Wow. It was such a joy to behold people getting together, breaking off in small clusters, interacting with each other, strangers meeting and hitting it off. I mean, just what a wonderful meeting this is.
Dr. Fumiko Chino: Yeah, I have to highlight that. Certainly, at my first ASCO Quality meeting at this point, I think eight years ago, I went to one of those Meet the Expert luncheons, had a great conversation with a phenomenal researcher who I still obviously very much admire. And I was sitting at a table at a Meet the Expert luncheon today. And I just felt so invigorated by some of the conversations that I had with the next generation of researchers about how to define their lane, their passion, and how to continue to advance the field.
Thank you, Ray, for sharing your key takeaways from the 2024 ASCO Quality Care Symposium and for leading a truly robust program this year.
Dr. Raymond Osarogiagbon: Thank you, Fumiko. This has been a labor of love as you will find when you take on this responsibility for next year's meeting. This has been my pleasure.
Dr. Fumiko Chino: Thank you so much. I'm really excited about the program that we're going to start planning in Chicago next year. Everyone listening can mark their calendars for October in Chicago. I really want to thank our listeners for your time today. You will find the links to the sessions and the abstracts that we discussed in the transcript of this episode. And if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Follow today’s speakers:
Dr. Fumiko Chino
@fumikochino
Dr. Raymond Osarogiagbon
@ROsarogiagbon
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Fumiko Chino:
No relationships to disclose
Dr. Raymond Osarogiagbon:
Stock and Other Ownership Interests: Lilly, Pfizer, Gillead
Honoraria: Medscape, Biodesix
Consulting or Advisory Role: AstraZeneca, American Cancer Society, Triptych Health Partners, Genetech/Roche, National Cancer Institute, LUNGevity
Patents, Royalties, Other Intellectual Property: 2 US and 1 China patents for lymph node specimen collection kit and metho of pathologic evaluation
Other Relationship: Oncobox Device, Inc.
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Dr. Lillian Siu and Dr. Melvin Chua discuss the new technologies and novel therapeutics that were featured at the 2024 ASCO Breakthrough meeting.
TRANSCRIPT
Dr. Lillian Siu: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Lillian Siu, a medical oncologist and director of the Phase 1 Trials Program at the Princess Margaret Cancer Center in Toronto, Canada, and a professor of medicine at the University of Toronto. On today's episode, we'll be discussing key takeaways from the 2024 ASCO Breakthrough meeting in Yokohama, Japan. Joining me for this discussion is Dr. Melvin Chua, who served as the chair of Breakthrough’s Program Committee. Dr. Chua is the head of the Department for Head, Neck and Thoracic Cancers in the Division of Radiation Oncology at the National Cancer Center in Singapore.
Our full disclosures are available in the transcript of this episode.
Dr. Chua, it's great to be speaking with you today and congratulations on a very successful Breakthrough meeting.
Dr. Melvin Chua: Thanks Dr. Siu. It was really inspiring to come together again to showcase the innovative work of world-renowned experts, clinicians, researchers, med-tech pioneers, and drug developers from around the globe. Our theme this year was inclusivity and thus it was important to bring people together again in the Asia Pacific region and to foster international collaborations that are so important in advancing cancer care. This year, we invited 65 international faculty, of which 55% were from Asia. Also, importantly, we achieved approximately a 50-50 split for male to female representation. These are remarkable statistics for the meeting, and we really hope to retain this for future Breakthrough [meetings].
Dr. Lillian Siu: The meeting featured renowned keynote speakers who shared great insights on new technologies and therapies that are shaping the future of drug development and care delivery. Let's first talk about artificial intelligence and the keynote address by Dr. Andrew Trister. He gave a very interesting talk titled, “Plaiting the Golden Braid: How Artificial Intelligence Informs the Learning Health System.” What are the key messages from his talk?
Dr. Melvin Chua: Couldn’t agree with you more, Dr. Siu. Dr. Trister is the chief medical and scientific officer of Verily, a precision health company. He previously worked in digital health and AI at The Bill and Melinda Gates Foundation, and worked at Apple where he led clinical research and machine learning with Apple partners. But perhaps it was really his background and training as a radiation oncologist that was most pertinent as he was able to weave both the components of new AI models and the applications and pitfalls in the clinic to the audience.
Dr. Trister provided a very high-level view through the history of AI and showcased the progression of the different AI models and he basically explained between deep and shallow methods as well as deductive logic versus inductive probabilistic methods. He then provided several clinical examples where these models have shown their utility in the clinic, for example, pathology and so forth. At the same time, he illustrated several pitfalls with these models. So overall, I think Dr. Trister's talk was very well received by the audience with several key messages, including the importance of [using] high-quality data as the basis of a good AI model.
AI was also addressed in an Education Session that looked at Artificial Intelligence in the Cancer Clinic. And we had a panel of experts that highlighted current progress and successes with AI in the clinic, advances with AI assisted pathology for clinical research and precision medicine, large language models (LLMs) for applications in the clinic, and how we could leverage AI in precision oncology. And from this session, I had several key takeaways. Dr. Alexander Pearson [of the University of Chicago] gave a very illustrative talk on how multimodal information across clinical omics, radiological information and multi omics could be used to improve diagnostic tasks and clinical prediction across different cancers. And Dr. Joe Yeong [of Singapore General Hospital] gave a very good talk on how AI can be applied in digital pathology to accelerate research in immunology and help in the development of immunotherapies. Dr. Danielle Bitterman [of Brigham and Women’s Hospital] shared very good examples of how LLMs could be used in a clinic. And I think the example that really stood out for me was how LLMs could be deployed to create responses to patient queries. And of course, the big question in the room was: How could AI eventually encapsulate compassion in their response? I think this again showcased how LLMs could really help to accelerate our clinical work going forward. And ultimately circling back to data, Dr. Caroline Chung [of MD Anderson] gave a very poignant description on the importance of data quality and how poor-quality data could eventually lead to underperforming AI models. So all in all, I think this was a great session. And what do you think, Dr. Siu?
Dr. Lillian Siu: Melvin, I totally agree with you. I like all your comments and I really enjoyed the keynote as well as the session on AI in the cancer clinic chaired by Dr. Pearson. I think all these sessions were really informative. Discussions on the latest AI and machine learning, algorithms and technologies on digital pathology, LLMs and big data, as you said, really enables the attendees, especially clinicians like me, to gain a deep understanding of how AI can be translated to practical applications.
Dr. Melvin Chua: Great. So, Dr. Siu, let's talk about some of the novel therapeutics that were featured at the meeting. Again, this was an important session for Breakthrough, and it's always been there. So could you share some highlights from the sessions on novel drug development from your perspective?
Dr. Lillian Siu: Yes, indeed. Drug development is such an exciting aspect of this meeting. On Day 3 of the meeting, we had a keynote by Dr. Shimon Sakaguchi of Osaka University, who discussed “Targeting Regulatory T cells (Tregs) in Cancer: The Science, Trials, and Future.” And he talked about T cells, especially Treg biology, the role of Tregs in immune regulation, new developments in Treg immuno-oncology drugs, and how we can actually target Tregs to treat early cancers, etc. This talk is particularly exciting because there are now anti CCR8 antibodies in the clinic that specifically target Tregs, and some early signals of anti-tumor activities are already being observed. Dr. Sakaguchi also emphasized the importance of combination sequence and timing of drugs for the successful use of cancer immunotherapeutic agents.
I also want to emphasize the Education Session that followed, titled, “The Future of Immunotherapy, New Drugs and New Ideas.” In that particular session, we heard about engineering T-cell immunity to eradicate tumors. We heard about CAR T-cell therapy in GI cancers, novel immunotherapeutic combinations, and T-cell engagers, which are bispecifics in cancer. While success with some of these immunotherapeutic modalities, such as cell therapies and T-cell engagers have been largely seen in hematological malignancies, we are beginning to observe efficacy signals in solid tumors. For example, the CAR T targeting Claudin18.2 in gastrointestinal cancers and the recently approved FDA-approved DLL3/CD3 bispecific T-cell engager, tarlatamab, in small cell lung cancer are really exciting examples.
We also heard from investigators who are exploring neoadjuvant therapies in the neoadjuvant therapy session, and the key takeaway from that session is that we have growing interest in using neoadjuvant therapy or perioperative therapy. In other words, neoadjuvant plus adjuvant therapy in different cancers. In the neoadjuvant session, there were updates provided by different experts on the roles of neoadjuvant therapy in melanoma, liver cancer, bladder cancer, and nasopharyngeal cancer. Increasingly, there is randomized trial evidence to support the use of neoadjuvant therapy or perioperative immunotherapy in several cancer types with survival-based endpoints. Very exciting indeed.
Dr. Melvin Chua: Indeed, I couldn't agree with you more. I think one of the things that went into designing the case-based discussions this year was that we wanted to talk about cancers that were relevant to this part of the world and hence we again showcased lung cancers, gastric cancers and melanomas, and whereby we have again perspectives from an expert from the West coupled to an expert from the East, thereby showcasing the diversity of practice around the world. The other thing that we did this year was we decided to pair the case-based discussions with the keynotes and the Education Sessions as well. For example, on Day 3, we had Dr. Sakaguchi speak on Tregs, as you mentioned. And this was followed by an in-depth session on new immunotherapies, and then followed by a case-based discussion on different melanoma cases on the role of neoadjuvant immunotherapy in this disease, and the strikingly relevance of response to prognostication. This is an important trait that we're seeing now that seems to pan out across different cancers, where we find that neoadjuvant response to combination systemic therapies and/or radiotherapy is a strong prognosticator.
Dr. Lillian Siu: So, Dr. Chua, we've discussed some breakthrough treatments and promising advances in cancer care, and we've touched upon some barriers to success in cancer treatment. I would like to ask you about the keynote address by Dr. Raffaella Casolino of the World Health Organization, who spoke passionately about efforts by the WHO and its partners to build equity in cancer care. Can you share some highlights with us?
Dr. Melvin Chua: Absolutely, Dr. Siu. In spite of the tremendous advances we’ve seen in recent years in oncology, there are still major disparities in cancer care, such as cost and access, which affect patients worldwide. I think Dr. Casolino’s talk was a very nice overview whereby she showed, first of all, the WHO's impact in terms of the WHO Cancer Resolution initiative that was implemented in 2017, where through this initiative, WHO has impacted 100 countries, invested $1 billion in funds, and that has led to millions of lives saved. But she then really drilled down to some of the key examples of the focus of the WHO in terms of equalizing care in cancer. I think one which struck me was the appreciation of the disparities in the clinical trials landscape. I think it is clear that there's still a huge barrier to clinical trials between the high- and middle-income countries and the low- and middle-income countries, and the majority of clinical trials these days are industry sponsored and we really need to look at leveling the playing field in this regard.
Then she highlighted the WHO’s work on trying to lower the barriers to precision oncology. And I think there are several issues in that sense, but I think what the WHO has really worked hard on is promoting education for genomic medicine, where they've done several reviews with experts around the world to educate the field across the world on how we interpret and apply genomics in the clinic.
So all in all, it was very interesting to hear Dr. Casolino’s insights from a policy perspective, and again, this emphasizes that there's so much work to be done at the end of the day and the dialogue needs to continue. We also heard about policy, academic and industry perspectives in the context of clinical trials, and that led to a discussion on real-world evidence generation for regulatory approvals. It was very nice that we had a session on that at the end of Breakthrough 2024 (Real-World Evidence and Clinical Trials: Beyond the Ivory Tower). And in that session, we heard from Dr. Shaalan Beg [of the NIH], and Dr. Janet Dancey [of Queen’s University] who represented views from academia and Dr. Hidetoshi Hayashi [of Kindai University Hospital] shared perspectives on decentralized trials. I’d like to encourage our listeners to watch these sessions if they were unable to attend. The content is very rich, and I'm sure they'll learn from it.
Dr. Lillian Siu: Thank you so much, Dr. Chua. Is there anything else you would like to cover before we wrap up the podcast today?
Dr. Melvin Chua: Thank you, Dr. Siu. The thing I really want to emphasize is, apart from all these Educational Sessions and having very eminent keynote speakers, one of the key points that we really want to bring out for Breakthrough is to showcase the high-quality research. This year we had 300 abstracts submitted and they were all high quality, cutting across trials, omics research, AI and technology, and eventually we selected 235 of them and we were able to showcase some of them across three oral sessions over three days. I think this is an important component of Breakthrough that we really wish to continue building upon where people are now excited to use this forum to present their work.
Dr. Lillian Siu: Thank you so much, Dr. Chua. I really enjoyed our discussions today. I look forward to seeing how the Breakthrough meeting will continue to grow in future years.
Dr. Melvin Chua: Thank you again, Dr. Siu. Thank you for all your leadership and efforts in making Breakthrough a successful meeting series the past few years.
Dr. Lillian Siu: Thank you to our listeners for your time today. You'll find links to the session discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Lilian Siu
@lillian_siu
Dr. Melvin Chua
@DrMLChua
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Lillian Siu:
Leadership (Immediate family member): Treadwell Therapeutics
Stock and Other Ownership Interests (Immediate family member): Agios
Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen
Dr. Melvin Chua:
Leadership, Stock and Other Ownership Interests: Digital Life Line
Honoraria: Janssen Oncology, Varian
Consulting or Advisory Role: Janssen Oncology, Merck Sharp & Dohme, ImmunoSCAPE, Telix Pharmaceuticals, IQVIA, BeiGene
Speakers’ Bureau: AstraZeneca, Bayer, Pfizer, Janssen
Research Funding: PVmed, Decipher Biosciences, EVYD Technology, MVision, BeiGene, EVYD Technology, MVision, BeiGene
Patents, Royalties, Other Intellectual Property: High Sensitivity Lateral Flow Immunoassay for Detection of Analyte in Samples (10202107837T), Singapore. (Danny Jian Hang Tng, Chua Lee Kiang Melvin, Zhang Yong, Jenny Low, Ooi Eng Eong, Soo Khee Chee)
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Dr. Shaalan Beg and Dr. Arturo Loaiza-Bonilla discuss the potential of artificial intelligence to assist with patient recruitment and clinical trial matching using real-world data and next-generation sequencing results.
TRANSCRIPT
Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host for the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center in Dallas and senior advisor for clinical research at the National Cancer Institute. On today's episode, we will be discussing the promise of artificial intelligence to improve patient recruitment in clinical trials and advanced clinical research. Joining me for this discussion is Dr. Arturo Loaiza-Bonilla, the medical director of oncology research at Capital Health in Philadelphia. He's also the co-founder and chief medical officer at Massive Bio, an AI-driven platform that matches patients with clinical trials and novel therapies.
Our full disclosures are available in the transcript of this episode.
Arturo, it's great to have you on the podcast today.
Dr. Arturo Loaiza-Bonilla: Thanks so much, Shaalan. It's great to be here and talking to you today.
Dr. Shaalan Beg: So we're all familiar with the limitations and inefficiencies in patient recruitment for clinical trials, but there are exciting new technologies that are addressing these challenges. Your group developed a first-in-class, AI-enabled matching system that's designed to automate and expedite processes using real-world data and integrating next-generation sequencing results into the algorithm. You presented work at the ASCO Annual Meeting this year where you showed the benefits of AI and NGS in clinical trial matching and you reported about a twofold increase in potential patient eligibility for trials. Can you tell us more about this study?
Dr. Arturo Loaiza-Bonilla: Absolutely. And this is just part of the work that we have seen over the last several years, trying to overcome challenges that are coming because of all these, as you mentioned, inefficiencies and limitations, particularly in the manual patient trial matching. This is very time consuming, as all of us know; many of those in the audience as well experience it on a daily basis, and it’s resource intensive. It takes specialized folks who are able to understand the nuances in oncology, and it takes, on average, even for the most experienced research coordinator or principal investigator oncologist, 25 minutes per trial. Not only on top of that, but in compound there's a lack of comprehensive genomic testing, NGS, and that complicates the process in terms of inability to know what patients are eligible for, and it can delay also the process even further.
So, to address those issues, we at Massive Bio are working with other institutions, and we're part of this … called the Precision Cancer Consortium, which is a combination of 7 of the top 20 top pharma companies in oncology, and we got them together. And let's say, okay, the only way to show something that is going to work at scale is people have to remove their silos and barriers and work as a collaborative approach. If we're going to be able to get folks tested more often and in more patients, assess for clinical trials, at least as an option, we need to understand further the data. And after a bunch of efforts that happened, and you're also seeing those efforts in CancerX and other things that we're working on together, but what we realize here is using an AI-enabled matching system to basically automate and expedite the process using what we call real-world data, which is basically data from patients that are actually currently being treated, and integrating any NGS results and comparing that to what we can potentially do manually. The idea was to do multi-trial matching, because if we do it for one study, yeah, it will be interesting, but it will not show the potential applicability in the real world.
So with all that background, the tool itself, just to give you the punchline of it, was proven highly effective in terms of efficiency. We were able to increase the number of potential matches, and not only that, but reducing the time to the matching. So basically, instead of spending 25 minutes, it could be done in a matter of seconds. And when you compound all that across multiple clinical trials, in this case, it was several sponsors coming together, we were able to reduce the manual effort of seeing patients and testing for clinical trials to basically 1 hour when it would have otherwise taken a ridiculous amount of time. And it was quantified as 19,500 hours of manual work, compared to 1 hour done by the system to uniquely match a cohort of about 5,600 patients that came into the platform. And this was across 23 trials. Now imagine if we can do it for the 14,000 clinical trials currently in clinicaltrials.gov.
So for us, this kind of was an eye-opening situation that if we can increase not only the efficiency but find even more trials by integrating comprehensive genomic testing, which in this case was a twofold increase in eligibility for clinical trials, that gives us not only the opportunity for optimized processes using AI but also a call to action that there is still a lot of under-genotyping. And I know American Cancer Society and ASCO and many others are working hard on getting that into fruition, but we need to have systems that remind us that certain patients are not tested yet and that can improve not only real patients, but the R&D and the process of innovation in the future.
Dr. Shaalan Beg: Yeah, it's always an important reminder that even some of the highest impact IT solutions or AI solutions are most effective if they can be integrated into our normal clinical processes and into the normal workflow that we have in our clinics to help clinicians do their work quickly and more efficiently.
Can you talk about how, over the last few years, the availability of NGS data in our electronic medical record (EMR) has evolved and whether that's evolving for the better? And what are some next steps in terms of making that data available at EMR so that such solutions can then pull that data out and do clinical trial matching?
Dr. Arturo Loaiza-Bonilla: Yes. So one of the things that we have seen over the last couple of years is because of the applicability of the 21st Century Cures Act, there is less “information blocking,” which is patients not being able to access their information in real time. Now, with the appearance of health exchanges, with patient-centric approaches, which is something that many innovators, including ours, are trying to apply, it's really becoming more relevant. So it's not only helping us to find the patients when they really need to get tested, but also is giving us the opportunity to put those patients into the right treatment pathway when found.
Something that's still a challenge and I think we can work by being more collaborative once again – is my dream – is having these pre-screening hubs where no matter where you are in your cancer journey, you just go into that funnel and then are able to see, “Okay, you are in the second-line setting for non-small cell lung cancer, EGFR-mutated. Now, do you have a meta amplification, then you go for this study or this trial. Oh, you haven't been tested yet. You should get tested. You're a pancreas cancer patient who is KRAS wild type; well, there is a significant chance that you may have a biomarker because that's where most patients are enriched for.”
So having that opportunity to at scale, just for the whole country, to get those patients access to that information, I think is crucial for the future of oncology. And I think you working at the NCI, more than most, know how the impact of that can help for those underrepresented patients to get more access to better treatment options and whatnot. And we can activate clinical trials as well in new models, decentralized models, adjusting time models, all those things can be leveraged by using biomarker testing in real time. Identification when the patient really needs a trial option or a medication option, because the data is telling us when to activate that in real time.
Dr. Shaalan Beg: And identifying the patient for a potential clinical trial is one challenge. In oncology, given a lot of our trials, we are looking to enroll people at a specific time in their disease journey. So we call it first-line or second-line or third-line, becomes the next challenge. So just knowing someone has mutation number 1, 2, or 3 isn't enough to say they would be eligible for a second-line BRAF X, Y and Z mutation at a given trial. I've heard you talk a lot about this last-mile navigation for people once you've identified that they may be a soft match for a clinical trial. Can you talk about what you've seen in the ecosystem being developed on how AI is helping both clinics and patients navigate this last mile from the time they're identified for a clinical trial to the time they actually receive cycle 1, day 1?
Dr. Arturo Loaiza-Bonilla: Yeah, absolutely. And that is such a critical point because, as you know, we have helped tons of patients getting trial options in thousands of cases. But even my own patients, I give them a report for trial options and they're like, “Okay, I still need help.” And we have been talking with ASCO, with the American Cancer Society, and many other very good teams, and what we see as an opportunity in technology here is leveraging those cancer journeys to know when the patient really has the opportunity to enroll in a trial, because this is a very dynamic environment. Not only the patient's condition changes because their cancer progresses, the hemoglobin changes, the cancer moves from one place to the other, and there's nuances in between, but also new medications are coming up, studies open and close, sites open and close.
So having this information as a hub, as what we call a command center, is the key to make this happen. And we can use the same tools that we use for Uber or for Instacart or whichever thing you want to do; it's already the same concept. When you need groceries, you don't need groceries every day. But Amazon gives you a ding that’s like, “Well, I think you may be running out of milk,” because they already know how often you buy it, or just having the data behind the scenes of how typically these, in this case, patient journeys, may manifest based on the biomarker. So let's say a smoldering multiple myeloma is not the same across. One patient with biomarkers that make them very high risk, the risk of progressing to a multiple myeloma, first-line treatment-eligible patient is going to be much different than someone who has better risk cytogenetics. So using that tool to optimize the cancer journeys of those patients and being able to notify them in real time of new trial options, and also knowing when the patient really has that disease progression so there's a time of activation for trial matching again, the same way you get a credit score for buying a house, then you know exactly what options are in front of you at that very moment. And that is the last-mile component, which is going to be key.
What we have seen that we feel is important to invest on, and we have invested heavily on it, is that until the patient doesn't sign the consent form for the clinical trial, that patient is completely unknown to most people. The site doesn't know them because they haven't been there, and they may be there, but they don't know about the options sometimes. But no one's going to invest in getting that patient to the finish line. There's a lot of support for patients on trials, but not before they enroll on trials. And we feel that this is a big opportunity to really exponentially grow the chances of patients enrolling in trials if we support them all the way from the very time they get diagnosed with cancer in any setting. And we can help that patient on a very unique journey to find the trial options using technology. So it's very feasible. We see it once again in many other equally complex tasks, so why not do it in oncology when we have all the bonafides across wanting to do this.
Dr. Shaalan Beg: Can you give examples of where you are seeing it done outside of oncology that's a model that one can replicate?
Dr. Arturo Loaiza-Bonilla: I mean, oncology is the toughest use case to crack. You have experiences with DCTs in the past and all that. So the big opportunities are for patients, for example, in psychiatry, when they need certain counseling and help. We see that also in medical devices, when people have diabetes and they really need a device specifically for that unique situation, or also for patients with cardiovascular risk that they can in real time get access to novel therapeutics. And that's how they have been able to enroll so quickly. And all these GLP-1 inhibitors, all those models are really almost completely decentralized nowadays in something that we can extrapolate for oncology once we have aligned the ecosystem to make it see them. This is something that we can really revolutionize care while we manage all the complex variables that typically come with oncology uses.
Dr. Shaalan Beg: I would imagine while you translate those learnings from outside of oncology into oncology, a lot of those processes will be human and AI combination activities. And as you learn more and more, the human component becomes a smaller fraction, and the technology and the AI becomes more of a component. Are you seeing a similar transition in the clinical trial matching space as well?
Dr. Arturo Loaiza-Bonilla: Yes. So that's why people say humans are going to be replaced. They're not. Patients still want to see a human face that they recognize, they trust. Even family members of mine want to hear from me, even if they are in the top place in the world. What we can change with technology are those things that are typically just friction points. In this case, information gathering, collecting records, getting the data structured in a way that we can use it for matching effectively, knowing in real time when the patient progresses, so we can really give them the chances of knowing what's available in real time. And collecting the information from all these other stakeholders. Like, is the site open? Is the budget approved for that place? Is the insurance allowing the specific … do they have e-consent? Those things can be fully automated because they're just burdensome. They're not helping anyone. And we can really make it decentralized for e-consent, for just getting a screening. They don't need to be screened at the site for something that they're going to receive standard of care. We can really change that, and that's something that we're seeing in the space that is changing, and hopefully we can translate it fully in oncology once we are getting the word out. And I think this is a good opportunity to do so.
Dr. Shaalan Beg: You talked about your dream scenario for clinical trial matching. When you think about your dream scenario as a practicing oncologist, what are the AI tools that you are most excited about making their way into the clinic, either wishful thinking or practically?
Dr. Arturo Loaiza-Bonilla: I typically get feedback from all over the place on doing this, and I also have my own thoughts. But I always come to this for a reason. We all became physicians and oncologists because we like being physicians. We like to talk to patients. We want to spend the time. I tell folks in my clinic, I will see a thousand patients all the time as long as I don't have to do notes, as long as I don't have to place orders. But of course, they will have to hire 1,000 people ancillary to do all the stuff that we do.
If we can go back and spend all that time that we use on alert fatigue, on clicking, on gathering things, fighting insurance, and really helping align those incentives with clinical trials and biomarker testing and really making it a mankind or a humankind situation where we're all in this really together to solve the problem, which is cancer, that will be my dream come true. So I don't have to do anything that is clerical, that is not really helping me, but I want to use that AI to liberate me from that and also use the data that is generated for better insights.
I think that I know my subject of expertise, but there's so many things happening all the time that it is hard to keep up, no matter how smart you are. If the tool can give me insights that I didn't even know, then leverage that as a CME or a board certification, that would be a dream come true. Of course, I'm just dreaming here, but it's feasible. Many of these ideas, as I mentioned, they're not new. The key thing is getting them done. The innovative part is getting stuff done, because I'm sure there's a gazillion people who have the same ideas as I did, but they just don't know whom to talk to or who is going to make it happen in reality. And that's my call to action to people: Let's work together and make this happen.
Dr. Shaalan Beg: Well, Arturo, thanks a lot for sharing your insights with us today on the ASCO Daily News Podcast.
Dr. Arturo Loaiza-Bonilla: Well, thank you so much for the time and looking forward to having more exchanges and conversations and seeing everyone in the field.
Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find a link to the studies discussed today in the transcript of this episode. And if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Shaalan Beg
@ShaalanBeg
Dr. Arturo Loaiza-Bonilla
@DrBonillaOnc
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Arturo Loaiza-Bonilla:
Leadership: Massive Bio
Stock and Other Ownership Interests: Massive Bio
Consulting or Advisory Role: Massive Bio, Bayer, PSI, BrightInsight, Cardinal Health, Pfizer, Eisai, AstraZeneca, Regeneron, Verily, Medscape
Speakers’ Bureau: Guardant Health, Bayer, Amgen, Ipsen, AstraZeneca/Daiichi Sankyo, Natera
Dr. Shaalan Beg:
Consulting or Advisory Role: Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen
Speakers’ Bureau: Sirtex
Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics
Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune
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Dr. Allison Zibelli and Dr. Erika Hamilton discuss the results of the DESTINY-Breast06 trial in HR+, HER2-low and HER2-ultralow metastatic breast cancer and the A-BRAVE trial in early triple-negative breast cancer, the results of which were both presented at the 2024 ASCO Annual Meeting.
TRANSCRIPT
Dr. Allison Zibelli: Hello, I'm Dr. Allison Zibelli, your guest host of the ASCO Daily News Podcast. I'm an associate professor of medicine and breast medical oncologist at the Sidney Kimmel Cancer Center of Jefferson Health in Philadelphia. My guest today is Dr. Erika Hamilton, a medical oncologist and director of breast cancer research at the Sarah Cannon Research Institute. We'll be discussing the DESTINY-Breast06 trial, which showed a progression-free advantage with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) compared to chemotherapy in hormone receptor-positive HER2-low or HER2-ultralow metastatic breast cancer. We'll address the implications of this study for the community, including the importance of expanding pathology assessments to include all established subgroups with HER2 expression, and the promise of expanding eligibility for antibody-drug conjugates. We'll also highlight advances in triple-negative breast cancer, focusing on the A-BRAVE trial, the first study reporting data on an immune checkpoint inhibitor avelumab in patients with triple-negative breast cancer with invasive residual disease after neoadjuvant chemotherapy.
Our full disclosures are available in the transcript of this episode.
Erika, it's great to have you on the podcast today.
Dr. Erika Hamilton: Thanks so much, Allison. Happy to join.
Dr. Allison Zibelli: Antibody-drug conjugates are rapidly changing the treatment landscape in breast cancer. The data from the DESTINY-Breast06 trial suggests that trastuzumab deruxtecan may become a preferred first-line treatment option for most patients with HER2-low or HER2-ultralow metastatic breast cancer after progression on endocrine therapy. First, could you remind our listeners, what's the definition of HER2-ultralow and what were the findings of this trial?
Dr. Erika Hamilton: Yeah, those are fantastic questions. Ultralow really has never been talked about before. Ultralow is part of a subset of the IHC zeros. So it's those patients that have HER2-tumor staining that's less than 10% and incomplete but isn't absolutely zero. It's even below that +1 or +2 IHC that we have classified as HER2-low. Now, I think what's important to remember about D-B06, if you recall, D-B04 (DESTINY-Breast04) was our trial looking at HER2-low, is that D-B06 now included HER2-low as well as this HER2-ultralow category that you asked about. And it also moved trastuzumab deruxtecan up into the frontline. If you recall, D-B04 was after 1 line of cytotoxic therapy. So now this is really after exhausting endocrine therapy before patients have received other chemotherapy.
And what we saw was an improvement in progression-free survival that was pretty significant: 13.2 months versus 8.1 months, it was a hazard ratio of 0.62. And you can ask yourself, “well, was it mainly those HER2-low patients that kind of drove that benefit? What about the ultralow category?” And when we look at ultralow, it was no different: 13.2 months versus 8.3 months, hazard ratio, again, highly significant. So I think it's really encouraging data and gives us some information about using this drug earlier for our patients with hormone receptor-positive but HER2-negative disease.
Dr. Allison Zibelli: I thought this study was really interesting because it's a patient population that I find very difficult to treat, the hormone receptor-positive metastatic patient that's not responding to endocrine therapy anymore. But it's important to mention that T-DXd resulted in more serious toxicities compared to traditional chemotherapy in this study. So how do you choose which patients to offer this to?
Dr. Erika Hamilton: Yeah, those are both great points. So you're right, this is after endocrine therapy. And in fact, about 85% of these patients had received at least 2 prior lines of endocrine therapy. So I have some people kind of asking, “Well, if endocrine therapy really isn't benefiting everyone in the second-line setting post-CDK, should we just move to the ADCs?” And, no, probably we should really make sure that we're exhausting endocrine therapies for those patients that are going to benefit. And once we determine somebody has endocrine-resistant disease, that's when we would think about switching.
In terms of the side effects, I think you're right. It's mainly ILD that's probably the more serious side effect that we worry about a little bit with trastuzumab deruxtecan. The good news is, through multiple trials, we've gotten a little bit better at managing this. We've pretty much all but eliminated any fatal cases of ILD, definitely less than 1% now. ILD rates, depending on what study you look for, kind of ranges in that 10% to 15% range. Any grade ILD on D-B06 was 11.3%. So really kind of making sure that we look for ILD at scans, making sure that patients are educated to tell us about any new pulmonary symptoms: cough, exertional dyspnea, shortness of breath at rest, etc. But I think the most common side effects that we really deal with on a daily basis with trastuzumab deruxtecan, luckily, is nausea, which we've gotten better at managing with the 2- or 3-drug antiemetic regimen, and probably a little bit of fatigue as well.
Dr. Allison Zibelli: Thank you. So, I think for most people in the community, the sticking point here will be expanding pathology assessments to include all of the subgroups, including the ultralow. Most patients in the community are not testing for HER2-low and HER2-ultralow now.
Dr. Erika Hamilton: Historically, we kind of all did HER2 IHC, right? And then as FISH became available, there were a lot of institutions that moved to FISH and maybe didn't have IHC anymore. And now, at least in my institution, we do both. But I think it's a very important point that you made that IHC was really designed to pick out those patients that have HER2-high, the 3 pluses or the FISH amplified cases. It was not to tell the difference between a 1+ or a 2+ or a 0 that's not quite a 0 and a 1+. So I think you're right. I think this is tough. I probably have a little bit more of an interesting take on this than some people will. But data from ASCO, not this year but in 2023, there was actually a pretty eloquent study presented where they looked at serial biopsies in patients, and essentially, if you got up to 4 or 5 biopsies, you were guaranteed to have a HER2-low result. Now, this didn't even include ultralow, which is even easier. If we know we include ultralow, we're really talking about probably 85% to 90% of our patients now that have some HER2 expression. But if we biopsy enough, we're guaranteed to get a HER2 low.
And so I think the question really is, if we know IHC wasn't really designed to pick out these ultralows, and we know kind of greater than 90% of patients are going to have some expression, did we kind of develop this drug a little bit backwards? Because we thought we understood HER2, and the reality is this drug is a little bit more like a sacituzumab govitecan, where we don't test for the TROP2. Should we really be kind of serial biopsying these patients or should maybe most patients have access to at least trying this drug?
Dr. Allison Zibelli: So I don't think that most of my patients will really be happy to sign up for serial biopsies.
Dr. Erika Hamilton: Agreed.
Dr. Allison Zibelli: Do we have any emerging technologies for detecting low levels of HER2? You talked about how the IHC test isn't really designed to detect low levels of HER2. Do you think newer detection techniques such as immunofluorescence will make a difference, or will we have liquid biopsy testing for this?
Dr. Erika Hamilton: Yeah, I think liquid biopsy may be a little bit hard, just because some of those circulating tumor cells are more of a mesenchymal-type phenotype and don't necessarily express all of the same receptors. Normally, if they're cytokeratin-positive, they do, but certainly there is a lot out there looking at more sensitive measures. You mentioned immunofluorescence, there are some even more quantitative measures looking at lower levels of HER2. I definitely think there will be. I guess, ultimately, with even the IHC zeros that are the less than 10% incomplete staining, having a PFS that was absolutely no different than the HER2 low, I guess the question is, how low can we really go? We know that even the IHC zeros doesn't mean that there's no HER2 expression on the cell surface. It just means that maybe there's a couple of thousand as opposed to 10,000 or 100,000 copies of HER2. And so it really appears that perhaps this drug really is wedded to having a lot of HER2 expression. So ultimately, I wonder how much we're going to have to use those tests, especially with what we know about tumor heterogeneity. We know that if we biopsy 1 lesion in the liver, biopsy a lymph node, or even another lesion in the liver, that the HER2 results can have some heterogeneity. And so ultimately, my guess is that most people have some HER2 expression on their breast cancer cells.
Dr. Allison Zibelli: So maybe we're going to be using this for everybody in the future.
Dr. Erika Hamilton: It certainly seems like we keep peeling back the onion and including more and more patients into the category that are eligible to receive this. I agree.
Dr. Allison Zibelli: Let's move on to triple-negative breast cancer, namely the A-BRAVE trial. This was an interesting trial for patients that did not get neoadjuvant immunotherapy and testing 2 groups. The first group was those with residual disease after neoadjuvant conventional chemotherapy. The second group was people with high-risk disease identified upfront that had upfront surgery. The study found that adjuvant avelumab did not improve disease-free survival versus observation, which was the study's primary endpoint. But interestingly, there was a significant improvement in 3-year overall survival and distant disease-free survival. Can you give us your thoughts on that?
Dr. Erika Hamilton: Yeah, I think this study was really interesting. Right now, the standard for our patients with larger or node-positive triple-negative cancers is KEYNOTE-522. It's a pretty tough regimen. It's kind of 2 sequential uses of 2 chemotherapies, so 4 chemotherapy agents total with pembrolizumab. But you're right, this study looked at those that had residual disease after neoadjuvant that didn't include immunotherapy, or those patients that didn't get neoadjuvant therapy, went to surgery, and then were receiving chemotherapy on the back end. I'm going to give you the numbers, because you're right. The 3-year disease-free survival rates were not statistically significant. It was 68.3% among those that had avelumab, 63.2% with those that had observation only. So the difference was 5.1% in favor of avelumab, but it wasn't statistically significant. A p value of 0.1, essentially. But when we looked at the 3-year overall survival rates, we saw the same pattern, those patients with the avelumab doing better, but it was 84.8% overall survival and not, unfortunately, dying, versus 76.3%. So the magnitude of benefit there was 8.5%, so about 3% higher than we saw for disease-free survival, and this was statistically significant.
So is this going to change practice for most patients? I probably don't think so. I think for our patients that have larger tumors that's recognized upfront or have node positivity, we're probably going to want to use neoadjuvant chemo. Being able to get a PCR is very prognostic for our patients and enables us to offer things on the back end, such as PARP inhibitors or further chemotherapy of a different type of chemotherapy. But for our patients that go to surgery and maybe the extent of their disease just isn't recognized initially, this could be an option.
Dr. Allison Zibelli: I agree. I think this will be a really useful regimen for patients where we get the surprise lymph node that we weren't expecting, or somebody who comes to us, maybe without seeing the medical oncologist, who got upfront surgery. So I thought this was really interesting. What kind of translational studies do you think we're going to do to try and understand which patients would benefit from avelumab?
Dr. Erika Hamilton: Yeah, I think that's a great question, and honestly, it's a question that we haven't really answered in the neoadjuvant setting either. Immunotherapy in breast cancer is just a little bit different than it is in some other diseases. We have a benefit for those patients that are PD-L1 positive in the first line. We really haven't seen benefit for metastatic outside of first line. And then in neoadjuvant, it was among all comers. We don't have to test for PD-L1. And now we have this avelumab data from A-BRAVE. I think the question is, is there’s probably a subset of patients that are really getting benefit and a subset that aren't. And I don't know that PD-L1 testing is the right test. We know a lot of people are looking at TILs, so kind of lymphocytes that are infiltrating the tumor, a variety of other kind of immunologic markers. But my guess is that eventually we're going to get smart enough to tease out who actually needs the immunotherapy versus who isn't going to benefit. But we're not quite there yet.
Dr. Allison Zibelli: Thank you, Erika, for sharing your valuable insights with us on the ASCO Daily News Podcast today.
Dr. Erika Hamilton: Thanks so much for having me.
Dr. Allison Zibelli: And thank you to our listeners for joining us. You'll find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you like this podcast and you value our insights, please take a moment to rate, review, and subscribe wherever you get your podcasts. It really helps other people to find us. So thank you very much for listening today.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Allison Zibelli
Dr. Erika Hamilton
@ErikaHamilton9
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Allison Zibelli:
None Disclosed
Dr. Erika Hamilton:
Consulting or Advisory Role (Inst): Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnologies, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Hosun Pharma, Zentalis Pharmaceuticals, Jefferies, Tempus Labs, Arvinas, Circle Pharma, Janssen, Johnson and Johnson
Research Funding (Inst): AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Millenium, TapImmune, Inc., Lilly, Pfizer, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceuticals, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Zenith Epigentics, Arvinas, Harpoon, Black Diamond, Orinove, Molecular Templates, Seattle Genetics, Compugen, GI Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akesobio Australia, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repetoire Immune Medicines, Treadwell Therapeutics, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Cullinan Oncology, Bristol-Myers Squib, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics
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Dr. Shaalan Beg and Dr. Arjun Gupta discuss the rationale behind treatment breaks and assess the pros and cons based on feedback and data from patients with advanced-stage gastrointestinal cancers.
TRANSCRIPT
Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center in Dallas and senior advisor for clinical research at the National Cancer Institute. I'll be your guest host for the podcast today.
On today's episode, we'll be discussing treatment holidays in GI cancers. Treatment holidays, also known as drug holidays, are increasingly being discussed in clinical practice and involve voluntarily halting treatment for a duration determined by a health care provider if believed to be beneficial for a patient's well-being. We'll address the rationale behind treatment holidays and explore their potential risks and benefits. Joining me for this discussion is Dr. Arjun Gupta, a GI medical oncologist and health services researcher at the University of Minnesota. Dr. Gupta's research on treatment-related time toxicity has explored the benefits of taking a break from treatment.
Our full disclosures are available in the transcript of this episode.
Arjun, it's great to have you on the podcast today.
Dr. Arjun Gupta: Thanks, Shaalan. It's a joy to be here.
Dr. Shaalan Beg: Your research at the intersection of oncology, supportive care, and care delivery is extremely interesting and important in today's day and age. And you've done extensive work on the concept of time toxicity in cancer treatment. So as we think about these discussions in the clinic on treatment holidays and we talk about risks and benefits, I was hoping that you could help explain the concept of time toxicity in cancer treatment and what our listeners should remember from this.
Dr. Arjun Gupta: Sure. So time toxicity is simply the time commitments that cancer care imposes on people with cancer and their loved ones, and the burden that comes along with these commitments. When we specifically think about time toxicity associated with a particular cancer treatment, such as chemotherapy, it's the time costs of pursuing, receiving, and recovering from cancer treatment. Now, we have to acknowledge that much of cancer care is essential. We need blood tests to monitor organ function, we need chemo to shrink tumors, and we need a caring oncologist to break bad news. But we have to remember that oncology care is delivered in an imperfect world. Appointments that should take 10 minutes can take 5 hours. People can have uncoordinated appointments, so they're coming to the clinic 3, 4, 5 times a week. And this affects, of course, not only the patient themselves but also their informal care partners and the entire network around them. And this cancer care can completely consume people's lives, leaving no time for rest, recovery, or pursuing joyful activities.
We interviewed patients and care partners in some qualitative work, and this was specifically people with advanced-stage gastrointestinal cancers. And we asked them what cancer care was like, and some of the words will shock you. People said things like, “It's like being on a leash.” “My life is like being on an extended COVID lockdown.” “Cancer is a full-time job.” A very experienced oncologist said, “It's like being on call. You may or not get called into the hospital, but you need to always be available.” And so this concept of time toxicity really applies to all people with cancer, but perhaps most so for people with advanced-stage, incurable cancer, when time is limited and when treatment regimens are perhaps not offering massive survival benefits. And in some cases, the time costs of pursuing the treatment can even overtake the very marginal survival benefit offered by the treatment.
Dr. Shaalan Beg: This is particularly relevant for gastrointestinal cancers that, even in the world of advanced cancers, are highly burdensome in terms of their symptoms and the concept of being on call, whether you're a patient or a caregiver, and the burden that it has, I think will resonate with a lot of us, that it's always in the back of our mind on what if X, Y or Z were to happen? In the FOCUS4-N trial, a randomized trial from the UK, investigators assessed whether taking a treatment holiday for maintenance therapy for metastatic colorectal cancer would have a detrimental effect on progression free survival, overall survival, tolerability and toxicity. It looks like the study found that these decisions regarding maintenance therapy should be individualized, but there were not major differences in outcome. Can you comment on this and what applications that has for us in the clinic?
Dr. Arjun Gupta: Sure. But before diving into the FOCUS4-N clinical trial, I just wanted to share a story from the clinic yesterday. It happened in my clinic yesterday, but I'm sure it happens to thousands of patients across the world every single day. So it was the first visit for a patient with stage 4 colon cancer, and they had polymetastatic disease with disease in the lungs and the liver, no actionable biomarkers, and so very likely to be incurable. And so we discussed the usual port and palliative care appointments and chemotherapy backbone, and doing this every 2 weeks, and then doing scans after 4 to 6 doses of chemo to see how the cancer has responded. And then the patient looks up and asks that question, “Okay. So when does this end? When are we done? Do I need to do this forever and the rest of my life?” These are just such innocent and hopeful questions, because the truth is, there is no established end date. But I shared this story that right off the bat, people are looking for breaks. They've not even started chemo, they've not experienced physical or financial or time toxicity, but just psychologically, being on chemo long-term or forever is a very, very hard adjustment.
And so it's in this context that we should look at the FOCUS4-N clinical trial, which was a sub- study of a larger umbrella trial investigating whether continuing on maintenance chemo with oral capecitabine versus taking a treatment break from chemo affected the progression-free survival in people with metastatic colorectal cancer who had disease control after 4 to 6 months of upfront chemotherapy. So they randomized approximately 250 people. These people had largely been treated with FOLFOX or FOLFIRI. Most did not receive a biologic, and approximately half had partial response and half had stable disease. And then they did scans on these patients every two months or so. And the primary endpoint was progression free survival. The median PFS was approximately 4 months in the capecitabine arm and 2 months in the no treatment arm. Of course, as expected, side effects were higher in the capecitabine arm. But impressively, the overall survival was not different between these two arms. So what we're seeing here is that after this period of 4 to 6 months of intensive chemo, if we take a chemo break versus we get some oral chemotherapy, it may affect how quickly the cancer grows on scans, but it maybe does not affect how long patients live.
Now, how do these data apply for an individual patient? Now, these are incredibly nuanced and personal decisions and patients can and should choose what aligns best with their values. In some work done by Dr. Mike Brundage and colleagues in Canada, they asked 100 people with advanced cancer to consider hypothetical scenarios where a new treatment did not increase the overall survival, but potentially increased the progression free survival at the cost of some physical and other toxicities. And then they asked patients if and what PFS thresholds they would accept for this treatment. And around half of patients said no matter how big the PFS is, we do not want to accept the treatment because it causes some toxicity if I'm not going to live longer. Around a quarter of patients said that if the drug elongated progression free survival by three to six months, I would take it, because that's valuable to me even if I don't live longer. But surprisingly, 1 in 6 patients said that they would accept a treatment with no PFS benefit and no overall survival benefit, even at the cost of side effects. And there was a spectrum of reasons for these preferences that they maybe had the battle narrative that “I want to be a fighter, and I don't want to have any regrets,” just showing how complex people's attitudes and values can be. So the point is that continuing on maintenance treatment versus not doing it is not wrong. The point is we often don't even have these data to offer treatment breaks to patients so that they can make decisions that align with their goals.
So I think that's the biggest takeaway from the FOCUS4-N trial for me is that we have some hard data now to guide patients [FOCUS4-N Editorial]. Now, strictly speaking, when I'm talking to a patient about these data, doing oral capecitabine in 3-week cycles may not feel like much. It's perhaps a visit every 3 weeks for blood work and for meeting someone from the oncology team. There are no IV drugs given. If one does well, this might literally be one visit every 3 weeks. But we have to consider that things rarely go as smoothly as we plan them to. For someone living 100 miles away and having diarrhea and needing IV fluids, they may require 3 to 4 clinic visits for labs and monitoring.
In the FOCUS4-N trial, 50% of patients on capecitabine had at least one treatment delay, denoting some toxicity. In a different but similar CAIRO3 clinical trial that tested capecitabine and bevacizumab, 10% of patients had to discontinue treatment due to toxicity. And so it's important to remember that what might seem a simple and low burden to us may be very burdensome to patients. In some work that we've done ourselves [published in The Oncologist], even a single simple appointment to a clinic, such as a lab test, often ends up taking patients hours and hours. So I think it's all of this that we have to consider when we present these data to patients.
Dr. Shaalan Beg: You've talked about the FOCUS4-N trial, you mentioned the CAIRO3 study as well. How do you see this playing in the clinic? Somebody may be looking to attend a child's wedding or a notable birthday or a trip with the family, and you have the data from these trials supporting you. What are the patient factors in terms of their disease factors, patient factors that you think of when you recommend such a treatment break to a patient? Or, let me flip that over. Who would be a patient that you would be uncomfortable offering a treatment break for with metastatic colorectal cancer?
Dr. Arjun Gupta: Yes, I think disease characteristics are a crucial consideration when we consider who we're even offering these treatment breaks to. I think, number one, is the overall disease burden, and if there's any critical visceral disease and how that's responded and how much it's responded to the upfront chemotherapy induction. I think patients where we're worried about having several sites of bulky disease, some that have not responded as well, I think we have to be very, very careful considering complete chemotherapy breaks. In the FOCUS4-N trial, in subgroup analysis, patients who had stable disease tended to not benefit as much from the chemotherapy break, perhaps indicating that it's really people whose disease is responding, who are doing well, who don't have as much disease burden, who may be better served by these treatment breaks.
Dr. Shaalan Beg: Fantastic. I think that provides very good direction for our listeners on how they can apply the results of these trials in their clinic.
So we've talked about treatment breaks as a way to give people their time back and to reduce time toxicity. What are other treatment strategies that you have seen deployed to reduce the burden of receiving cancer treatments in general?
Dr. Arjun Gupta: You specifically asked about treatment strategies, so I'll start with that before moving to more broad interventions. We actually interviewed patients and care partners to ask them this question, and one of the things that they said was having prospective information from their oncology care team just about what my expected burden was going to be. So I think people recognize that they need oncology care and the clinicians are trying to help them and it's a broken system, but just knowing that 1 in 4 days will be spent with health care contact or not, or you will spend two hours arguing on the phone with a payer, for example, preparing and supporting people for these burdens is very important. There are obviously some alternative treatment schedules. Certain chemotherapies can be given less frequently now. So if you look at cetuximab in GI cancers, for example, when the initial trials were done, it was given every week, but now we more and more use it every two weeks. And it might not seem like much, but it can open up an entire week for a patient when they can think that I don't need to go in this week at all. So these are just some minor adjustments that we can make in the clinic.
But patients often highlight things that may perhaps not be in the direct control of the oncologist, but in the direct control of us as an oncology community. And perhaps the most frequently cited suggestion was having more care coordination and navigation services. So patients really requested more flexibility in the site of care: “Can I come closer to home?’’ In the timing of their care, ‘’Can I come in at 2:00 PM after I get childcare instead of coming in at 9:00 AM?” They really requested cluster scheduling or having appointments on the same day, if possible, instead of taking up Monday, Tuesday, Wednesday, Thursday, coming in so many times. And all of this could potentially be achieved by having a designated care coordinator, someone working directly with the patient and their care partner. And then some patients also highlighted the benefits of telemedicine and home-based care, where they were able to be home more.
But we have to also recognize that those things are not universally good and often can increase burdens on the patients and care partners. Also, I wanted to highlight some feedback we received from oncology clinicians. We asked a variety of oncology clinicians, including nurses, APPs, physicians, schedulers, and social workers, what they thought were the causes of patients’ time burden. You'll be surprised to hear that when they started talking about patients’ time burdens, they slowly started to talk about their own time burdens. And they said, ‘‘We really want to help people, but we're just doing prior authorization and spending hours on the electronic medical record. And please fix my own time toxicity, and I will fix the patients’ time toxicity,” which I thought was very profound because I think everybody who goes into medicine goes into it for the right reasons, and we end up not providing perfect care, not because of us, but because of the system. I take this as a very, very positive sign and as a hope for change.
Dr. Shaalan Beg: What inspired you to focus on this topic and your research?
Dr. Arjun Gupta: So I personally just hate waiting at the doctor’s office. But yes, it's also been wise mentors, including you, Shaalan, during residency and fellowship, who always told me to keep my ear to the ground and listen to patients. And in full disclosure, time toxicity, and what we've done with it recently, it's nothing new. It's been around for decades. And I think our research group has just sort of named it and shamed it, and now more and more people are starting to think about it.
But I can point to two specific instances that I think of. One was when I was starting fellowship in 2018, I read a piece by Dr. Karen Daily in the Journal of Clinical Oncology, where she quoted Henry Thoreau and said, “The price of anything is the amount of life, or time, that you exchange for it.” And it really struck a chord with me, entering the oncology discipline and seeing what people with cancer go through.
And then the second instance is, I remember my granddad, who was perhaps the most formative person in my life. We were very, very close. And when I was about to enter medical school, he was undergoing chemotherapy for lymphoma. The image that's imprinted in my head is of him putting ketchup on gulab jamun. And I can see Shaalan salivating. But for the listeners who may not know, gulab jamun is an Indian sweet made out of milk, flour, sugar, ghee, molded into balls, deep fried and then served in sugar syrup. And my granddad could not taste anything. He could not taste gulab jamun. All he could taste was ketchup. And so he would put ketchup on everything. And at his oncologist visits when I would accompany him, they would discuss the good news about the cancer shrinking and there being a response, and he was happy, but he could just not taste his gulab jamuns. And it made me realize very early on that the tumor is not the only target.
Dr. Shaalan Beg: What a wonderful story. I think those are really hard to measure, quantify, and when patients do bring those stories into the clinic, I think you realize that you have a very special connection with those patients as well, and it does help us as clinicians give personalized advice. So thanks for sharing.
Arjun, thanks for sharing your valuable insights with us on the ASCO Daily News Podcast today.
Dr. Arjun Gupta: Thanks so much for having me, Shaalan.
Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the studies discussed today in the transcript of the episode. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Arjun Gupta
@guptaarjun90
Dr. Gupta’s Research on Time Toxicity:
· The Time Toxicity of Cancer Treatment, JCO
· Consuming Patients’ Days: Time Spent on Ambulatory Appointments by People With Cancer, The Oncologist
· Evaluating the Time Toxicity of Cancer Treatment in the CCTG CO.17 Trial, JCO OP
· Patients’ considerations of time toxicity when assessing cancer treatments with marginal benefit, The Oncologist
· Health Care Contact Days Experienced by Decedents With Advanced GI Cancer, JCO OP
· Health Care Contact Days Among Older Cancer Survivors, JCO OP
Dr. Shaalan Beg
@ShaalanBeg
Follow ASCO on social media:
@ASCO on Twitter
ASCO on Facebook
ASCO on LinkedIn
Disclosures:
Dr. Arjun Gupta:
Employment (An Immediate Family Member): Genentech/Roche
Dr. Shaalan Beg:
Consulting or Advisory Role: Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen
Speakers’ Bureau: Sirtex
Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics
Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune
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Drs. Hope Rugo, Diana Lam, Sheri Shen, and Mitchell Elliott discuss key strategies and emerging technology in early-stage breast cancer survivorship, including mitigating risk through lifestyle modification, surveillance for distant recurrence, and optimization of breast imaging.
TRANSCRIPT
Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. I'm also an associate editor of the ASCO Educational Book.
There are currently about 4 million breast cancer survivors in the United States, according to the American Cancer Society, and this number is expected to rise as more women are being diagnosed at early stages of this disease, thanks to advances in early detection and the delivery of more effective adjuvant and neoadjuvant treatment leading to successful outcomes.
In today's episode, we'll be discussing current and emerging clinical strategies for the survivorship period, focusing on a multidisciplinary approach. Joining me for this discussion are Drs. Mitchell Elliott, Sherry Shen, and Diana Lam, who co-authored, along with others, a recently published article in the 2024 ASCO Educational Book titled, “Enhancing Early-Stage Breast Cancer Survivorship: Evidence-Based Strategies, Surveillance Testing, and Imaging Guidelines.”
They also addressed this topic in an Education Session presented at the recent ASCO Annual Meeting. Dr. Elliott is a drug development fellow and clinician scientist trainee at the Princess Margaret Cancer Center in Toronto, Canada. Dr. Sherry Shen is a breast oncologist and assistant attending at the Memorial Sloan Kettering Cancer Center in New York. Dr. Diana Lam is a breast radiologist and associate professor at the University of Washington Fred Hutchinson Cancer Center in Seattle.
Our full disclosures are available in the transcript of this episode.
It's great to have you all on the podcast today. Thank you for being here.
Dr. Mitchell Elliott: Thank you so much.
Dr. Sherry Shen: Thank you.
Dr. Hope Rugo: Let's go into the meat of the article now and try to provide some interesting answers to questions that I think come up for clinicians all the time in practice. Your article points out that addressing the challenges in early-stage breast cancer survivorship requires a comprehensive, patient-centered approach, focusing on mitigating risk through lifestyle modification, surveillance for distant recurrence, and optimization of breast imaging.
Dr. Shen, surveillance can facilitate the early detection of recurrence, but ultimately the goal is to prevent recurrence. Lifestyle modifications are a key component of survivorship care, and there are many interventions in this context. Could you summarize the best approaches for mitigating risk of breast cancer recurrence through lifestyle modification and how we might accomplish that in clinical practice?
Dr. Sherry Shen: Absolutely. This is a question that we get asked a lot by our breast cancer patients who are so interested in what changes they can make within their lifestyle to improve their breast cancer outcomes. I always tell them that there are three main things, three main lifestyle factors that can improve their breast cancer outcomes.
Firstly, enough physical activity. So the threshold for physical activity seems to be around 150 minutes of a moderately vigorous level per week. So moderately vigorous means something that gets the heart rate up, like walking quickly on rolling hills, for example. Or patients can do a vigorous level of physical activity for at least 75 minutes per week. Vigorous meaning playing a sport, swimming, for example, running, something that really gets the heart rate up.
The second really important lifestyle modification is limiting alcohol use. Keeping alcohol to less than 4 to 7 drinks per week is particularly important for breast cancer outcomes, especially in women who are postmenopausal and have hormone receptor positive diseases. That's where the strongest connection is seen.
Lastly, maintaining a healthy weight. We know that women who gain more than 5% to 10% of their diagnosis body weight have a higher risk of breast cancer recurrence and worse breast cancer outcomes. That, of course, is easier said than done, and it's primarily through dietary modifications.
I always tell women that in terms of specific things in the diet, it's really hard to study at a population level because diets vary so much between patients. But what is really important is consuming a plant-forward whole foods diet that prioritizes nutrients and the quality of the diet. A little bit more specifically, it's important to limit the amount of red and processed meats in the diet, really limit the amount of sugar sweetened beverages, ideally to cut that out of the diet entirely, and to consume an appropriate amount of dietary fiber in the range of 20 to 30 grams per day. Those are more specific things that have been associated with breast cancer outcomes.
Dr. Hope Rugo: This is such helpful, practical information for clinicians and for patients. Thank you.
But let's move on to another area, surveillance testing for distant recurrence, an area of great interest, in fact highlighted in a special session at ASCO 2024. In clinic, we've seen that many cancer survivors expressed surprise at the less intensive approach to surveillance testing for recurrence, with the whole idea that if you detected it earlier, the outcome would be better. But it does raise an important question. What is the optimal strategy for monitoring for recurrence? And importantly, can early detection through surveillance testing impact outcome?
Dr. Elliott, your research has focused on ctDNA surveillance and the evolving role of minimal residual disease, or MRD. Can you comment on the current surveillance guidelines for distant recurrence, and then, how we really define true MRD?
Dr. Mitchell Elliott: Those are excellent questions, and I think leaving that Education Session at ASCO left us with even more questions than answers with the current role of MRD in this setting. I think a lot of this comes from wanting to help patients and trying to identify the patients at highest risk of cancer recurrence, with the goal of intervening with effective targeted therapy to prevent metastatic relapse.
Current international guidelines in the United States done by ASCO and the NCCN, as well as ESMO guidelines in Europe and even our local Canadian guidelines, do not suggest that patients undergo routine screening in asymptomatic individuals, whether it be blood work or routine radiographic imaging, as there were some studies that were done in the late 1990s and early 2000s that didn't actually show benefit and actually maybe favored a little bit of harm in these situations. So these recommendations are based on these initial studies. However, we know that in the last 10, 15 years, even 20 years, that breast cancer and the landscape of breast cancer has changed significantly with the introduction of our typical standard classification of breast cancer, the emergence of HER2 positive breast cancer, and thus triple negative breast cancer, which was not actually routine standard testing at the time of these studies, and also the most effective therapies we have to date, including immunotherapy, HER2 targeted therapy and the advent of antibody drug conjugates. We're at prime time right now to potentially revisit this question, but the question is, do we have the right technology to do so? And this is where the circulating tumor DNA has really emerged as a potential option, given its minimally invasive opportunity with a standard blood test to actually identify tumor specific DNA that is highly predictive of distant metastatic recurrence or patient recurrence in general.
The evolving role – we still have a lot of questions in this setting. There have been a lot of retrospective analyses of cohort studies and clinical trials that have shown that modern fit for purpose MRD based tests actually have a high positive predictive value at identifying patients with imminent risk of breast cancer recurrence. The most important thing in this setting is that there are different fit for purpose tests. The initial ctDNA assays were actually genotyping based assays, which look for the presence of mutations in the blood. But we know that the sensitivity of these assays is quite challenging at the level of ctDNA required to actually diagnose patients with very small amounts of residual disease. So the fit for purpose MRD assays are now emerging on the market. And we have several that are in clinical development, several that are in research development, but the high specificity in the setting is very important, which we're seeing some evolving and emerging technologies in this setting. We really don't have the data about if these interventions, so if we were to effectively deploy these MRD based ctDNA assays prospectively in patients, if they will actually improve patient outcomes, and how do we correct and address lead time bias, which might potentially affect study results?
Also, the important thing to think about in this setting is if we are able to find something, we also should have an effective therapy to actually intervene for patients, because the outcome in these trials will actually be dependent not only on identifying early breast cancer occurrence, but also delivering the best targeted intervention for that individual patient, which currently we don't understand fully.
Another really interesting thing is there was a trial, the ZEST trial, as many of our listeners may know, that was randomizing patients with patients with ctDNA detected in the adjuvant setting were randomized through either intervention or standard follow up. And going forward, is it actually an opportunity, or is it possible to actually randomize patients knowing that they have a near 100% likelihood of breast cancer recurrence to observation? So these are several ongoing questions that we have to address as we move forward to deploying this technology in the clinical space.
Dr. Hope Rugo: Really fascinating, and thanks for sharing that. I think really broad and helpful information on these ctDNA [assays] and also our surveillance guidelines, which I think really suggests that you only do surveillance for cause, other than looking for local recurrence and new cancers with breast imaging. So it is really an interesting time where we're seeing evolving technologies and evolving understanding of how we can best do this kind of testing when there are so many different assays out there. I think it's going to take a little while. And also understanding, as you pointed out, trying to target treatments when patients have emerging ctDNA to mutations. And we just have no idea yet if we're going to ultimately change outcomes. This is really helpful, and I think we'll give people a good understanding of where to think about this right now, what to look for in the future.
Now, of course, it's a nice segue into the idea of breast imaging for early breast cancer survivors because that's where we do have data. Dr. Lam, let's talk about how we optimize breast imaging in early-stage breast cancer survivors, because there's such a wide variation in breast cancer imaging survival protocols between different centers and different countries. And of course, here our group is representing two countries and really a broad geographic area. So some of the variations are when to do imaging in terms of frequency, when to start imaging and what kind of examination to do, screening versus diagnostic, MRI versus mammogram. And of course, there are some emerging imaging techniques as well. Could you tell us a little bit about the variation in imaging surveillance protocols in survivors, and the challenges and what you recommend?
Dr. Diana Lam: First off, I want to say that surveillance mammography saves lives and annual intervals are uniformly recommended among both national and international guidelines. However, we know that in practice there are variations in imaging surveillance protocols, with approximately 40% of sites performing imaging at more frequent or six-month intervals for at least one to two years. In addition, there's variation in what type of mammogram someone gets in terms of the indication. They might be getting initial diagnostic mammograms for a short period of time or screening mammograms. However, overall, there is limited evidence in improved outcomes in women getting a diagnostic versus a screening exam for asymptomatic surveillance. In addition, there is limited evidence in increased frequency of surveillance, for example, every six months versus one year.
The real difference between a screen and a diagnostic mammogram, if someone is asymptomatic in the surveillance population, primarily has to do with workflow. For screening examinations, the imaging is generally viewed after a patient leaves the facility, and it might actually take days, maybe even weeks, for the results to be delivered to the patient. In addition, if more imaging is needed, the patient will need to return back to the facility, which does diagnostic imaging work for us to work up this finding. And this practice approach causes diagnostic delays in care. It also disproportionately affects Black and Hispanic women. For diagnostic mammography surveillance, there's generally real time interpretation with immediate results. However, there are both access and scheduling limitations, as not all facilities actually perform these types of examinations. There may also be out of pocket costs which are increased due to the diagnostic indication of this exam.
So what we found, which is an approach that can aid in minimizing patient costs and decreasing these health disparities, is to provide immediate interpretations of these screening mammography surveillance exams, or so-called online screens where diagnostic workup and potential biopsy can be performed on the same day.
Dr. Hope Rugo: This is all very interesting, but what do we tell our patients? How do we, as oncologists, decide on how frequently to get mammograms? Should we be getting diagnostic or screening? And do we sequence MRI with mammograms for everybody or just for certain patients? And then some patients will say, “Well, my doctor does an ultrasound to mammogram.” We don't do that for screening. When do you recommend that?
Dr. Diana Lam: We do know that compared to people without a personal history of breast cancer, surveillance mammography is actually less sensitive. It's only about 70% versus 87% or so percent sensitive with over four times more interval cancers or cancers diagnosed after a negative surveillance mammogram compared to the general screening population without a personal history of breast cancer. In addition, about 35% of invasive second breast cancers are actually interval cancers or those not detected by surveillance mammography. However, there is currently no guideline consensus on supplemental breast imaging or additional imaging beyond surveillance mammography. Contrast-enhanced breast MRI is most often recommended, particularly for patients who are already at high risk for breast cancer, such as those with genetic mutations, or patients who have had primary breast cancer diagnosed at a younger age to less than 50 years old, or those patients who have dense breast tissue on mammography.
There is a question about whole breast ultrasound and this is generally not specified or recommended unless the patient is unable to undergo breast MRI. This is primarily due to the number of false positive examinations or findings that are seen that do not amount to breast cancer. We do have the opportunity here to tailor surveillance imaging by selecting people who are at high risk for interval second breast cancers in order to decrease harms and improve patient outcomes. We know that there are a number of factors such as primary breast cancer subtype which affects second breast cancer risk. We know that women who have ER negative and/or hormonal negative breast cancers have significantly higher recurrence rates within the five years of treatment with no significant difference after that 5 years. We also know that there are certain factors such as imaging factors where patients are more likely to develop an interval second cancer with mammography surveillance only. And these are factors such as if their primary breast cancer was hormone negative, if they had an interval presentation to start, or if they had breast conservation without radiation therapy. So, in terms of the future of local breast imaging surveillance, this can be improved with upfront risk prediction and stratification based on the patient, primary breast cancer and treatment factors, as well as looking at imaging test performance to optimally guide the modality and frequency of surveillance imaging.
Dr. Hope Rugo: Really interesting.
Well, thank you all three of you for sharing your valuable insights. This has been so interesting and a great addition to the ASCO Daily News Podcast. I would encourage everyone to actually read the article as well because there's some really great tables and interesting information there that of course we don't have time to cover, but thank you, all three of you.
Dr. Diana Lam: Thank you.
Dr. Mitchell Elliott: Thank you for having us.
Dr. Hope Rugo: And thank you to our listeners for joining us today. You'll find a link to the article that you can read and look at and cut out the tables discussed today in the transcript of this episode. I encourage all of our listeners also to check out the 2024 ASCO Educational Book where there is an incredible wealth of useful information. Finally, if you value the insights that you've heard today and here on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thanks again.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinion of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Follow today’s speakers:
Dr. Hope Rugo
@hoperugo
@MitchElliott18
Dr. Sherry Shen
@SherryShenMD
Follow ASCO on social media:
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Disclosures:
Dr. Hope Rugo:
Honoraria: Mylan/Viatris, Chugai Pharma
Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Sanofi
Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Hoffmann-LaRoche AG/Genentech, Inc., Stemline Therapeutics, Ambryx
Dr. Diana Lam:
No relationships to disclose
Dr. Sherry Shen:
Honoraria: MJH Life Sciences
Research Funding (Inst.): Merck, Sermonix Pharmaceuticals
Dr. Mitchell Elliott:
No relationships to disclose
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Dr. Nathan Pennell and Dr. Christopher Booth discuss Common Sense Oncology, a global initiative that aims to advance patient-centered, equitable care and improve access to treatments that provide meaningful outcomes.
TRANSCRIPT
Dr. Nate Pennell: Hello. I'm Dr. Nate Pennell, your guest host today for the ASCO Daily News Podcast. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center, and I also serve as the editor-in-chief of the ASCO Educational Book. My guest today is Dr. Christopher Booth, a professor of oncology and health sciences at Queen's University in Kingston, Ontario, where he also serves as the director of the Division of Cancer Care and Epidemiology. He joins me today to discuss his recently published article in the 2024 ASCO Educational Book titled, “Common Sense Oncology: Equity, Value, and Outcomes that Matter.” Dr. Booth also addressed this topic during a joint ASCO/European Cancer Organization session at the 2024 ASCO Annual Meeting.
Dr. Booth, welcome. Thanks for joining me.
Dr. Christopher Booth: Thanks for inviting me here, and I look forward to our conversation.
Dr. Nate Pennell: In your article in the Educational Book, and again, thank you so much to you and your co-authors for writing that for us, and during your presentation at the ASCO Annual Meeting, I think your topic really resonated with a lot of people. You explained that the essence of oncology is delivering compassionate care, and I really was struck by the statement, “the treatments need to provide meaningful care, meaningful improvements in outcomes that matter regardless of where the patients live.” Can you just tell us what exactly is Common Sense Oncology? What's your vision for what it can do to help address some of our growing challenges today?
Dr. Christopher Booth: Thanks, Nate. So, the Common Sense Oncology initiative was launched just over a year ago, and it really was a grassroots gathering of clinicians, policymakers, academics, as well as patients and patient advocates who recognize that there's many things we do well in the current cancer care system, but there's also areas that we can improve. And so it was created as a space for us to advocate for greater access for the things that we know really help people, but also to create a space where we can be willing to have some tough conversations and some humility and look within our field at some of the things that maybe aren't working as well as they should, and try to be constructive and not just be critics of the system, but actually be solution-focused and to try to move things forward. The Common Sense Oncology initiative, which has really taken off over the last year, really brings together people from all health systems who care deeply about people and their families who are with cancer. And our mission is that cancer care systems deliver treatments that have outcomes that matter to patients. And the vision is that, as you stated in your introduction, regardless of where someone lives, they have access to those cancer treatments which really do make a difference in their lives.
Dr. Nate Pennell: That certainly sounds like something everyone should be behind. Before we talk about some of what Common Sense Oncology may be doing to help address some of the inequities in cancer care, one of the challenges that is addressed in your paper is the focus on modern clinical trials and perhaps some of the mistakes that we're making in how they are designed. In many ways, we sort of live in a golden age of clinical trials with biomarker driven treatments, which can be incredibly effective in small populations of people, sometimes at great expense. So, focusing on our modern clinical trials, some of the criticisms that have arisen are that perhaps the endpoints that are being designed really aren't ones that are meaningful for patients, or that the gains that they're trying to look for in these trials may not be particularly meaningful. So, talk a little bit about that, if you might.
Dr. Christopher Booth One day, I might write a book called Paradoxes in Cancer Care. But there's a number of these things I think about. I'll start, Nate, in response to your question by talking about something I think of called the ‘three buckets paradox.’ The three buckets paradox, I think, reflects a communication failure on the part of our field whereby if a patient or member of the public only reads the newspapers about cancer, they might wonder why we even have cancer hospitals and why Dr. Pennell and Dr. Booth even have a job, because everything we're doing is curing cancer. But we know the reality is different. And so, I conceptualize cancer treatments as going into three different buckets. We have the red bucket, which are those treatments, which really are transformational, and I've been working in oncology for 20 years now and we've seen a number of these treatments. They markedly increase cure rates or help people live for many, many months or extra years of life. And we have those treatments; they're almost out of a science fiction movie. The green bucket is a series of treatments. They're not perhaps transformational, but they're very, very good. They offer substantial benefits to our patients, and we have quite a few of those.
The concern that I think many of us recognize, and just to state emphatically that the problems that CSO is thinking about are not new problems; I think every oncologist has struggled with these things throughout each of our own careers. The concern is the third bucket, which includes many of our newer treatments, some of which, of course, are transformational. But many of the new treatments fall into this bucket, which have important side effects. They have major financial toxicity for patients' families and the system. They have time toxicity, especially in the last year of life. And the reality is most of these new treatments, either there's no proven benefit they help people live longer or better lives, or if they do, it's measured in a number of weeks. I think we need to reconcile the fact that we need to maybe speak honestly about some of the challenges in our field to recognize there's probably too many treatments going into that last bucket, and we need to push harder in the research ecosystem and the policy space to ensure we have more treatments in the first two buckets and that they remain widely available to everyone.
So, to get to the specific issues you raised in your question, Nate, some of the effect sizes and the endpoints we're choosing are problematic, I think. We have many, many examples of incredible clinical trials and new treatments that really make a difference for the lives of our patients. I want to state emphatically that the RCT remains the best tool we have to identify new treatments for patients of tomorrow, and any challenges with clinical trials, actually, it's not the fault of the RCT; these are self-inflicted by us who design, interpret, and act on clinical trials. And so the use of surrogate endpoints is a major issue in our field. And I just want to also state emphatically that there are circumstances where surrogate endpoints make a lot of sense and we should be using them. The problem is, I think with our excitement to get treatment answers more quickly, we've really embraced surrogate endpoints in a very, very rapid way. And in fact, I shouldn't even refer to them as surrogate endpoints. Maybe we should use the term alternative endpoints because in many cases they have been found to not be valid surrogates for those things which we know matter to patients: overall survival and quality of life. So certainly, there's a place for surrogate endpoints. I think we live in an era now where the majority of clinical trials are being designed to detect improvements in progression-free survival rather than overall survival. So historically, most clinical trials were being launched to see if we could help people live longer or feel better.
Now, the default endpoint is progression-free survival, which largely is based on tumor measurements on a CAT scan. And certainly, there are circumstances where those tumor measurements do relate to how someone feels or how long they live, but in most circumstances, that's not the case. I think we need to take a step back and just see the big picture here about where it is that we're going, and how can we raise the bar and ensure that we're identifying treatments that really offer meaningful gains to patients. Because we have to be honest about the fact that the patients and families are the ones who need to live through the side effects, the time toxicity and financial toxicity of these treatments. So, this is about maybe raising the bar and aiming a bit higher than we currently are.
Dr. Nate Pennell: And it looks like CSO basically is putting together teams around evidence generation, evidence interpretation and evidence communication that I guess, is trying to advocate and influence this?
Dr. Christopher Booth: Yeah. So, when we launched this initiative, which now is this large global coalition of people, we wanted it to be really solution focused. So, our workstream is oriented around trying to improve how we generate evidence, how we interpret evidence, and how we communicate evidence. So, the evidence generation workstream is being led by a series of leading clinical trialists from all over the world, together with patients and patient advocates who are looking at how we can come up with a framework and principles to design, perhaps a more thoughtful approach to the design, reporting, and conduct of clinical trials. So that's kind of a clinical trials workstream. And I should mention all of these project teams are populated by clinicians, academics, members of the public, as well as patient and patient advocates who, in some cases, are co-leaders of the workstreams.
The evidence interpretation workstream is an educational bucket being led by clinicians and educators, together with patients, to see how we can improve the skill set of the next generation of oncologists to be better equipped in skills and epidemiology, critical appraisal, and critical thinking, so we can better dissect trials which have been well designed from those which might have some limitations, identify those treatments which have very substantial gains from those which are perhaps more marginal. And then the third workstream relates to how we communicate evidence. And this is communication broadly, how we talk about these very complex and nuanced issues at the bedside between oncologist and patient. But how we talk more broadly in society, through the media, with public and policy makers, about some of the challenges in cancer care, recognizing, of course, that no one individual, group or person is going to have the answer for what treatments matter for any specific patient. This is going to vary by every patient with their unique values, preferences and goals in life. But we think we can do a better job of talking about these issues and empowering patients to have the information they need so they can make the treatments that match their own goals and wishes.
Dr. Nate Pennell: Oh, thank you. Another thing that I was interested in in your paper, and when we talk about value and whether these endpoints that are being released for drugs that become approved are meaningful to patients, the other aspect of value is, of course, the cost. And we know that basically every new drug that gets approved, just an astronomical cost these days, which doesn't often factor into whether to approve them. It doesn't often factor into a doctor's decision about whether to use them. Can you talk a little bit about this? And is cost of drugs something that CSO is interested in addressing, or is that more of just a part of the equation in determining value of these?
Dr. Christopher Booth: No, I think it's a really important point. So the value construct, I'm not an economist, so I think about this as a simple Canadian chemotherapy doctor would, which is the interface of what you get - so the magnitude of benefits, that's the endpoint, and the effect size - relative to the downsides, the cost, the clinical toxicity, time toxicity, and financial toxicity. So historically, I mean, I think, Nate, you and I will remember maybe 10 or 15 years ago when this really came on the scene, all the conversations focused on the denominator, the cost of cancer medicines, which became astronomical over the last 10 or 20 years. And we've learned a few things about that over time, and I'll get to that in a moment in reference to your question. But I think as individual clinicians or investigators, or even people writing guidelines, we don't have a lot of ability to influence the price of cancer medicines, although I think we still need to speak out about these prices, which are largely unjustified. I'll come back to that. But where I think there's growing interest, and we've seen this in the last five years, is the numerator in that value construct, which is the magnitude of benefit, the endpoint, the effect size. And I think that's where we actually have much more ability to influence. We are the doctors who make treatment recommendations, the experts who write guidelines, the investigators who design trials and so I think we need to take a bit more ownership when it comes to this magnitude of benefit construct. And that's where a lot of the work that Common Sense Oncology is doing rests.
But to answer your question about cost, this is a major problem. We've known that it's been shown by several groups that the price of a cancer medicine is not justified by the R and D cost, that's been shown over time. We also have a problem where the magnitude of benefit offered by that drug also has no bearing to the price. And so this speaks to the need to really, I think, undertake more rigorous health technology assessment and think very carefully about- you know every other economic model that you and I live in, Nate, if, you know, if we have a growing family, we need a larger apartment or house, we spend more money, we get a bigger house. If we want to keep up with our kids on their fast bicycles, we spend more money, we get a better bicycle. And when it comes to cancer medicines, we found that not only is there no relationship between how well the drug works and its price, our group and others have found, if anything, there's an inverse relationship, whereby the drugs with the smallest benefit have the largest price tag. And I don't think you need a PhD in economics to know that is an incredibly broken system. So, I think there's a lot that we need to talk about when it comes to cost. Common Sense Oncology cares deeply about this because it's a huge issue about health justice and global equity and access to cancer medicines. And I think we need to work on that. But we also can't forget about the numerator, which is, to what extent do these treatments help people?
Dr. Nate Pennell: I know that every time I see one of these fabulous new presentations at ASCO Plenary or something like that, I just imagine many of the doctors and patients who live outside the U.S., maybe in low- and middle-income countries, who don't have the same access to basic oncology care and specialty oncology care that we do in Western countries, and what goes through their minds when they think about this. And so, I know that this is another big part of what CSO is doing, is thinking about global equity and access to cancer care. And so, can you tell me a little bit about how you're hoping to address that?
Dr. Christopher Booth: Yeah. And so, you're right. I guess I'll tell you another Booth cancer paradox. I call this the cancer medicine paradox, which is, on the one hand, in many health systems, I think we'll recognize that there's often overutilization of cancer medicines that are toxic, expensive, and small benefits, especially in the last year of life. So, we have that kind of overutilization paradigm in some parts of the world, but we also have this paradox where we have massive underutilization of those treatments that we know actually have large benefits. And the tragic part of this is many of those treatments are old, generic drugs that actually should be very affordable. Some of this work comes out of myself and a number of my founding colleagues of Common Sense Oncology have a policy role with the World Health Organization Essential Medicine list. My interest in this started, I guess, many years ago when I had a sabbatical in India and lived and worked at a large government cancer hospital for a period of time. And so, from this WHO working group, we launched a project. It's been called the Desert Island study. It was called the Desert Island Project for reasons I'll tell you in a moment. But essentially it was a survey of 1,000 oncologists on the frontlines of care in 82 countries worldwide. And what we are interested in doing is in our role as an advisory group to the WHO Essential Medicine List, we come up with a list of those medicines which are really most important and should be provided in all health systems. And we were interested in going to the frontlines of care, leaving the boardroom of Geneva, and going to the frontlines of care and asking real doctors in the real world, “What medicines do you think are the most important for the patients that you look after?”
So, it was a survey. We asked a lot of demographic questions about their clinical practice and their health system, but we called it the Desert Island Project, because the core question of the survey was based on the thought experiment that you and I have done many times with friends at dinner parties. For example, if you're moving to a desert island and you could only take three books, what would those books be? If you're going to have dinner with any famous podcast host in the world other than Dr. Pennell, who would that person be? And so the thought experiment was, imagine your government has put you in charge of cancer care for your country. You can choose any cancer medicines you want that will be freely available for all cancers and all people in your country. Cost is not an issue, but you can only choose 10. You can only choose 10 of those medicines to take to the desert island to look after all the people in your country, what would those medicines be? And it's amazing; of those thousand oncologists, we found, first of all, remarkable convergence between doctors, regardless of where they work, whether it was a high-income country, middle-income country, lower-income country, the doctors were very pragmatic. When we looked at the drugs that went in that suitcase over and over again, the most common drugs were the good old fashioned cytotoxic chemotherapy drugs and hormone drugs we've been using for 20 or 30 years that we know have very, very large benefits, and in the modern era now should be very affordable because they've been off patent for many years.
In that list of medicines that went to the desert island, there also were some of our newer drugs that are new and they're very expensive. But they are those drugs that have very large benefits. And, of course, all of us would want access to those for our patients. So we found that the doctors are pretty pragmatic about which medicines if they're pushed to offer the largest benefit. But the next part of the question was, okay, you've told us which medicines you want to put in your suitcase to take to the desert island, please now tell us the reality in your health system to what extent can you deliver these medicines? And it was shocking. The vast majority of oncologists, a huge number of them, said they could not even provide doxorubicin or cisplatin without causing major financial toxicity for that patient and family. Even for trastuzumab, now available as a biosimilar, only 15% of oncologists globally said they could provide it universally to all women with breast cancer. Two thirds of oncologists said, “Look, I can give it, but I will catastrophically ruin that patient's family's finances for generations to come.” So, we have a big problem in the sense that we need to focus on those treatments which make a big difference and ensure that they're available to all patients who could benefit, while at the same time raise the bar so that the modern treatments that we're offering also have large benefits.
Dr. Nate Pennell: I think that's really eye opening, and I hope lots of people take away from this, that this is the reality for a huge number, potentially billions of people on the planet that don't have easy access to the same kinds of drugs. We're not even necessarily talking about the expensive drugs with the three-week DFS benefit, but ones that actually could be curing them of their breast cancer and their testicular cancer and their lymphomas, and they can't even get access to those, even though here we might say that they're inexpensive and relatively accessible. So how do we fix that? Maybe this is too big a question for a few minutes in a podcast, but I'm curious to see what CSO is doing to try to help.
Dr. Christopher Booth: Well, the challenges are substantial, and so that's why we've kind of created this group, because it's going to require kind of collective input, I think, of everyone in our field and beyond. And I also think, one of the reasons we've been overwhelmed with interest by the next generation, the young, the trainees, the young oncologists who are very interested in this, and I think they're recognizing that this might be an alternative place for them to put their energy, talent, as they build their own academic careers, is tackling some of these really, really tricky problems where the solutions are not immediately obvious. One thing I think, Nate, that's important is for us to talk about these things and recognize that there's a range of cancer treatments, and that this might help set better expectations for the patients and families when they walk into our cancer centers, let alone in the U.S. and Canada, but also globally. We've seen challenges with all of us as human beings are technophiles, we’re drawn towards the new shiny targeted therapy or a robot or treatment in cancer care, and we've seen that play out somewhat tragically. Some of my friends and colleagues in LMICs have told stories where the Minister of Health is about to make a major investment in cancer care, but they want the shiny new monoclonal antibody, because that's perceived as being newer and better, when the reality is that that might add two months of PFS compared to other agents that are much, much- have much larger benefits and, of course, are much more affordable. And there's modeling where even just one of these new medicines, for one cancer, would wipe out the entire cancer medicine budget for that country. Yet we don't have tamoxifen, doxorubicin, cisplatin or even morphine for palliative care available. So, some of this is about socializing these issues, talking about these things that, again, these are not new problems. I think every oncologist worldwide has wrestled with these things, but just at least creating a space where we can talk honestly about this and work towards solutions.
Dr. Nate Pennell: Yeah, I think even just having the framework and the awareness and getting people involved is going to make a big difference. And of course, the people who ultimately are impacted the most by this are the patients with cancer. One of the big aspects in your paper is talking about how patients and patient advocates are central to the CSO movement. So, tell me a little bit about how they became involved and what role they play in CSO.
Dr. Christopher Booth: Yeah, so this has been a very intentional and deliberate part of the building of the Common Sense Oncology initiative. So this started with a planning meeting of- a very small planning meeting of 30 people in Kingston, here at Queen's University just over a year ago, with 30 people from 15 different countries, a mix of academics, clinicians, editors, and in that room were five or six patients and patient advocates from day 1, because we wanted to make sure that this is really all about their needs and creating a system that revolves around the outcomes that matter to patients and families. So since then, we've continued to engage broadly. We have a patient priorities project team. There's co-leadership there. One is a colleague and oncologist from New Zealand, but the other co-leader is a patient advocate from- a breast cancer patient advocate from the United States. And all of our project teams have patients and patient advocates as part of their membership. The Patient Priorities Team is working to design a patient charter to guide the design and implementation of clinical trials from the patient's perspective. And as part of that exercise we've been undertaking, we call the CSO speaking and listening tour, where we've had a series of webinars with patient advocacy groups from all over the world, where part of the webinar is us talking about the CSO mission vision, workstream and some of the challenges and solutions we see so that we can provide some education, but also get honest feedback from the front lines to learn kind of where we might be off, what we might be missing, what we should focus on. But then also, the second part of the webinar is about sharing this kind of draft patient charter and getting more broad input from patients and families about what it is they're looking for in a cancer system. And I can tell you that some of the most gratifying correspondence I've had since launching CSO, which has been essentially become my third full time job, is letters from patients and family members of former patients who have since deceased or active patients on treatment, who are saying how much they appreciate this work and how much they feel that oncology can perhaps do a better job talking about some of these things. And they've been giving us some very good ideas and suggestions that, in fact, I'm already incorporating into my clinical practice, because ultimately all of us came into this field to help people with cancer, and I think they can and should and are remaining the center of everything.
Dr. Nate Pennell: I think, thankfully, that is a movement throughout medicine, certainly cancer medicine, that patients are becoming more involved much earlier in the process of designing trials. And hopefully that alone will help change the endpoints that we're building into these studies to make them much more meaningful.
So, people are going to read your paper, they're going to get excited, they're going to listen to this podcast, they're going to get even more excited about how they're going to change the world through a little more common sense. So how can they get involved? Is this something that you're open to people working with you? Are there other things people can do to try to help solve some of these frustrating problems?
Dr. Christopher Booth: Yeah, absolutely, Nate. So, we have a website at commonsenseoncology.org. Some of our co-leaders are very active on social media, so they can follow us through social media channels. If you go to our website, there is a membership button where people can join. There's no fee and we won't bombard you with too many emails. But what that has allowed us to do is build this network of people who have diverse interests and skill sets that we can then tap into various projects and workstreams where we could use the help and support. And members have access to things like virtual webinars, journal clubs, critical appraisal sessions, and they get a newsletter from us every two or three months about activities and about ideas and allow exchange of dialogue going back and forth. So certainly, we look forward to growing this initiative, and the challenges are large, but we think that with the collective input of stakeholders from around the world, we could make a difference in moving towards some solutions.
Dr. Nate Pennell: And for our listeners, that is commonsenseoncology.org. You can go check this out and join if you are interested in learning more.
Chris, thanks so much for sharing your insights and for all of your work on addressing these complex challenges in cancer care.
Dr. Christopher Booth: Thanks, Nate. Grateful for the interview and also for ASCO for giving us the opportunity in the Educational Book and at the Annual Meeting to talk about this work.
Dr. Nate Pennell: Thank you. And I also want to thank our listeners for joining us today. You'll find links to the article discussed today, as well as Dr. Booth's presentation at the Annual Meeting, in the transcript of the episode. Finally, if you value the insights that you heard on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Find out more about today’s speakers:
Dr. Nathan Pennell
@n8pennell
Dr. Christopher Booth
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Disclosures:
Dr. Nathan Pennell:
Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron
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Dr. Christopher Booth:
No relationships to disclose
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Dr. Pedro Barata and Dr. Lillian Siu discuss recent advances in cancer vaccines and biomarkers, including the potential of the neoantigen and immune modulatory vaccines and the challenges surrounding cancer vaccine development.
TRANSCRIPT
Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host for the ASCO Daily News Podcast today. I'm a GU medical oncologist at the University Hospitals Seidman Cancer Center in Cleveland, Ohio, and an associate professor of medicine at Case Western Reserve University School of Medicine. I'm also an associate editor of the ASCO Educational Book. And today we'll be discussing a timely article that was recently published in the Educational Book titled, “State-Of-The-Art Advancements on Cancer Vaccines and Biomarkers.”
I'm delighted to welcome one of the article's co-authors and a world-renowned oncologist, Dr. Lillian Siu. She is a senior medical oncologist and director of the Phase 1 Program at the Princess Margaret Cancer Center and a professor of medicine at the University of Toronto.
Welcome, Dr. Siu.
Dr. Lillian Siu: Thank you, Dr. Barata; it's great to be here.
Dr. Pedro Barata: Wonderful. Dr. Siu will discuss new tools for cancer vaccine development, strategies for combating the immunosuppressive and tumor microenvironment. She will also address cancer vaccine guidelines and patient recruitment strategies to optimize patient selection and access to cancer vaccine trials. I should say that Dr. Siu and her co-authors also addressed this topic during an Education Session at the ASCO 2024 Annual Meeting.
Finally, our full disclosures are available in the transcript of this episode.
So again, Dr. Siu, great to be speaking with you today. I'm looking forward to our discussion.
Dr. Lillian Siu: Thank you, Dr. Barata. And before I begin, I want to acknowledge Dr. Jeffrey Weber and Dr. Inge Marie Svane, who both presented during the ASCO session you mentioned. They gave excellent presentations related to the topic of neoantigen vaccines and immune-modulatory vaccines, which we will talk about later.
Dr. Pedro Barata: Wonderful. So let's get started. Cancer vaccines are among the most promising frontiers for breakthrough innovations and new strategies in the fight against cancer. The successes in vaccine development during the COVID-19 pandemic, I think, inspired further research in this area. Why do you think it's important that we harness these recent successes and technological advances to really accelerate progress in vaccine development?
Dr. Lillian Siu: Absolutely. I think all of us who have lived through COVID really appreciated how important the COVID vaccine development was to all of us. It saved millions of lives. And I think we witnessed a paradigm change in drug development that none of us thought was possible, that we're able to actually bring a concept to a drug from bench to bedside within an extremely short time. That timeline is not something we would ever imagine to have happened, and it did. And I think it gives us hope that perhaps this is not just limited to the COVID vaccine; it's also extrapolatable to other therapeutics – that we can bring promising medicines to our patients in a really expedited timeline, obviously without compromising their safety.
We now know that cancer vaccines have entered a new, or maybe I should say, renewed era of promise. And it's holding promise on many fronts, Pedro, if I may. It's very exciting in the area of molecular residual disease. In other words, a setting where the cancer is treated definitively by surgery or radiation, plus adjuvant treatment. And we know some patients will relapse because we know they're at high risk. And now we also have different ways to detect these microscopic risks, such as by ctDNA, circulating tumor DNA, or biomarkers. And we know that having some therapeutic that can eradicate these cancers at such microscopic levels would be very attractive, especially with low toxicity, and I think cancer vaccine is such a candidate. And of course, we can even look further into the future of using such treatment in cancer prevention, especially in those with high risk of developing cancer, for example, those with hereditary syndromes like lynch syndrome. We're not there yet, but I think it holds that promise.
So I think, going back to your original question, if we can develop such a therapeutic that is showing promise in a very short period of time, it brings the timeline and the hope to a much shorter timeframe to really deliver to our patients in a very timely manner while safeguarding all the important parts, such as safety and tolerability.
Dr. Pedro Barata: Wow, those are such important points. I couldn't agree with you, more. It’s really exciting. As I think through this, and as I was reading through your piece, I was thinking it would be great if you could highlight some of the novel approaches to personalized neoantigen vaccine development that are driving progress in this space.
Dr. Lillian Siu: Absolutely. And during the session, Dr. Weber spoke about the neoantigen vaccine, and he's a pioneer in this space. So I can only try to iterate some of the points he had delivered during his talk. Neoantigen is a very exciting space for immunologists because we know that tumors express these neoantigens. Many of these are unique antigens that are only expressed in tumors, so-called tumor specific antigens, that we can use as our targets, including vaccines, but not limited to vaccines. And with these altered sequences in DNA in different forms, they could be mutations and splice alterations, etc. We expect that we have modified proteins that are expressed by tumor cells, and these become targets for our drug development of vaccines. And now we can have very specific strategies, very sophisticated algorithms to figure out which neoantigens are more so called immunogenic, more likely to stimulate or activate the immune system, and they can be recognized by T cells. So leveraging this knowledge and technology, we have been able to develop especially mRNA vaccines that are deliverable to our patients through different mechanisms, for example, in lipopeptides, etc., so that we can deliver to the patients in a safe way, such that we can use it to deliver vaccines, such as in the MRD setting that I mentioned earlier, as well as in the advanced disease setting.
So Dr. Weber, in his presentation, highlighted one of such vaccines that have been tested in a randomized controlled trial that is KEYNOTE-942, which randomized 157 patients to the mRNA vaccine plus pembrolizumab versus pembrolizumab alone in patients with advanced melanoma. This is a vaccine against 34 mutated neoantigens, and it showed a significant difference in the recurrence free survival with a hazard ratio of 0.56. And if you look at the 18-month relapse free survival rate, it was 78.6% versus 62.2%. Obviously, these are still fairly early data and numbers are still small. I think we would definitely look forward to the randomized phase 3 study of neoantigen vaccine in melanoma and other cancers.
Dr. Pedro Barata: No, absolutely. And I agree, it's really exciting. Dr. Weber did a fantastic job going through some of that data.
So let me ask you Dr. Siu, as you think about this cancer vaccine field, what are the limitations that you'd highlight when you think about cancer vaccine development? What challenges do you encounter, obstacles do you encounter?
Dr. Lillian Siu: There are many, many potential challenges. And to some extent, that's probably why cancer vaccine development has been somewhat slow for the many decades until more recently. We know first of all; the target has to be recognized. So we need immunogenic targets. So I think a lot of the effort has been put into trying to understand which antigens expressed by cancer cells are immunogenic, able to activate the immune system. They're obviously assay based methods. You're going to try and see if you can ex vivo stimulate immune cells on dishes and models, etc. But we need to also develop in silico computerized algorithms, and now with AI, I think that makes it even more tangible and exciting that we can actually understand through a large number of neoantigens or other antigens, whether we can choose the ones that are most likely going to actually stimulate T cells to be activated. And I think that is one area that there is a lot of interest in development, how to really develop ways to select out the most attractive antigens.
I would also want to highlight that the platforms, which is how we deliver the vaccine, can also pose significant challenges. For example, vaccines can be delivered using peptide-based formulation, cell-based formulation, nucleic acids and viral vectors. For some of these formulations, for example, the peptides very often are restricted to HLA. They can be rapidly degraded in the body, such that they become not really visible to the T cells anymore. Some of the formulations can be very complex. For example, the cell-base; it may need to have cells isolated from patients, cultured, stored and transported to the site of delivery, which can be very complex. For some of the nucleic acid vaccines, they can have very low transfection efficiency. It could be at risk for also having, for example, DNA vaccines integrated into the host genome. And then lastly, there's also the immune suppressive environment in the TME, such that it does not really have the effect when you give it repeatedly. It becomes attenuated and no longer effective. So these are some of the challenges associated with cancer vaccines.
Dr. Pedro Barata: Thank you for that summary. I think it's really important for folks out there, including researchers getting into this field, to be aware of potential obstacles they might encounter.
So let me ask you the opposite question as we see more compelling preclinical and clinical data emerging in this field of vaccine development, what is really exciting you the most about the newest technologies that are shaping the future of cancer vaccines, in your opinion?
Dr. Lillian Siu: I think one I want to highlight is the immune-modulatory vaccine that Dr. Svane, Dr. Inge Marie Svane had presented during the presentation at ASCO. This is a completely different strategy from the neoantigen vaccine. It targets antigens in the tumor microenvironment. And we know that in the tumor microenvironment, we have tumor cells, we have immune cells, and there are many types of cell types, including, for example, macrophages, cancer associated fibroblasts, regulatory T cells, etc. And using these particular cell types, we know that we can really develop vaccines that can stimulate the body's immune system to attenuate, to downgrade some of the negative factors in the tumor microenvironment. And this is what Dr. Svane and her group is trying to do. For example, they have an IDO vaccine that is able to actually target these antigens in the tumor microenvironment, and by that, not just suppressing the negative forces, so to speak, but also activate T cells to help attack cancer cells. I think that's a very interesting area. Very early promise has been seen already in non-small cell lung cancer in early phase trials using the immune-modulatory vaccine.
But going back to your question, what kind of advances; I mentioned earlier about having novel ways to select our antigens that are most immunogenic. There are many algorithms that are being developed, and I think we can try and leverage that kind of knowledge from artificial intelligence, machine learning. So I think that's definitely very exciting. There are also new vaccine platforms coming out. For example, there's recent data using modification of peptides, so called amphiphile vaccines, that already show very early promise in colorectal cancer, microsatellite status, colorectal cancer, as well as in pancreatic cancer in the molecular residual disease setting, where these long peptide vaccines targeting KRAS mutants together with adjuvant oligonucleotide DNA, combined together, can actually be given to patients and reduce the chance of cancer relapse in patients with resected colorectal cancer, as well as pancreatic cancer, with endpoints such as ctDNA or biomarker being downregulated. I think that's a very exciting example.
Another very exciting example is cell-based vaccines that are being developed in Europe by the NKI Netherlands Cancer Institute Group, where they are looking at plasmacytoid dendritic cells that are loaded with peptides from different tumor associated antigens and then given to patients, which, again, in non-small cell lung cancer, together with pembrolizumab, has yielded very high response rate. And we will almost certainly see more trials coming out using that particular platform with the dendritic cells. So that's just some of the examples of exciting things that are happening in the vaccine field.
Dr. Pedro Barata: Thank you. I’m wondering if you can share with our listeners about what really are the existing guidelines for using these new tools for discovery, methods of treatment, and perhaps optimizing patient selection to access trials.
Dr. Lillian Siu: To be honest, the latest guideline that was published from the FDA that I can find is almost 13 years ago in 2011. So I think it is time for a new guidance, or at least a draft guidance, to give some additional support and guidance in terms of what to do with these new treatments from the FDA and perhaps other regulatory agencies as well. I think we're now entering a very exciting time that cancer vaccines are no longer an ineffective therapeutic. It is now showing evidence of efficacy, not just in the advanced setting, but also in the molecular residual disease setting. There're so many questions to be answered, like how to develop these trials in early disease; what's the end point? Can we incorporate them into the neoadjuvant setting, and if so, how do we give these drugs before surgery, and do we give them maintenance after surgery? I think guidance from the regulatory authorities would be extremely helpful and informative to guide academic groups as well as the pharmaceutical sector to develop these agents in the right way.
Dr. Pedro Barata: Dr. Siu, this is a fantastic summary, and we certainly are on the cusp of a new dawn of discovery and development in cancer vaccines, and super interesting to hear from you talking about it. Before letting you go, do you have any final thoughts that you'd like to share with the listeners, with all of us about this topic?
Dr. Lillian Siu: I think as a drug developer like you are, I'm extremely excited because we now have yet another way to leverage the host immunity as a cancer therapeutic, and it is going to be opening a new door to combination therapy because we can imagine combining these treatments with other immunotherapeutics such as bispecific molecules such as CAR Ts and even vaccine plus vaccine combination is feasible. That came up actually during the session as a question from the audience. Can we combine neoantigen vaccines and immune-modulatory vaccines together? And both of our speakers who presented felt that it was possible. Obviously, we have to understand the sequence question and the endpoints question, but the fact that it opens a new door to combinatorial therapy, not just with immunotherapeutics, but perhaps with other therapeutics as well, antibody drug conjugates, etc., really, I think, is very exciting for this field to become further explored.
I mentioned earlier in the podcast that the whole area of cancer prevention is something that we have not been tapping into for the last decade with vaccines because it has not been very effective. Viral vaccines, of course, HPV and other vaccines targeting viruses, but targeting cancer cells is not something we have been successful using vaccines to prevent cancer from developing. I think we would be very interested to see if this will become a reality in the next decade. I think we would start off with patients with high risk of developing cancers such as, as I mentioned earlier, those with lynch syndrome, those harboring BRCA alterations, for example. Can we use these vaccines to actually prevent the cancers from developing in such high-risk individuals? I think the field is definitely open to that consideration.
Dr. Pedro Barata: Definitely. And I'd like to thank you, Dr. Siu, for sharing these great insights with us today on the ASCO Daily News Podcast.
Dr. Lillian Siu: Thank you so much for your time.
Dr. Pedro Barata: And thank you to all the listeners for your time today. You'll find a link to the article discussed today in the transcript of this episode, and I encourage you to check out the 2024 ASCO Educational Book. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So again, thank you so much for your time and see you soon.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Disclosures:
Dr. Pedro Barata:
Honoraria: UroToday
Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon
Speakers’ Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas
Research Funding (Inst.): Blueearth, AVEO, Pfizer, Merck
Dr. Lillian Siu:
Leadership (Immediate family member): Treadwell Therapeutics
Stock and Other Ownership Interests (Immediate family member): Agios
Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen
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Dr. Neeraj Agarwal and Dr. Rana McKay discuss promising studies in GU cancers featured at the 2024 ASCO Annual Meeting that highlighted improved outcomes in urothelial carcinoma, improved survival in renal cell carcinoma, and the role of ctDNA as a potential biomarker for predicting outcomes.
TRANSCRIPT
Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I’m Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah’s Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News.
I am delighted to welcome Dr. Rana McKay, a GU medical oncologist and associate professor at the University of California San Diego. Today, we’ll be discussing some key GU abstracts featured at the 2024 ASCO Annual Meeting.
Our full disclosures are available in the transcript of this episode.
Rana, we’re thrilled to have you on the podcast today to share your insights on key advances in GU oncology from ASCO24.
Dr. Rana McKay: Thank you so much, Neeraj; it’s a pleasure to be here.
Dr. Neeraj Agarwal: So, Rana, let’s start with some bladder cancer abstracts. Could you tell us about Abstract 4503, titled “Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer”?
Dr. Rana McKay: Of course, I would be delighted to. First, I would like to remind our listeners that enfortumab vedotin (EV) was approved as a monotherapy for the treatment of locally advanced or metastatic urothelial cancer based on the results of EV-201 and EV-301 trials. In these pivotal studies, EV was initiated at a dose of 1.25 mg/kg, and dose modifications, such as reductions and interruptions, were used to manage adverse events. In the abstract presented at ASCO 2024, Dr. Daniel Petrylak and colleagues conducted a post-hoc exploratory analysis to evaluate the association between EV plasma exposure and outcomes. They used multiple pharmacokinetic samples collected during the first two cycles and pre-dose samples from 3 EV monotherapy studies, namely EV-101, EV-201, and EV-301, that were conducted in patients with previously treated locally advanced or metastatic urothelial carcinoma. Dose reductions to 1 mg/kg were required in 42.1% and 35.1% of patients in the EV-201 and EV-301 trials, respectively, and reductions to 0.75 mg/kg were required in 13.6% and 11.1% in the EV-201 and EV-301 trials, respectively. Higher EV exposure during the first two cycles was associated with a higher objective response rate. The ORR was 21.4% for the dose of 0.75 mg/kg, while it was 18.5% for the dose of 1.0 mg/kg. Interestingly, increasing the dosage to 1.25 mg/kg improved the ORR, which ranged from 40 to 51.1% across various studies. In the EV-301 trial, when comparing the efficacy of EV to chemotherapy, EV improved PFS and OS across all dose quartiles, and there was no evidence that recommended dose modifications impacted long-term efficacy outcomes.
Dr. Neeraj Agarwal: Thank you, Rana, for this great summary. I would like to add that the meticulously conducted pharmacokinetic studies demonstrated that serum levels of EV correlated with responses. Importantly, patients who had to decrease the dose did not experience compromised outcomes as EV improved PFS and OS outcomes vs chemotherapy in across all exposure quartiles in the EV-301 trial where EV was compared with chemotherapy. These findings highlight the need to start at the recommended dose of 1.25 mg/kg and reduce it, if necessary, however, clinicians should not start at a lower dose.
Dr. Rana McKay: I totally agree with you, Neeraj. Now, moving on to a different setting in bladder cancer, what can you tell us about LBA4517, titled “Perioperative sacituzumab govitecan alone or in combination with pembrolizumab for patients with muscle-invasive urothelial bladder cancer: SURE-01/02 interim results”?
Dr. Neeraj Agarwal: Of course! So, SURE was a multicohort, open-label, phase 2 study in patients with muscle-invasive bladder cancer assessing sacituzumab govitecan as a neoadjuvant therapy either alone in SURE-01 or as a combination with pembrolizumab followed by adjuvant pembro in SURE-02 in a flexible design allowing a bladder-sparing approach. In the abstract presented at ASCO 2024, Dr. Antonio Cigliola and colleagues report interim results of the SURE-01 study. Patients with cT2-4N0M0 urothelial carcinoma who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant sacituzumab govitecan at a dose of 10 mg/kg followed by radical cystectomy.
An extensive assessment was performed at baseline and after the 4 cycles for response assessment. Patients with clinical complete response defined with negative MRI, cystoscopy and ctDNA assays refusing radical cystectomy were offered redo transurethral resection of the bladder tumor or repeat TURBT followed by observation in the absence of viable high-grade tumor in the bladder. The primary endpoint was pathological complete response rate, while secondary endpoints included pathological downstaging rate and safety. After the first 8 patients were enrolled, the protocol was amended due to the occurrence of grade 3 and 4 neutropenia and diarrhea in 75% and 50% of patients, respectively, and 2 deaths – one of which was deemed to be treatment-related due to sepsis. Key protocol changes included the reduction of the dose of sacituzumab govitecan to 7.5 mg/kg, the introduction of G-CSF as primary prophylaxis, and the exclusion of patients at high risk of febrile neutropenia per ASCO guidelines.
Among 21 patients who received at least one cycle of sacituzumab govitecan and included in the intention-to-treat population, 47.6% had a complete pathological response, and 52.4% had pathological downstaging. 11 patients underwent radical cystectomy, while 7 received repeat-TURBT due to complete clinical response or patient preference. Regarding the safety profile, grade 3 or more adverse events occurred in 42.5% of patients. Treatment-related adverse events leading to dose interruptions or discontinuations were more common before the protocol amendment. It is noteworthy that 3 patients died after treatment discontinuation, with one deemed treatment-related, as previously mentioned.
Dr. Rana McKay: Thank you, Neeraj, for a great summary. The pathological complete responses observed show promising activity for sacituzumab govitecan as a neo-adjuvant therapy and a window for bladder-sparing approaches, which is definitely exciting news for our patients! However, although the 3 deaths encountered in a neo-adjuvant setting could be concerning, the improvement of the safety profile after protocol amendments is reassuring and supports the continuation of the study.
Dr. Neeraj Agarwal: Before wrapping up the bladder cancer section, would you like to share your insights with our listeners on Abstract 4518, titled “Quantitative circulating tumor DNA (ctDNA) assessment in patients with advanced urothelial carcinoma treated with pembrolizumab or platinum-based chemotherapy from the phase 3 KEYNOTE-361 trial”?
Dr. Rana McKay: Sure. So, the KEYNOTE-361 trial was a randomized phase 3 study with 3 arms that included pembrolizumab plus chemotherapy, pembrolizumab monotherapy, or chemotherapy alone in patients with previously untreated advanced urothelial carcinoma. The results showed that neither the combination of pembrolizumab plus chemotherapy nor pembrolizumab monotherapy improved survival outcomes compared to the chemotherapy arm.
So, in this exploratory analysis presented at ASCO24, Dr. Tom Powles and colleagues sought to assess the role of ctDNA as a potential biomarker between the pembrolizumab monotherapy arm and the chemotherapy arm. Tumor tissue mutations were evaluated using whole exome sequencing, and plasma ctDNA was assessed with the Guardant 360 assay. Changes in ctDNA from pre-treatment cycle 1 to on-treatment cycle 2, so 3 weeks post-baseline assessment, were quantified by the maximum variant allele frequency of tumor tissue-specific mutations.
Results showed that lower baseline ctDNA levels were associated with improved clinical outcomes of response in the pembrolizumab arm but not in the chemotherapy arm. This improvement in the pembrolizumab arm was also robust to adjustment for tumor mutational burden and PD-L1. Additionally, chemotherapy led to a ctDNA clearance rate of 41% compared to 11% in the pembrolizumab arm. Patients who had a large ctDNA reduction with pembrolizumab had significantly improved outcomes compared to those achieving a large reduction with chemotherapy with a hazard ratio of 0.25. However, this did not replicate in patients who did not achieve a large reduction, as these patients had similar outcomes across both arms.
Let’s switch gears to kidney cancer and start with Abstract 4508, reporting the final OS analysis from the JAVELIN Renal-101 trial. Neeraj, what would you like to tell us about this abstract?
Dr. Neeraj Agarwal: Well, as a quick reminder, the JAVELIN Renal-101 was a randomized phase 3 trial where patients with previously untreated advanced or metastatic clear cell renal cell carcinoma were randomized to receive either the combination of avelumab plus axitinib or sunitinib. In previous analyses, the combination of avelumab and axitinib significantly improved PFS compared to sunitinib and was subsequently approved by the FDA for the first-line treatment of patients with advanced RCC in 2019. This superiority in PFS was maintained across the different analyses; however, OS data remained immature. In the abstract presented at ASCO24 by Dr. Robert Motzer from Memorial Sloan Kettering Cancer Center and colleagues, the authors reported OS results at a median follow-up of around 73 months and a minimum of 68 months for all patients, which is the longest follow-up for any ICI-TKI combination in RCC. The final analysis in the overall population favored the combination of avelumab plus axitinib with a median OS of 44.8 months compared to 38.9 months with sunitinib, however, this did not reach statistical significance with a hazard ratio of 0.88. The PFS results and safety profile were consistent with previous analyses.
Dr. Rana McKay: Thank you, Neeraj, for such a nice overview of this abstract. These new data could make this regimen less optimal than other ICI-TKI combinations in the first-line mRCC setting.
Dr. Neeraj Agarwal: I concur, Rana. Moving on to perhaps one of the most exciting GU abstracts featured, Abstract 4506, titled “Circulating kidney injury molecule-1 biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant atezolizumab vs placebo in patients with renal cell carcinoma at increased risk of recurrence after resection.” Rana, what are your thoughts on this abstract?
Dr. Rana McKay: Well, first, I would like to take a step back and remind our audience that in the IMmotion010 trial, patients with resected intermediate to high-risk RCC with clear cell and/or sarcomatoid component were randomized in a 1:1 ratio to receive either atezolizumab or placebo. Investigator-assessed disease-free survival, which was the primary endpoint, favored the atezolizumab arm but did not reach statistical significance. In the abstract featured at ASCO24, Dr. Laurence Albiges and colleagues build on data previously reported in the ASSURE and CheckMate 914 trials and report provocative findings regarding a molecule known as kidney injury molecule 1 or KIM-1, which is a type 1 membrane glycoprotein that has been identified as a minimally invasive potential peripheral blood circulating biomarker. The KIM-1 level of 86 pg/ml was identified as the optimized threshold for defining post-nephrectomy KIM-1 high vs KIM-1 low subgroups in the IMmotion010 trial. KIM-1 levels were measured at baseline or pre-treatment, at cycle 4 day 1, and at disease recurrence or discontinuation without disease recurrence. Baseline characteristics were balanced between the KIM-1 high and KIM-1 low groups, except perhaps for a slightly higher pathological stage in the KIM-1 high subgroup.
I would like to highlight 3 key takeaways from this abstract. First, KIM-1 high level was associated with significantly worse DFS with a hazard ratio of 1.75. Second, patients in the KIM-1 high subgroup receiving atezolizumab had a 28% reduction in the risk of recurrence or death compared to those receiving placebo, while those in the KIM-1 low subgroup had comparable outcomes across both treatment arms. Third, patients in the KIM-1 high subgroup receiving atezolizumab were significantly less likely to experience an on-treatment increase in KIM-1 levels, which was associated with worse DFS in both high and low KIM-1 subgroups, regardless of treatment arm. Thus, these findings support the use of KIM-1 as both a predictive and prognostic biomarker in patients with RCC.
Dr. Neeraj Agarwal: Yes, Rana, this is amazing data! I would like to add that these results warrant larger and, ideally, prospective studies to validate the utility of KIM-1 as a noninvasive biomarker for identifying minimal residual disease after nephrectomy and for predicting outcomes to immune checkpoint inhibitors.
Dr. Rana McKay: Also, in the field of biomarkers, 2 abstracts interrogating different biomarkers in a different setting, so in patients with advanced or metastatic RCC were presented. Neeraj, could you tell us more about these abstracts?
Dr. Neeraj Agarwal: Of course! I think you are referring to Abstracts 4504 and 4505. In abstract 4504, Dr. Toni Choueiri and colleagues sought to assess the clinical implications of different biomarkers in the CLEAR trial, which was a randomized phase 3 trial that led to the approval of the combination of pembrolizumab plus lenvatinib in the first-line mRCC setting. On the other hand, in abstract 4505, Dr. Brian Rini presented biomarker results in KEYNOTE-426, which was also a randomized phase 3 trial based on which the combination of pembrolizumab plus axitinib was approved in patients with mRCC. The authors in both trials sought to investigate the role of biomarkers in predicting treatment outcomes from 3 different angles. Starting with PD-L1 expression, the superiority of the combination arms over sunitinib was not impacted by PD-L1 status in both trials. Moving on to RCC driver gene mutations on whole exome sequencing, such as VHL, SETD2, PBRM1, and BAP1, ICI combination therapies improved outcomes regardless of mutation gene status, and this improvement was statistically significant with PBRM1 mutations in KEYNOTE-426 compared to wild-type PBRM1, but this did not replicate in the CLEAR trial. Finally, using transcriptomic signatures derived from RCC trials, especially the IMmotion 151 and JAVELIN Renal 101 trials, where 7 clusters or molecular subtypes were identified, the combination arms outperformed sunitinib in all clusters in both trials and the magnitude of this benefit differed across clusters.
Dr. Rana McKay: Thank you for this very interesting summary and comparison of the results of these 2 abstracts. These findings support the use of ICI-based combinations in all patients with mRCC as a first-line option. Although these abstracts could not identify specific biomarkers that could guide us clinicians in treatment selection, they provide very interesting biological insights on these molecular biomarkers that are, however, not yet clinically actionable.
Dr. Neeraj Agarwal: Very interesting point, Rana. Moving on to prostate cancer, let’s start with abstract LBA5000 titled, “Cabazitaxel with abiraterone versus abiraterone alone randomized trial for extensive disease following docetaxel: The CHAARTED2 trial of the ECOG-ACRIN Cancer Research Group (EA8153).” Rana, what is your takeaway on this abstract?
Dr. Rana McKay: As a reminder to our audience, the CHAARTED2 trial was a randomized open-label phase 2 study that compared the combination of cabazitaxel and abiraterone to abiraterone alone in patients with mCRPC previously treated with ADT plus docetaxel in the hormone-sensitive setting. The primary endpoint was progression-free survival. After a median follow-up of 47.3 months, Dr. Christos Kyriakopoulos and colleagues reported in LBA5000 that patients receiving the combination of cabazitaxel plus abiraterone had a 27% reduction in the risk of progression or death. However, there was no significant difference in overall survival between the two arms, with a median OS of 25 months in the cabazitaxel+abiraterone arm and 26.9 months in the abiraterone arm, although the study was underpowered for this endpoint. Regarding the toxicity profile, the combination of cabazitaxel and abiraterone was overall well tolerated with more cytopenias, as expected.
Dr. Neeraj Agarwal: Very nice summary of this abstract, Rana. I would like to add that the treatment landscape of patients with mHSPC has evolved since the design of the study and now includes combination therapies of ADT + ARPI with or without docetaxel, and ADT + docetaxel is no longer a standard of care, which limits the applicability of these results in clinical practice today.
Dr. Rana McKay: Excellent point, Neeraj. Let’s discuss Abstract 5001, titled “CYCLONE 2: A phase 3 study of abemaciclib with abiraterone in patients with metastatic castration-resistant prostate cancer”.
Dr. Neeraj Agarwal: Sure! In the abstract featured at ASCO24, Dr. Matthew Smith and colleagues report the primary results of the CYCLONE 2 trial, which was a randomized phase 2/3 study that investigated the combination of abemaciclib plus abiraterone versus abiraterone monotherapy in patients with mCRPC. Stratification factors included radiographic progression at study entry, presence of measurable disease, and prior docetaxel for mHSPC. Part 1 of the study established the recommended phase 2 dose of abemaciclib at 200 mg twice daily. In part 2, patients were randomized to placebo or abemaciclib, and an adaptive interim analysis using prespecified criteria was performed and recommended the expansion of the study to part 3. The primary endpoint was investigator-assessed radiographic progression-free survival by RECIST 1.1 and PCWG3 criteria in the intention-to-treat population. At the time of the primary analysis, adding abemaciclib to abiraterone did not improve rPFS, with a hazard ratio of 0.83. The median rPFS was 22 months for the combination arm and 20.3 months for the abiraterone arm. The combination was well tolerated, and the safety profile was consistent with the known adverse events.
Dr. Rana McKay: So, the addition of abemaciclib to abiraterone did not improve outcomes in patients with mCRPC. These findings suggest that no further investigation is warranted for abemaciclib or CDK4/6 inhibitors in biomarker-unselected patients with prostate cancer.
Dr. Neeraj Agarwal: Rana, what’s your take-home message on Abstract 5006, titled “Health-related quality of life results from PRESTO (AFT-19), a phase 3 randomized trial of intensification of androgen blockade in patients with high-risk biochemically relapsed castration sensitive prostate cancer”?
Dr. Rana McKay: So, as a reminder to our audience, the PRESTO trial was a randomized phase 3 study that assessed the effects of intensified androgen receptor blockade in patients with biochemically recurrent prostate cancer following local therapies. Patients with a PSA doubling time of less than 9 months and no evidence of metastatic disease were randomized to receive either 52 weeks of ADT alone, ADT plus apalutamide, or ADT plus apalutamide plus abiraterone. In their paper published earlier this year in the Journal of Clinical Oncology, the authors showed that patients receiving ADT plus apalutamide with or without abiraterone had significantly longer PSA-progression-free survival than those receiving ADT alone. In the oral presentation featured at ASCO24, Dr. Ronald Chen and colleagues report health-related quality of life outcomes that were assessed using various questionnaires or scales at baseline, at cycle 7, which is around 6 months on treatment, and at the end of treatment. Results showed that this intensified approach with apalutamide did not significantly increase severe adverse events, did not lengthen the time to testosterone recovery, and did not meaningfully increase common treatment-related symptoms such as hormonal symptoms, sexual dysfunction, hot flash interference, and fatigue. Importantly, additional intensification with abiraterone did not further improve PSA-PFS but did increase the rate of serious adverse events, lengthened the time to testosterone recovery, and increased hot flash interference.
Dr. Neeraj Agarwal: So, in conclusion, the PRESTO trial supports using intensified androgen blockade with apalutamide to improve PSA-PFS in patients with high-risk biochemically recurrent prostate cancer without compromising health-related quality of life. However, adding abiraterone did not offer additional benefits and increased side effects.
Dr. Rana McKay: Let’s move on to LBA5002 titled, “A randomized, double-blind, placebo-controlled trial of metformin in reducing progression among men on expectant management for low-risk prostate cancer: The MAST (Metformin Active Surveillance Trial) study.” Would you like to share your insights on this abstract with our listeners?
Dr. Neeraj Agarwal: Absolutely. MAST was a randomized, double-blinded, placebo-controlled trial that investigated the impact of metformin on the progression of low-risk localized prostate cancer in patients choosing to undergo active surveillance. Eligible patients had biopsy-proven, low-risk, localized prostate cancer diagnosed within the past 6 months, characterized by a Gleason score of less than 6 observed in less than one-third of the total cores, less than 50% positivity in any one core, a PSA level of less than 10 ng/ml, and a clinical-stage between T1c and T2a. Patients were randomized in a 1:1 ratio to receive either metformin 850 mg twice daily or placebo for three years. All patients underwent repeat prostate biopsy at 18 and 36 months. The primary endpoint was time to progression, defined as the earliest occurrence of primary prostate cancer therapy, such as prostatectomy, radiation, hormonal therapy, or pathological progression on subsequent biopsies, which was defined as more than 1/3 of total cores involved, at least 50% of any one core involved, or Gleason pattern 4 or higher. The study included 407 patients, with 204 receiving metformin and 203 receiving a placebo. Results presented by Dr. Anthony Joshua showed no statistically significant difference in progression-free survival, including therapeutic and pathologic progression, with an unadjusted hazard ratio of 1.08. Interestingly, there was a signal that patients with a BMI more than 30 had a detriment to taking metformin with a higher risk of progression compared to those receiving placebo with an unadjusted HR of 2.39 and a p-value of 0.01.
Dr. Rana McKay: I would like to add that this study showed that metformin use does not prevent the progression of low-risk localized prostate cancer on active surveillance and could represent a potential detriment for patients with high BMI at study entry.
Dr. Neeraj Agarwal: Yes, Rana, I concur. Any final remarks before we conclude today's podcast?
Dr. Rana McKay: Thank you, Neeraj; it’s been wonderful being here with you today and you having me on the podcast to highlight these important advances and the amazing work that many investigators are conducting and the patients who were involved in the context of these trials. It’s really excellent to see these updated results.
Dr. Neeraj Agarwal: Before we wrap up this podcast, I would like to say that we have reviewed a selection of abstracts addressing prostate, bladder, and kidney cancer, which are significantly impacting our medical practices now and in the near future. Rana, thank you for sharing your insights today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion. Many thanks.
And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
Find out more about today’s speakers:
Dr. Neeraj Agarwal
@neerajaiims
Dr. Rana McKay
@DrRanaMcKay
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Disclosures:
Dr. Neeraj Agarwal:
Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences
Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas
Dr. Rana McKay:
Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelxis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Pfizer, Bayer, Tempus
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Drs. John Sweetenham and Angela DeMichele discuss potentially ground-breaking abstracts in breast and lung cancer as well as notable research on artificial intelligence and its impact on cancer care, all of which were featured at the 2024 ASCO Annual Meeting.
TRANSCRIPT
Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. My guest today is Dr. Angela DeMichele, the Marianne and Robert McDonald Professor in Breast Cancer Research and co-leader of the Breast Cancer Program at the University of Pennsylvania's Abramson Cancer Center. Dr. DeMichele also served as the chair of the 2024 ASCO Annual Meeting Scientific Program. Today, she'll be sharing her reflections on the Annual Meeting and we'll be highlighting some advances and innovations that are addressing unmet needs and accelerating progress in oncology.
Our full disclosures are available in the transcript of this episode.
Dr. DeMichele, congratulations on a very robust and highly successful program at ASCO24, and thanks for joining us on the podcast today.
Dr. Angela DeMichele: Well, thanks so much for having me, Dr. Sweetenham. It's a pleasure to be here.
Dr. John Sweetenham: The presidential theme of the Annual Meeting this year was the "The Art and Science of Cancer Care: From Comfort to Cure." And this was certainly reflected throughout the meeting in Chicago that welcomed more than 40,000 attendees from across the globe. I know our listeners will be interested to hear some of your own reflections from the meeting now that we're on the other side of it, so to spea
Dr. Angela DeMichele: Yes. Well, I will say that playing this role in the annual meeting really was a highlight of my career, and I feel so fortunate to have had the opportunity to do it. We had over 200 sessions, and in many, if not all of these sessions, we really tried to make sure that there was a case that really sort of grounded the session to really help people understand: you're going to hear about science, but how are you going to apply that? Who is the patient for whom this science really is important?
We had over 7,000 abstracts submitted, and our 25 tracks and their chairs really pulled through to find really the best science that we could present this year. I think what you saw really was a representation of that across the board: incredible advances in lung cancer, breast cancer, melanoma, GI cancers; also really cutting-edge technologies: AI, as we'll talk about in a little while circulating markers like ctDNA, new drug development, new classes of drugs. So it was really an exciting meeting. I mean, some highlights for me, I would say, were certainly the Plenary, and we can talk a little bit about that. Also, we had a fantastic ASCO/AACR Joint Session on “Drugging the “Undruggable Target: Successes, Challenges, and the Road Ahead.” And, if any of the listeners have not had a chance to hear this, it's really worth going in and watching this because it really brought together three amazing speakers who talked about the successes in KRAS, and then really, how are we using that success in learning how to target KRAS to now targeting a variety of other previously thought to be undruggable targets. I learned so much. And there's really both the academic and the pharma perspective there. So I'd really encourage watching this session.
The other session that I really thought was terrific was one that I was honored to chair, which was a fireside chat (“How and Where Will Public Investment Accelerate Progress in Oncology? A Discussion with the NIH and NCI Directors”) with both Dr. Monica Bertagnolli, who is the director of the NIH, and Dr. Kim Rathmell, who's now the director of the NCI. And boy, I'll tell you, these two incredibly smart, thoughtful, insightful women; it was a great conversation. They were really understanding of the challenges we face conducting research, practicing medicine. And maybe different from leadership at the NIH in the past, they've really taken the approach to say that everything they do is focused on the patient, and they don't limit themselves to just research or just science, that everything that the NIH does, and particularly the NCI does, really has to be focused on making sure we can give patients the best possible care. And I think they're being very thoughtful about building important infrastructure that's going to take us into the future, incorporating AI, incorporating new clinical trial approaches that are going to make it faster and easier to conduct clinical trials and to get the results that we need sooner. So just a few of the highlights, I think, from some really interesting sessions.
Dr. John Sweetenham: It certainly was an extremely enriching and impactful ASCO24. And I think that the overall theme of the meeting was extremely well reflected in the content with this amazing mix of really, truly impactful science, along with a great deal of patient-centered healthcare delivery science to accompany it. So, I completely agree with you about that. There was a lot, of course, to take in over the five days of the meeting, but I'm sure that our listeners would be very interested to hear about one or two abstracts that really stood out for you this year.
Dr. Angela DeMichele: Sure. I'm a breast cancer specialist, so I can't help but feel that the late breaking abstract, the DESTINY-Breast06 trial, was really important for the field of breast cancer. So just briefly, this is a study of the antibody drug conjugate T-DxD, trastuzumab deruxtecan. This is a drug that is actually now approved in metastatic breast cancer, really effective in HER2-positive disease. But the question that this trial was trying to answer is, can this drug, which is built with the herceptin antibody against HER2, then linked to a chemotherapeutic molecule, can this work even in the setting of very, very low HER2 expression on a tumor? I think this is an incredibly important question in the field of antibody drug conjugates, of which there are now many across diseases, is how much of the target do you really need to have on the surface of the tumor?
We had seen previously HER2 overexpressing tumors respond really well to this drug. HER2 tumors that have an intermediate level of expression were tested in the DP04 trial, and we saw that even those 2+ intermediate tumors responded well to this drug. The DP06 trial that was presented at ASCO was looking at this group of patients that have even less HER2 on the surface. So we typically measure HER2 by immunohistochemistry as 0, 1+, 2+, or 3+. And this was looking at patients whose tumors were over 0, but were at 1+ or below, so low and ultra-low. And it turned out that compared to treatment of physician’s choice, the drug really had quite a lot of activity, even in these patients who have very little HER2 on their tumors, really showing progression-free survival benefits in the HER2-low and HER2-ultra-low groups that were appreciable on the order of about 5 months, additional progression free survival hazard ratios around 0.6, so really demonstrating that utilizing an antibody drug conjugate, where you've got very little target, can still be a way to get that drug to a tumor.
And I think it'll remain to be seen whether other ADCs can have activity at very low levels of IHC expression of whatever target they're designed against. I think one of the tricky things here for implementing this in breast cancer will be how do pathologists actually identify the tumors that are ultra-low because it's not something that we typically do. And so we’ll go through a period, I think, of adjustment here of really trying to understand how to measure this. And there are a bunch of new technologies that I think will do a better job of detecting low levels of the protein on the surface of the tumor because the current IHC test really isn't designed to do that. It was only designed to be focused on finding the tumors that had high levels. So we have some newer technologies with immunofluorescence, for example, that can really get down to very low levels. And I think this is going to be a whole new area of ADCs, target detection – how low can you go to still see activity? So I thought that this was an important abstract for many reasons.
I will just say the second area that I was really particularly impressed with and had a big impact on me were the two lung cancer abstracts that were presented in the Plenary, the LAURA trial (LBA4) and the ADRIATIC trial (LBA5). And I think, I've been in the field of oncology for 30 years now, and when I started in the late ‘90s, lung cancer was a disease for which we had very few treatments. If we didn't catch it early and surgery wasn't possible for non-small cell lung cancer, really, it was a horrible prognosis. So we knew this year was the 20th anniversary of the discovery of EGFR as a subtype of lung cancer. That was really, I think, a turning point in the field of non-small cell lung cancer – finding a target. And now seeing the LAURA trial show that osimertinib really had such an enormous impact on progression-free survival amongst these patients who had EGFR-positive non-small cell lung cancer, progression-free survival hazard ratio of 0.16; there was a standing ovation.
And one of the really big privileges of being the Scientific Program Chair is getting to moderate the Plenary Session, and it's a really amazing experience to be standing up there or sitting there while the presenter is getting a standing ovation. But this was well deserved because of the impact this is having on patients with EGFR positive lung cancer. And it was similar with the ADRIATIC trial, which looked at the benefits of adding immunotherapy in limited-stage small-cell lung cancer. Again, a disease that treatment has not changed in 30 years, and so the addition of durvalumab to the standard backbone of chemotherapy for small cell lung cancer had its survival advantage. These patients are living longer and it was really an impressive improvement. And I think it really underscores just the revolution that has happened in lung cancer between targeted therapy and immunotherapy has completely changed the prognosis for patients with this disease. So to me, these were really landmark reports that came out at ASCO that really showed us how far we've come in oncology.
Dr. John Sweetenham: Yeah, absolutely. I think that, as you mentioned, those results are truly remarkable, and they reflect extraordinary advances in science. I think we see that both in terms of the therapeutic arena, but also, I think we've started to see it in other areas as well, like symptom control, remote patient monitoring, and so on and so forth, where some of the newer virtual technologies are really having major impacts as well.
Dr. Angela DeMichele: Yes, we really wanted to have a focus on artificial intelligence in this meeting, because it's having such an enormous impact on our field in everything from care delivery to diagnostics. I'd love to hear what you thought was the most interesting, because there really was just new data across the board presented.
Dr. John Sweetenham: I've actually chosen 3 abstracts which I thought were particularly interesting for a couple of reasons, really. They're all based on virtual health interventions, and I think they're interesting in really reflecting the theme of the meeting, in that they are extremely advanced technology involved in the virtual platforms, a couple of which are artificial intelligence, but very impactful to patients at the same time in terms of remote symptom control, in terms of addressing disparities, and in one case, even influencing survival. So I thought these were three really interesting abstracts that I'll walk the listeners through very quickly.
The first of these was a study, Abstract 1500 (“National implementation of an AI-based virtual dietician for patients with cancer”) which looked at an artificial intelligence-based virtual dietitian for patients with cancer. This is based on the fact that we know nutritional status to be a key driver of patient experience and of cancer outcomes. And as the authors of the presentation noted, 80% of patients look for nutritional support, but many of them don't get it. And that's primarily a workforce issue. And I think that's an important thematic point as well, that these new technologies can help us to address some of the workforce issues we have in oncology. So this was an AI-based platform developed by experts in nutrition and cancer patients, based on peer reviewed literature, and a major effort in terms of getting all of these data up together. And they developed an artificial intelligence platform, which was predominantly text message based. And this platform was called INA. And as this is developing as a platform, there's a machine learning component to it as well. So in theory, it's going to get better and better and better over time.
And what they did in their study was they looked at little over 3,000 patients across the entire country who were suffering from various types of cancer, GU, breast, gynecological malignancy, GI and lung. And most of them had advanced-stage disease, and many of them had nutritional challenges. For example, almost 60% of them were either overweight or obese by BMI. And the patients were entered into a text exchange with the AI platform, which would give them advice on what they should eat, what they shouldn't eat. It would push various guidance and tips to them, it would develop personalized recipes for them, and it would even develop menu plans for the patients. And what's really interesting about this is that the level of engagement from the patients was very high, with almost 70% of patients actually texting questions to this platform. About 80% of the patients completed all of the surveys, and the average time that patients interacted with the platform was almost nine months, so this was remarkable levels of engagement, high levels of patient satisfaction. And although at this point, I think it's very early and somewhat subjective, there was certainly a very positive kind of vibe from patients. Nearly 50% have used the recommended recipes. More than 80% of them thought that their symptoms improved while they were using this platform. So I think as a kind of an assistant for remote management of patients, it's really remarkable. And the fact that the level of engagement was so high also means that for those patients, it's been very impactful.
The second one, this was Abstract 100 (“AI virtual patient navigation to promote re-engagement of U.S. inner city patients nonadherent with colonoscopy appointments: A quality improvement initiative”) looked again at an AI-based platform, which in this case was used in an underserved population to address healthcare disparities. This is a study from New York which was looking at colorectal cancer screening disparities amongst an underserved population, where historically they've used skilled patient navigators to address compliance with screening programs, in this case specifically for colorectal cancer. And they noticed in the background to this study that in their previous experience in 2022, almost 60% of patients either canceled or no-showed for colonoscopy appointments. And because of this and because of the high burden of patients that this group has, they decided to take an AI-based virtual patient navigator called MyEleanor and introduce this into their colorectal cancer screening quality improvement.
And so they introduced this platform in April of 2023 through to the end of the year, and their plan was to target reengagements of around 2,500 patients who had been non adherent with colonoscopy appointments in a previous year. And so the platform MyEleanor would call the patients to discuss rescheduling, it would assess their barriers to uptake, it would offer live transfer to somebody to schedule for them, and then it would go on closer to the point of the colonoscopy to call the patients and give them advice about their prep. And it was very nuanced. The platform would speak in both English and Spanish versions. It could detect nuances in the patient's voice, which might then trigger it to refer the patient to a live agent rather than the AI platform. So, very sophisticated technology. And what was most interesting about this, I think, was that over the eight months of the study, around 60% of patients actually engaged with this platform, with almost 60% of that group, or 33% overall, accepting a live transfer and then going on to scheduling, so that the completion rate for the no show patients went from 10% prior to the introduction of this platform to 19% after it was introduced. So [this is] another example, I think, of something which addresses a workforce problem and also addresses a major disparity within cancer care at the moment by harnessing these new technologies. And I think, again, a great interaction of very, very high-level science with things that make a real difference to our patients.
So, Dr. DeMichele, those are a couple of examples, I think, of early data which really are beginning to show us the potential and signal the impact that artificial intelligence is going to have for our patients in oncology. I wonder, do you have any thoughts right now of where you see the biggest impact of artificial intelligence; let's say not in 20 years from now, but maybe in the next year or two?
Dr. Angela DeMichele: Well, I think that those were two excellent examples. A really important feature of AI is really easing the workload on physicians. And what I hope will happen is that we'll be able to use AI in the very near future as a partner to really offload some of the quite time-consuming tasks, like charting, documentation, that really take us away from face-to-face interaction with patients. I think this has been a very difficult period where we move to electronic medical records, which are great for many reasons, but have really added to the burden to physicians in all of the extra documentation. So that's one way, I think, that we will hope to really be able to harness this. I think the other thing these abstracts indicate is that patients are very willing to interact with these AI chatbots in a way that I think, as you pointed out, the engagement was so high. I think that's because they trust us to make sure that what we're doing is still going to be overseen by physicians, that the information is going to get to us, and that they're going to be guided. And so I think that in areas where we can do outreach to patients, reminders, this is already happening with mammograms and other sorts of screening, where it's automated to make sure you're giving reminders to patients about things that they need to do for some of their basic health maintenance. But here, really providing important information – counseling that can be done by one of these chatbots in a way that is compassionate, informative and does not feel robotic to patients.
And then I was really impressed with, in the abstract on the screening colonoscopy, the ability of the AI instrument to really hear nuances in the patient's responses that could direct them directly to a care provider, to a clinician, if they thought that there might be some problem the patient was experiencing. So again, this could be something that could be useful in triaging phone calls that are coming in from patients or our portals that just feel like they are full of messages, no matter how hard you try to clear them all out, to get to them all. Could we begin to use AI to triage some of the more mundane questions that don't require a clinician to answer so that we can really focus on the things that are important, the things that are life threatening or severe, and make sure that we're getting to patients sooner? So there's just a few ways I really hope it'll help us.
Dr. John Sweetenham: Yeah, absolutely. I think we're just scratching the surface. And interestingly enough, in my newsfeed this morning through email, I have an email that reads, “Should AI pick immunotherapy combinations?” So we'll see where that goes, and maybe one day it will. Who knows?
Dr. Angela DeMichele There was a great study presented at ASCO about that very thing, and I think that is still early, but I could envision a situation where I could ask an AI instrument to tell me all of the data around something that I want to know about for a patient that could deliver all of the data to me in real time in the clinic to be able to help me make decisions, help me quote data to patients. I think in that way it could be very, very helpful. But it'll still need the physicians to be putting the data into context and thinking about how to apply it to the individual person.
Dr. John Sweetenham: Absolutely, yes. And so just to round off, the final abstract that caught my eye, which I think kind of expands on a theme that we saw at an ASCO meeting two or three years ago around the impact of [oncology] care at home, and this was Abstract 1503 (“Acute care and overall survival results of a randomized trial of a virtual health intervention during routine cancer treatment”). So, a virtual platform but not AI in this case. And this was a study that looked at the use of an Integrative Medicine at Home virtual mind-body fitness program. And this was a platform that was used to look at hospital admission and acute care of patients who used it, and also looked at survival, interestingly enough. So what was done in this study was a small, randomized study which looked at the use of virtual live mind, body and fitness classes, and compared this in a randomized fashion to what they called enhanced usual care, which essentially consisted of giving the patients, making available to the patients, some pre-recorded online meditation resources that they could use. And this was applied to a number of patients with various malignancies, including melanoma, lung, gynecologic, head and neck cancers, all of whom were on systemic therapy and all of whom were reporting significant fatigue.
This was a small study; 128 patients were randomized in this study. And what was very interesting, to cut to the chase here, is that the patients who had the virtual mind-body program, compared with the control group, actually were less likely to be hospitalized, the difference there being 6.3% versus 19.1%, respectively. They spent fewer days in the hospital. And remarkably, the overall survival was 24.3 months median for patients in the usual care arm and wasn't reached in those patients who were on the virtual mind-body fitness class platform. So very preliminary data, certainly are going to need more confirmation, but another example of how it appears that many of these non-pharmacological interventions have the potential to improve meaningful endpoints, including hospital stays and, remarkably, even survival. So again, I think that that is very consistent with the theme of this year's meeting, and I found that particularly interesting, too.
I think our time is up, so I want to thank you, Dr. DeMichele, for sharing your insights with us today on the ASCO Daily News Podcast. We really appreciate it. And once again, I want to congratulate you on what was really a truly remarkable ASCO this year.
Dr. Angela DeMichele: Well, thanks so much for having me. It's been a tremendous pleasure to be with you today.
Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in a transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Disclosures:
Dr. John Sweetenham:
Consulting or Advisory Role: EMA Wellness
Dr. Angela DeMichele:
Consulting or Advisory Role (an immediate family member): Pfizer
Research Funding (Inst.): Pfizer, Genentech, Novartis, Inviata/NeoGenomics
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Drs. John Sweetenham and Marc Braunstein discuss practice-changing studies in hematologic malignancies that were featured at the 2024 ASCO Annual Meeting, including the ASC4FIRST trial in chronic myeloid leukemia and IMROZ and CARTITUDE-4 in multiple myeloma.
TRANSCRIPT
Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. On today's episode, we'll be discussing practice-changing abstracts and other key advances in hematological malignancies that were featured at the 2024 ASCO Annual Meeting. Joining me for this discussion is an old friend, Dr. Marc Braunstein, a hematologist and oncologist from the NYU Langone Perlmutter Cancer Center.
Our full disclosures are available in the transcript of this episode.
Marc, it’s great to have you back on the podcast again. There were some important studies in the heme space at the Annual Meeting this year, and we're very pleased that you're able to share your takeaways.
Dr. Marc Braunstein: Thank you, John. It's great to be back again.
Dr. John Sweetenham: Let's start out, Marc, with LBA6500. This abstract reports the primary results of the ASC4FIRST trial, and this was a trial comparing asciminib with investigator selected tyrosine kinase inhibitors in newly diagnosed patients with chronic myeloid leukemia. Could you tell us a little about the trial and how you think it's going to impact clinical practice?
Dr. Marc Braunstein: Absolutely. So, asciminib is an oral tyrosine kinase of the ABL kinase domain. As we know in CML, the BCR-ABL translocation is characteristic of the disease, and asciminib is approved for chronic phase CML with a T315I resistance mutation or for patients who have received 2 or more prior lines of therapy. So the ASC4FIRST trial was a randomized trial of 405 patients with newly diagnosed chronic phase CML who are randomized one to one to receive either asciminib at 80 milligrams once daily, or investigator’s choice of a first generation TKI imatinib or one of three second generation TKIs nilotinib, dasatinib, or bosutinib. The primary endpoint of the study was the major molecular response, or MMR, at 48 weeks. Pretty much, the study met its primary endpoint with a 67% rate of MMR at 48 weeks, with asciminib versus 49% in patients treated with the investigator's choice of TKI. And in addition, the major molecular remission or MMR of 4.5, which is a deep remission, those rates were higher as well, with asciminib versus investigator’s choice at a rate of 39% versus 21% when comparing the groups. Furthermore, when we looked at toxicity, there were fewer grade 3 or higher adverse events, with the asciminib at 38% versus either 44% with the first generation, or 55% with the second generation TKI, and fewer discontinuations as well with asciminib.
So I think this abstract is practice-changing. I think it offers compelling data to use asciminib upfront for chronic phase CML. Those who don't agree with that sentiment might argue that we want to see longer term follow up. There's a planned follow-up at 96 weeks. We would want to see the rate of progression to acute myeloid leukemia and of course overall survival as well. But I think the abstract certainly shows an improvement in outcomes with asciminib versus our current array of TKIs.
Dr. John Sweetenham: Yeah, I think it certainly is, at least at minimum, potentially practice changing. I agree with you. Just one question, and this may be a little bit speculative, but do you have any thoughts about treatment free survival with asciminib and how that might line up against some of the other TKIs?
Dr. Marc Braunstein: Yeah, that's a great question. The abstract did not necessarily address that, patients were treated until progression, but we know that with the current landscape of TKIs, that in patients who have achieved a deep MR of 4 or 4.5 for at least 2 years who discontinue their TKI, the rate of relapse is about 50%. The current study, the ASC4FIRST, doesn't address that, but I think it's a really good question about whether, for those patients who have achieved a deep remission, whether they can eventually stop asciminib down the line.
Dr. John Sweetenham: Yeah, I guess it's one of those ‘watch this space’ things.
So we'll see how the data mature out. And let's move on to what I think is another potentially practice-changing study, at least in certain parts of the world. And that's [the] LBA7000 study in classical Hodgkin lymphoma. As you remember, this was a German Hodgkin lymphoma study group trial which looked at the tolerability and efficacy of a novel regimen, BrECADD versus eBEACOPP for patients with advanced stage classical Hodgkin lymphoma in their study, which is known as GHSG HD21. Can you give us your thoughts and take home messages from this trial?
Dr. Marc Braunstein: Yeah, John, absolutely. So the German HD21 study is a phase 3 study of 1,500 patients with classical Hodgkin lymphoma. The majority were stage 3 or 4, 84%, that compared two regimens BEACOPP to BrECADD. The major difference between these 2 groups being that the newer BrECADD regimen swaps out bleomycin for brentuximab vedotin, which is an anti-CD30 antibody drug conjugate. Also, in the BrECADD regimen they eliminate vincristine that's incorporated into BEACOPP. Those are kind of the global differences between these 2 regimens. And when comparing these, they looked at the primary endpoint of progression-free survival. Of note, in this study there was a PET adjusted approach where if patients achieved interim PET negativity after 2 cycles, that was followed by an additional 2 cycles of their treatment as opposed to 4 cycles if they were PET positive after the initial 2 cycles of their respective treatment. And of note, there were similar rates of PET2 negativity between both arms, about 58% in both arms.
So at a median follow-up of 48 months, the 4-year progression-free survival was significantly better with the brentuximab containing BrECADD regimen at 94% versus 91% with a hazard ratio of 0.66. And the overall survival of the BrECADD arm was 98.6%, which is very high and impressive. The 4-year overall survival was similar between the arms at around 98%, but of note, there were fewer severe adverse events with BrECADD, the brentuximab containing arm versus BEACOPP at about 42% versus 59% and interestingly less peripheral neuropathy with the brentuximab containing BrECADD. So we're doing extremely well in treating advanced stage classical Hodgkin lymphoma. So the bar is set very high. But in this study, the rates of progression-free survival and overall survival are very impressive.
While these intensive regimens tend to be used outside of the U.S., there are several notable benefits of the study, including greater than 50% PET2 negativity and high rates of progression-free survival at 4 years. In discussing this abstract, it's worth noting that there are other competing regimens, if you want to call it that, that are more commonly used in the U.S. So the ECHELON-1 study looked at brentuximab AVD compared with ABVD with bleomycin and it was a 94% versus 89% 6-year overall survival rate favoring the brentuximab containing A+AVD regimen. And lastly, more recently, the SWOG S1826 study that hasn't been published but was presented in abstract form looked at nivolumab AVD versus brentuximab AVD at a median follow up of 12 months showed a progression-free survival of 94% versus 86%. And that study still has yet to be published and needs to mature. But both of those regimens are in the NCCN guidelines. So, we're definitely pushing the bar higher in terms of improving responses in treating advanced classical Hodgkin lymphoma.
Dr. John Sweetenham: I think that there's no question that these results from BrECADD are very impressive. But I'm taken back to what I think has been a kind of philosophic discussion in Hodgkin lymphoma now for a number of years about balancing disease control and efficacy against the potential short-term and long-term toxicity of the regimens, particularly when you have very effective salvage therapies for those patients who may suffer a relapse. So I think that this is a discussion over whether you take a very intensive, upfront approach to Hodgkin lymphoma versus something that may be less and slightly less intensive. I suspect that's a discussion that's going to continue for a long time. I don't know what you feel, but my own feeling about this is that this study will likely have a major influence over treatment of Hodgkin lymphoma, particularly in western Europe. Less likely in the US.., I would think. I don't know what your thoughts about that are.
Dr. Marc Braunstein: Well, it's a great question. In SWOG S1826, that study did include pediatric patients. In HD21, the median age was 31 and did not include pediatric patients. So I think we have to be selective in terms of fitness and which patients may be better suited for different regimens. But I think what all these studies show is certainly when we incorporate novel immunotherapies, whether it's brentuximab vedotin, nivolumab, we improve progression-free survival and even overall survival.
Dr. John Sweetenham: Absolutely.
So let's shift gears now and take a look at Abstract 7500, the IMROZ study. This was the study of isatuximab, bortezomib, lenalidomide and dexamethasone versus VRD alone for transplant ineligible patients with newly diagnosed multiple myeloma. I know we discussed this in our preview podcast a few weeks back, Marc, but I just wonder now, having seen the data in more detail, what do you think of the important takeaways? And again, are we looking at a new standard of care?
Dr. Marc Braunstein: You know, there are many standards of care in multiple myeloma, but we're always looking to make improvements on the regimens we have at our disposal. So, just to recap, IMROZ is a phase 3 randomized study of the anti-CD38 monoclonal antibody isatuximab with the backbone of bortezomib, lenalidomide, dexamethasone or VRD versus VRD alone, specifically, in transplant ineligible newly diagnosed multiple myeloma patients age less than 80. They studied 446 patients in this study, randomized 3 to 2 to Isa-VRD versus VRD alone, with the primary endpoint of progression free survival. Now, similar to other studies where they included a monoclonal antibody up front, the study met its primary endpoint of improving progression-free survival with the quad regimen containing the monoclonal antibody isatuximab versus VRD alone.
So what was interesting about the study, it's really the first of its kind to be presented that specifically looked at transplant ineligible patients, which is presumably a less fit or perhaps more frail population that wouldn't go on to consolidation with stem cell transplant. And in this study, the progression-free survival at 5 years was 63% versus 45%, clearly superior when you included isatuximab. And the rates of complete remission and MRD negativity were all significantly improved, too. However, that was also met with slightly more grade 3 or higher treatment emergent adverse events, 92% versus 84% in the control arm. There are also 11% grade 5 treatment emergent adverse events with the isatuximab group versus 5.5% with VRD alone. Although there was no major difference in treatment discontinuation. One small caveat worth noting, too, is that high-risk patients in this study, when presented at ASCO, did not necessarily show a difference in benefit, although there wasn't necessarily a detriment either.
So, John, I think that clearly quadruplet regimens are superior in outcomes of efficacy to triplets, even in transplant-ineligible patients. But I think we have to tailor these treatments to individual patients because I think when it comes to transplant-ineligible patients, it's a spectrum of patients who may be more or less fit for quad regimens versus triplet regimens. It's also worth noting, though, that in this study, the patients are really only getting a quad regimen for 4 cycles. They get their Isa-VRD, and then you drop the bortezomib. So when we think about quads, it's not that they're getting the quad regimen indefinitely, it's really for the induction cycles. But still, I think we have to be aware of potential safety issues.
Dr. John Sweetenham: Okay, great. And let's stay on the theme of multiple myeloma, Marc, and talk a little bit about Abstract 7504, which was a subgroup analysis of the CARTITUDE-4 study. This is a report on the use of ciltacabtagene autoleucel versus standard of care in patients with functional high risk multiple myeloma. Can you give us your thoughts on this and maybe put it into a bit of context for us?
Dr. Marc Braunstein: Absolutely, John. It's really a great time to be in the field of multiple myeloma. We're making tremendous progress, but when we think about one of the unmet needs, it's just consistently the high-risk patients who have shorter responses and are at higher risk for poorer outcomes. Just to review, cilta-cel is one of the 2 available anti-BCMA CAR T-cell products available for the treatment of relapsed or refractory multiple myeloma. Very recently, the FDA approved cilta-cel for lenalidomide refractory patients after 2 or more prior lines of therapy based on the CARTITUDE-4 study, which was published by San-Miguel and colleagues in New England Journal of Medicine in July 2023. And that study randomized 419 patients with multiple myeloma with 1 to 3 prior lines of therapy to receive either cilta-cel or physician's choice of standard of care, which was either 1 of 2 triplet regimens, a pomalidomide, bortezomib, dexamethasone or daratumumab, pomalidomide and dexamethasone. It's worth noting that about 25% of the patients in the CARTITUDE-4 study had prior anti-CD38 antibody treatment previously and the carfilzomib was not included in one of the standard-of-care arms, and we know that those regimens containing carfilzomib do increase survival in relapsed myeloma.
Nevertheless, the primary outcome of progression-free survival was not reached in the CAR T-cell arm versus 11.8 months in the standard-of-care arm, with a significant reduction in progression of 74%. So clearly a positive study and CAR T-cell therapy is included in the NCCN guidelines for patients who have an early relapse from their myeloma. The current abstract by Costa et al focused specifically on a subgroup of 79 patients from CARTITUDE-4 in second line of treatment and looked at what they called functional high-risk myeloma, defined as progression of disease within 18 months of initial treatment or after stem cell transplant. Again, the study showed a retained benefit of cilta-cel with significant improvement in progression-free survival either not reached or 12 months with the control standard of care arm, as well as complete remission rate and rates of MRD negativity of 65% versus 10% in the control.
The overall survival outcome was still immature and not presented. Nevertheless, cilta-cel is clearly superior to standard-of-care triplet regimens. I think that for patients with high risk, they clearly derive a benefit from CAR T-cell therapy if they have short progression-free survival after initial therapy.
Dr. John Sweetenham: Thanks, Marc. So let's round this out by talking about another area of unmet need, I guess in a way in a difficult to treat patient group. And that's Abstract 7007, the SYMPATICO study. This is a study which looks at the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who had a mutated TP53. Can you just briefly review this for us and tell us what you think we should be taking away from this studys?
Dr. Marc Braunstein: So, mantle cell lymphoma typically has an aggressive behavior, but the subgroup of patients with a P53 mutation tend to have the poorest outcomes and do represent an area of unmet need. Although BTK inhibitors are making important improvements in mantle cell lymphoma, they have yet to be approved in newly diagnosed mantle cell lymphoma. Acalibutinib and zanubrutinib are FDA-approved BTK inhibitors for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market in the U.S. for mantle cell lymphoma. Dr. Michael Wang's group presented late-breaking data from the phase 3 SYMPATICO trial at ASH 2023, in which 267 patients with relapsed refractory mantle cell lymphoma were randomized to receive either ibrutinib plus the BCL2 inhibitor venetoclax or ibrutinib plus placebo after 1 to 5 prior lines of therapy. And that study showed a 32 versus 22 months progression-free survival at a median follow up of 51 months.
The current abstract, also by Dr. Wang and colleagues, looked at the subgroup of patients who had a P53 mutation and included an open label cohort of 44 patients in the first line of treatment and a relapse refractory cohort of 75 patients, and compared this subgroup of patients with P53 mutation to those without. When we look at the outcomes, the patients who did not have a P53 mutation clearly did better in terms of progression-free survival being not reached in first-line treatment compared to 22 months progression-free survival in those patients with first-line [treatment] with a P53 mutation. As well as in the relapsed refractory setting, the PFS without the P53 mutation was 47 months versus 21 months with the mutation. However, when you look at these patients treated with ibrutinib and venetoclax comparing whether they got treated in first line or the relapse refractory setting, the overall response rates are very similar at about 80% to 90% and the CR rates were very similar at about 55% to 58%, which to me suggests that although patients with P53 mutation do worse than those without it, whether they're treated in the first-line or the relapse setting with this combination of venetoclax, they tend to do somewhat similar, suggesting that you can overcome resistance to prior therapy in the relapse setting. So I think further data are certainly warranted to explore the role of combination therapies that include novel agents such as BTK inhibitors in the first line setting.
It's worth noting that the TRIANGLE study was recently published, and this study looked at including ibrutinib at various phases, including at induction in combination with intensive chemotherapy and during the maintenance phase. And that study showed encouraging outcomes in patients who received ibrutinib even without stem cell transplant compared to those who received stem cell transplant. So the role of BTKIs in mantle cell lymphoma is certainly evolving, and I think it offers a very effective intervention without the same kind of toxicities we see with cytotoxic chemotherapy that's traditionally used in mantle cell lymphoma. But I think the subgroup of patients with P53 mutation in this disease still represent an area of unmet need that unfortunately have worse outcomes. But novel agents may be able to overcome some of those adverse outcomes.
Dr. John Sweetenham: Yeah, I agree. I think these are intriguing data, and obviously it needs more follow-up and probably more prospective studies. But nevertheless, I think there are some signals there for sure that need to be followed up on.
Marc, as always, it's great to have your insights on key advances in the heme space from ASCO. An important year this year, and we really appreciate your time and effort in sharing with us your thoughts on what we've learned this year. So thank you as always.
Dr. Marc Braunstein: My pleasure.
Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.
Disclaimer:
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Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Disclosures:
Dr. John Sweetenham:
Consulting or Advisory Role: EMA Wellness
Dr. Marc Braunstein:
Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp
Speakers’ Bureau: Janssen Oncology
Research Funding (Institution): Janssen, Celgene/BMS
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Drs. Vamsi Velcheti and Nathan Pennell discuss novel approaches and key studies in lung cancer that were showcased at the 2024 ASCO Annual Meeting, including the Plenary abstracts LAURA and ADRIATIC.
TRANSCRIPT
Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. Today, I'm joined by Dr. Nate Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and the vice chair of clinical research at the Taussig Cancer Center in Cleveland Clinic. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Today, we will be discussing practice-changing abstracts and the exciting advances in lung cancer that were featured at the ASCO 2024 Annual Meeting.
You'll find our full disclosures in the transcript of the episode.
Nate, we're delighted to have you back on the podcast today. Thanks for being here. It was an exciting Annual Meeting with a lot of important updates in lung cancer.
Dr. Nate Pennell: Thanks, Vamsi. I'm glad to be back. And yes, it was a huge year for lung. So I'm glad that we got a chance to discuss all of these late-breaking abstracts that we didn't get to talk about during the prelim podcast.
Dr. Vamsi Velcheti: Let's dive in. Nate, it was wonderful to see all the exciting data, and one of the abstracts in the Plenary Session caught my attention, LBA3. In this study, the investigators did a comparative large-scale effectiveness trial of early palliative care delivered via telehealth versus in-person among patients with advanced non-small cell lung cancer. And the study is very promising. Could you tell us a little bit more about the study and your take-home messages?
Dr. Nate Pennell: Yes, I think this was a very important study. So just to put things in perspective, it's now been more than a decade since Dr. Jennifer Temel and her group at Massachusetts General Hospital did a randomized study that showed that early interventions with palliative medicine consultation in patients with advanced non-small cell lung cancer significantly improves quality of life and in her initial study, perhaps even overall survival. And since then, there have been numerous studies that have basically reproduced this effect, showing that getting palliative medicine involved in people with advanced cancer, multiple different cancer types, really, has benefits.
The difficulty in applying this has been that palliative care-trained specialists are few and far between, and many people simply don't have easy access to palliative medicine-trained physicians and providers. So with that in mind, Dr. Temel and her group designed a randomized study called the REACH PC trial, where 1,250 patients were randomized with advanced non-small cell lung cancer to either in-person palliative medicine visits which is sort of the standard, or one in-person assessment followed by monthly telemedicine video visits with palliative medicine. Primary endpoint was essentially to show that it was equivalent in terms of quality of life and patient satisfaction. And what was exciting about this was that it absolutely was. I mean, pretty much across the board in all the metrics that were measured, the quality-of-life, the patient satisfaction, the anxiety and depression scores, all were equivalent between doing telemedicine visits and in-person visits. And this hopefully will now extend the ability to get this kind of benefit to a much larger group of people who don't have to geographically be located near a palliative medicine program.
Dr. Vamsi Velcheti: Yeah, I think it's a great abstract, Nate and I actually was very impressed by the ASCO committee for selecting this for the Plenary. We typically don't see supportive care studies highlighted in such a way at ASCO. This really highlights the need for true interdisciplinary care for our patients. And as you said, this study will clearly address that unmet need in terms of providing access to palliative care for a lot of patients who otherwise wouldn't have access. I'm really glad to see those results.
Dr. Nate Pennell: It was. And that really went along with Dr. Schuchter’s theme this year of bringing care to patients incorporating supportive care. So I agree with you.
Now, moving to some of the other exciting abstracts in the Plenary Session. So we were talking about how this was a big year for lung cancer. There were actually 3 lung cancer studies in the Plenary Session at the Annual Meeting. And let's move on to the second one, LBA4, the LAURA study. This was the first phase 3 study to assess osimertinib, an EGFR tyrosine kinase inhibitor, in patients with EGFR mutant, unresectable stage III non-small cell lung cancer. What are your takeaways from this study?
Dr. Vamsi Velcheti: This is certainly an exciting study, and all of us in the lung community have been kind of eagerly awaiting the results of the study. As you know, for stage III non-small cell lung cancer patients who are unresectable, the standard of care has been really established by the PACIFIC study with the consolidation durvalumab after definitive concurrent chemoradiation. The problem with that study is it doesn't really answer the question of the role of immunotherapy in patients who are never-smokers, and especially in patients who are EGFR positive tumors, where the role of immunotherapy in a metastatic setting has always been questioned. And in fact, there have been several studies as you know, in patients with EGFR mutation positive metastatic lung cancer where immunotherapy has not been that effective. In fact, in the subgroup analysis in the PACIFIC study, patients with EGFR mutation did not really benefit from adding immunotherapy.
So this is an interesting study where they looked at patients with locally advanced, unresectable stage III patients and they randomized the patients 2:1 to osimertinib versus placebo following concurrent or sequential tumor radiation. The primary endpoint for the study was progression free survival, and a total of 216 patients were enrolled and 143 patients received a study treatment, which is osimertinib, and 73 received placebo. And 80% of the patients on the placebo arm crossed over to getting treatment at the time of progression.
So most of us in the lung cancer community were kind of suspecting this would be a positive trial for PFS. But however, I think the magnitude of the difference was truly remarkable. The median PFS in the osimertinib arm was 39.1 months and placebo was 5.6 months and the hazard ratio of 0.16. So it was a pretty striking difference in terms of DFS benefit with the osimertinib consolidation following chemoradiation. So it was truly a positive study for the primary endpoint and the benefit was seen across all the subgroups and the safety was no unexpected safety signals other than a slight increase in the radiation pneumonitis rates in patients receiving osimertinib and other GI and skin tox were kind of as expected. In my opinion, it's truly practice changing and I think patients with EGFR mutation should not be getting immunotherapy consolidation post chemoradiation.
Dr. Nate Pennell: I completely agree with you. I think that this really just continues the understanding of the use of osimertinib in EGFR-mutant lung cancer in earlier stages of disease. We know from the ADAURA trial, presented twice in the Plenary at the ASCO Annual Meeting, that for IB, stage II and resectable IIIA, that you prolong progression free or disease free survival. So this is a very similar, comparable situation, but at an even higher risk population or the unresectable stage III patients. I think that the most discussion about this was the fact that the osimertinib is indefinite and that it is distinct from the adjuvant setting where it's being given for three years and then stopped. But I think all of us had some pause when we saw that after three years, especially in the stage III patients from ADAURA, that there were clearly an increase in recurrences after stopping the drug, suggesting that there are patients who are not cured with a time limited treatment, or at least with 3 years of treatment.
The other thing that is sobering from the study, and was pointed out by the discussant, Dr. Lecia Sequist, is if you look at the two-year disease-free survival in the placebo arm, it was only 13%, meaning almost no one was really cured with chemo radiation alone. And that really suggests that this is not that different from a very early stage IV population where indefinite treatment really is the standard of care. I wonder whether you think that's a reasonable approach.
Dr. Vamsi Velcheti: I completely agree with you, Nate, and I don't think we cure a majority of our patients with stage III, and less so in patients who have EGFR-mutant, stage III locally advanced. As you just pointed out, I think very few patients actually make it that far along. And I think there's a very high rate of CNS micrometastatic disease or just systemic micrometastatic disease in this population that an effective systemic therapy of osimertinib can potentially have long term outcomes. But again, we perhaps don't cure a vast majority of them. I think that the next wave of studies should incorporate ctDNA and MRD-based assays to potentially identify those patients who could potentially go off osimertinib at some point. But, again, outside of a trial, I would not be doing that. But I think it's definitely an important question to ask to identify de-escalation strategies with osimertinib. And even immunotherapy for that matter, I think we all know that not all patients really require years and years of immunotherapy. They're still trying to figure out how to use immunotherapy in these post-surgical settings, using the MRD to de-escalate adjuvant therapies. So I think we have to have some sort of strategy here. But outside of a clinical trial, I will not be using those assays here to cite treatments, but certainly an important question to ask.
Moving on to the other exciting late-breaking abstracts, LBA5, the ADRIATIC study. This is another study which was also in the plenary session. This study was designed to address this question of consolidation immunotherapy, post chemo radiation for limited-stage small cell cancer, the treatment arms being durvalumab tremelimumab, and durvalumab observation. So what do you think about the study? This study also received a lot of applause and a lot of attention at the ASCO meeting.
Dr. Nate Pennell: It was. It was remarkable to be there and actually watch this study as well as the LAURA study live, because when the disease free survival curves and in the ADRIATIC study, the overall survival curves were shown, the speakers were both interrupted by standing ovation of applause just because there was a recognition that the treatment was changing kind of before our eyes. I thought that was really neat. So in this case, I think this is truly a historic study, not necessarily because it's going to necessarily be an earth shakingly positive study. I mean, it was clearly a positive study, but more simply because of the disease in which it was done, and that is limited-stage small cell lung cancer. We really have not had a change in the way we've treated limited-stage small cell lung cancer, probably 25 years. Maybe the last significant advances in that were the advent of concurrent chemotherapy and radiation and then the use of PCI with a very modest improvement in survival. Both of those, I would say, are still relatively modest advances.
In this case, the addition of immunotherapy, which we know helps patients with small cell lung cancer - it's of course the standard of care in combination chemotherapy for extensive stage small cell lung cancer - in this case, patients who completed concurrent chemo radiation were then randomized to either placebo or durvalumab, as well as the third arm of durvalumab tremelimumab, which is not yet been recorded, and co primary endpoints were overall survival and progression free survival. And extraordinarily, there was an improvement in overall survival seen at the first analysis, with a median overall survival of 55.9 months compared to 33.4 months, hazard ratio of 0.73. So highly clinically and statistically significant, that translates at three years to a difference in overall survival of 56.5%, compared to 47.6%, or almost 10% improvement in survival at three years.
There was also a nearly identical improvement in progression-free survival, also with a hazard ratio of 0.76, suggesting that there's a modest number of patients who benefit. But it seems to be a clear improvement with the curves plateauing out. In my opinion, this is very comparable to what we saw with the PACIFIC study in stage III, unresectable non-small cell lung cancer, which immediately changed practice back when that first was reported. And I expect that this will change practice pretty much immediately for small cell as well.
Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think it's an exciting advance in patients with limited-stage small cell lung cancer. For sure, it's practice-changing, and I think the results were exciting.
So one thing that really intrigued me was in the extensive-stage setting, the benefit was very mediocre with one-to-two month overall survival benefit in both the PACIFIC and in IMpower trial. Here we are seeing almost two-year of median OS benefit. I was kind of puzzled by that, and I thought it may have to do with patients receiving radiation. And we've seen that with the PACIFIC, and makes you wonder if both the CASPIAN and the IMpower studies actually did not allow consolidation thoracic radiation. Hypothetically, if they had allowed consolidation thoracic radiation, perhaps we would have seen better outcomes. Any thoughts on that?
Dr. Nate Pennell: We've been trying to prove that radiation and immunotherapy somehow go together better for a long time. Going back to the first description of the abscopal effect, and I'm not sure if I necessarily believe that to be the case, but in this setting where we truly are trying to cure people rather than merely prolong their survival, maybe this is the situation where it truly is more beneficial. I think what we're seeing is something very similar to what we're seen in PACIFIC, where in the stage IV setting, some people have long term survival with immunotherapy, but it's relatively modest. But perhaps in the curative setting, you're seeing more of an impact. Certainly, looking at these curves, we'll have to see with another couple of years to follow up. But a three-year survival of 56% is pretty extraordinary, and I look forward to seeing if this really maintains over the next couple of years follow up.
Moving beyond the Plenary, there were actually lots of really exciting presentations, even outside the Plenary section. One that I think probably got at least as much attention as the ones that we've already discussed today was actually an update of an old trial that's been presented for several prior years. And I'm curious to get your take on why you thought this was such a remarkable study. And we're talking about the LBA8503, which was the 5-year update from the CROWN study, which looked at previously untreated ALK-positive advanced non-small cell in cancer patients randomly assigned to lorlatinib, the third generation ALK inhibitor, versus crizotinib, the first generation ALK inhibitor. What was so exciting about this study, and why were people talking about it?
Dr. Vamsi Velcheti: Yeah, I agree, Nate. We've seen the data in the past, right? Like on the CROWN data, just first like a quick recap. This is the CROWN study, like the phase 3 study of third generation ALK inhibitor lorlatinib. So global randomized phase 3 study in patients with metastatic disease randomized to lorlatinib versus crizotinib, which is a controller. So the primary endpoint was PFS, and we've seen the results in the past of the CROWN readout quoted, with a positive study and the lorlatinib received FDA approval in the frontline setting. But the current study that was presented at the ASCO annual meeting is a kind of a postdoc analysis of five years. The endpoint for the study with central review stopped at three years, and this is actually a follow up beyond that last readout. Interestingly, in this study, when they looked at the median PFS at five years, the lorlatinib arm did not reach a median PFS even at five years and the hazard ratio is 0.19, which is kind of phenomenal in some ways. At 5 years, the majority of the patients were still on the drug. So that's quite incredible. And the benefit was more profound in patients with brain mets with a hazard ratio of 0.08. And again, speaking to the importance of brain penetrant, small molecule inhibitors, and target therapy, the safety profile, there were no additional safety signals noted in the study. We kind of know about the side effects of lorlatinib already from previous studies readouts. No unusual long-term toxicities.
I should note though, about 40% of patients did have CNS, AEs grade 1, 2 CNS toxicities on the lorlatinib arm. And the other interesting thing that was also reported in the trial was dose reduction of lorlatinib did not have an impact on the PFS, which is interesting in my opinion. They also did some subgroup analysis, biomarker testing, biomarker populations. Patients who had P53 cooperation did much better with lorlatinib versus crizotinib. So overall, the other thing that they also had shown on the trial was the resistance mechanisms that were seen with lorlatinib were very different than what we are used to seeing with the earlier generation ALK inhibitors. The majority of the patients who develop resistance have bypass mechanisms and alterations in MAP kinase pathway PI3K/MTOR/PTEN pathway, suggesting that lorlatinib is a very potent ALK inhibitor and on target ALK mutations don’t happen as frequently as we see with the earlier generation ALK inhibitors.
So I think this really begs the question, should we offer lorlatinib to all our patients with metastatic ALK-positive tumors? I think looking at the long-term data, it's quite tempting to say ‘yes’, but I think at the same time we have to take into consideration patient safety tolerability. And again, the competitor arm here is crizotinib. So lorlatinib suddenly seems to be, again, cross trial comparisons, but I think the long-term outcomes here are really phenomenal. But at the same time, I think we’ve got to kind of think about patient because these patients are on these drugs for years, they have to live with all the toxicities. And I think the patient preferences and safety profile matters in terms of what drug we recommend to patients.
Dr. Nate Pennell: I completely agree with you. I think the right answer, is that this has to be an individual discussion with patients. The results are incredibly exciting. I mean, the two-year progression free survival was 70%, and the five-year, three years later is still 60%. Only 10% of people are failing over the subsequent three years. And the line is pretty flat. And as you said, even with brain metastases, the median survival is in reach. It's really extraordinary. Moreover, while we do talk about the significant toxicities of lorlatinib, I thought it was really interesting that only 5% of people were supposedly discontinued the drug because of treatment related AEs, which meant that with dose reduction and management, it seems as though most patients were able to continue on the drug, even though they, as you mentioned, were taking it for several years.
That being said, all of us who've had experience with the second-generation drugs like alectinib and brigatinib, compared to the third-generation drug lorlatinib, can speak to the challenges of some of the unique toxicities that go along with it. I don't think this is going to be a drug for everyone, but I do think it is now worth bringing it up and discussing it with the patients most of the time now. And I do think that there will be many people for whom this is going to be a good choice, which is exciting.
Dr. Vamsi Velcheti: Absolutely, completely agree. And I think there are newer ALK inhibitors in clinical development which have cleaner and better safety profiles. So we'll have to kind of wait and see how those pan out.
Moving on to the other exciting abstract, LBA8509, the KRYSTAL-12 study. LBA8509 is a phase 3 study looking at adagrasib versus docetaxel in patients with previously treated advanced metastatic non-small cell cancer with KRASG12C mutation. Nate, there's been a lot of hype around this trial. You've seen the data. Do you think it's practice-changing? How does it differentiate with the other drug that's already FDA approved, sotorasib?
Dr. Nate Pennell: Yeah, this is an interesting one. I think we've all been very excited in recent years about the identification of KRASG12C mutations as targetable mutations. We know that this represents about half of KRAS mutations in patients with non-small cell lung cancer, adenocarcinoma, and there are two FDA-approved drugs. Sotorasib was the first and adagrasib shortly thereafter. We already had seen the CodeBreaK 200 study, which was a phase 3 study of sotorasib versus docetaxel that did modestly prolong progression free survival compared to docetaxel, although did not seem to necessarily translate to an improvement in overall survival. And so now, coming on the heels of that study, the KRYSTAL-12 study compared adagrasib, also the KRASG12C inhibitor versus docetaxel and those with previously treated non-small cell with KRASG12C. And it did significantly improve progression free survival with a hazard ratio of 0.58. Although when you look at the median numbers, the median PFS was only 5.5 months with the adagrasib arm compared to 3.8 months with docetaxel. So while it is a significant and potentially clinically significant difference, it is still, I would say a modest improvement.
And there were some pretty broad improvements across all the different subgroups, including those with brain metastases. It did improve response rate significantly. So 32% response rate without adagrasib, compared to only 9% with docetaxel. It's about what you would expect with chemotherapy. And very importantly, in this patient population, there was activity in the brain with an intracranial overall response rate among those who had measurable brain metastases of 40%. So certainly important and probably that would distinguish it from drugs like docetaxel, which we don't expect to have a lot of intracranial toxicity. There is certainly a pattern of side effects that go along with that adagrasib, so it does cause especially GI toxicity, like diarrhea, nausea, vomiting, transaminitis. All of these were actually, at least numerically, somewhat higher in the adagrasib arm than in docetaxel, a lot more hematologic toxicity with the docetaxel. But overall, the number of serious adverse events were actually pretty well matched between the two groups. So it wasn't really a home run in terms of favorable toxicity with that adagrasib.
So the question is: “In the absence of any data yet on overall survival, should this change practice?” And I'm not sure it's going to change practice, because I do think that based on the accelerated approval, most physicians are already offering the G12C inhibitors like sotorasib and adagrasib, probably more often than chemotherapy, I think based on perceived improvement in side effects and higher response rates, modestly longer progression-free survival, so I think most people think that represents a modest improvement over chemotherapy. And so I think that will continue. It will be very interesting, however, when the overall survival report is out, if it is not significantly better, what the FDA is going to do when they look at these drugs.
Dr. Vamsi Velcheti: Thanks so much. Very well summarized. And I do agree they look more similar than dissimilar. I think CodeBreaK-200 and the KRYSTAL-12, they kind of are very identical. I should say, though I was a little surprised with the toxicity profile of adagrasib. It seemed, I mean, not significantly, but definitely seemed worse than the earlier readouts that we've seen. The GI tox especially seems much worse on this trial. I'm kind of curious why, but if I recall correctly, I think 5% of the patients had grade 3 diarrhea. A significant proportion of patients had grade 3 nausea and vomiting. And the other complicating thing here is you can't use a lot of the antiemetics because of the QT issues. So that's another problem. But I think it's more comparable to sotorasib, in my opinion.
Dr. Nate Pennell: While this is exciting, I like to think of this as the early days of EGFR, when we were using gefitinib and erlotinib. They were certainly advances, but we now have drugs that are much more effective and long lasting in these patients. And I think that the first-generation inhibitors like sotorasib and adagrasib, while they certainly benefit patients, now is just the beginning. There's a lot of research going on, and we're not going to talk about some of the other abstracts presented, but some of the next generation G12C inhibitors, for example, olomorasib, which did have also in the same session, a presentation in combination with pembrolizumab that had a very impressive response rate with potentially fewer side effects, may end up replacing the first generation drugs when they get a little bit farther along.
And then moving on to another one, which I think potentially could change practice. I am curious to hear your take on it, was the LBA8505, which was the PALOMA-3 study. This was interesting in that it compared two different versions of the same drug. So amivantamab, the bispecific, EGFR and MET, which is already approved for EGFR exon 20 non-small cell lung cancer, in this case, in more typical EGFR-mutated non-small cell lung cancer in combination with osimertinib with the intravenous amivantamab, compared to the subcutaneous formulation of amivantamab. Why would this be an important study?
Dr. Vamsi Velcheti: I found this study really interesting as well, Nate. And as you know, amivantamab has been FDA approved for patients with exon 20 mutation. And also, we've had, like two positive readouts in patients with classical EGFR mutations. One, the MARIPOSA study in the frontline setting and the MARIPOSA-2, in the second-line post osimertinib setting. For those studies, the intravenous amivantamab was used as a treatment arm, and the intravenous amivantamab had a lot of baggage to go along with it, like the infusion reactions and VTEs and other classic EGFR related toxicity, skin toxicities. So the idea behind developing the subcutaneous formulation of amivantamab was mainly to reduce the burden of infusion, infusion time and most importantly, the infusion related reactions associated with IV formulation.
In a smaller phase 2 study, the PALOMA study, they had looked at various dosing schemas like, subcutaneous formulation, and they found that the infusion related reactions were very, very low with the subcutaneous formulation. So that led to the design of this current study that was presented, the PALOMA-3 study. This was for patients who had classical EGFR mutations like exon 19, L858R. The patients were randomized 1:1 to subcutaneous amivantamab with lazertinib versus IV amivantamab plus lazertinib. The endpoints for the study, it's a non-inferiority study with co primary endpoints of C trough and C2 AUC, Cycle 2 AUC. They were looking at those pharmacological endpoints to kind of demonstrate comparability to the IV formulation. So in this study, they looked at these pharmacokinetic endpoints and they were essentially identical. Both subcutaneous and IV formulations were compatible. And in terms of clinical efficacy as well, the response rate was identical, no significant differences. Duration of response was also identical. The PFS also was comparable to the IV formulation. In fact, numerically, the subcutaneous arm was a little better, though not significant. But it appears like, you know, the overall clinical and pharmacological profile of the subcutaneous amivantamab was comparable. And most interestingly, the AE profile, the skin toxicity was not much different. However, the infusion reactions were substantially lower, 13% with the subcutaneous amivantamab and 66% with IV amivantamab. And also, interestingly, the VTE rates were lower with the subcutaneous version of amivantamab. There was still a substantial proportion of patients, especially those who didn't have prophylactic anticoagulation. 17% of the patients with the subcutaneous amivantamab had VTE versus 26% with IV amivantamab. With prophylaxis, which is lower in both IV and subcutaneous, but still subcutaneous formulation at a lower 7% versus 12% with the IV amivantamab.
So overall, I think this is an interesting study, and also the authors had actually presented some interesting data on administration time. I've never seen this before. Patients reported convenience using a modified score of patient convenience, essentially like patients having to spend a lot of time in the infusion site and convenience of the patient getting the treatment. And it turns out, and no surprise, that subcutaneous amivantamab was found to be more convenient for patients.
So, Nate, I want to ask you your take on this. In a lot of our busy infusion centers, the time it takes for those patients to get the infusion does matter, right? And I think in our clinic where we are kind of fully booked for the infusion, I think having the patients come in and leave in 15, 20 minutes, I think it adds a lot of value to the cancer center operation.
Dr. Nate Pennell: Oh, I completely agree. I think the efficacy results were reassuring. I think the infusion related reaction difference, I think is a huge difference. I mean, I have given a fair amount of amivantamab, and I would say the published IRR rate of 66%, 67% I would say, is maybe even underestimates how many patients get some kind of reaction from that, although it really is a first dose phenomenon. And I think that taking that down to 13% is a tremendous advance. I think fusion share time is not trivial as we get busier and busier. I know our cancer center is also very full and it becomes challenging to schedule people, and being able to do a five-minute treatment versus a five-hour treatment makes a big difference for patients.
It's interesting, there was one slide that was presented from an efficacy standpoint. I'm curious about your take on this. They showed that the overall survival was actually better in the subcu amivantamab arm, hazard ratio of 0.62. Now, this was only an exploratory endpoint. They sort of talk about perhaps some rationale for why this might be the case. But at the very least, I think we can be reassured that it's not less effective to give it and does seem to be more tolerable and so I would expect that this hopefully will be fairly widely adopted.
Dr. Vamsi Velcheti: Yeah, I agree. I think this is a welcome change. Like, I think the infusion reactions and the resources it takes to get patients through treatments. I think it's definitely a win-win for patients and also the providers.
And with that, we come to the conclusion of the podcast. Nate, thank you so much for the fantastic insights today. Our listeners will find all the abstracts discussed today in the transcripts of the episode. Thank you so much for joining us today, Dr. Pennell.
Dr. Nate Pennell: Oh, thanks for inviting me. It's always fun to talk about all these exciting advances for our patients.
Dr. Vamsi Velcheti: Thanks to our listeners for your time today. You will find links to all the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.
Disclaimer:
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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Dr. Vamsi Velcheti
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Dr. Nathan Pennell
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Disclosures:
Dr. Vamsi Velcheti:
Honoraria: ITeos Therapeutics
Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus
Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline
Dr. Nathan Pennell:
Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron
Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi
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