Dec 9, 2021
Guest host, Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief and director of the Genitourinary Cancers Program at the University of Utah’s Huntsman Cancer Institute, discusses the practice-changing KEYNOTE-564 and SWOG 1500 trials with Drs. Toni Choueiri and Sumanta "Monty" Pal. Dr. Choueiri is director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Dr. Pal is co-director of City of Hope’s Kidney Cancer Program and associate editor of Cancer.Net. (This episode was recorded on 11/18/2021)
Transcript
Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News podcast. I am Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program, and the professor of Medicine at the University of Utah Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News.
I'm delighted to welcome two internationally recognized leaders in the field, Dr. Toni Choueiri and Dr. Sumanta (Monty) Pal, for a discussion about two practice-changing studies in kidney cancer published this year-- KEYNOTE-564 and SWOG 1500.
As a quick introduction, Dr. Choueiri is the director of Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute. He's also the Jerome and Nancy Kohlberg Chair, and professor of medicine at the Harvard Medical School. Dr. Sumanta "Monty" Pal is a professor in oncology, and co-director of City of Hope's Kidney Cancer Program, and he is an associate editor of cancer.net of ASCO.
Our full disclosures are available in the show notes. And disclosures relating to all episodes of podcasts can be found on our transcripts at ASCO.org/podcast.
Toni and Monty, what a day it has been for our patients with kidney cancer. I woke up with the news of the U.S. Food and Drug Administration (FDA) approval of the first ever adjuvant immunotherapy for patients with renal cell carcinoma. It is so great to have you both on the podcast today.
Dr. Monty Pal: Glad to be here. Thanks, Neeraj.
Dr. Toni Choueiri: Thank you, Neeraj. So glad to be here.
Dr. Neeraj Agarwal: So, let me start by asking questions to you first, Toni. So, you recently published the primary results of the phase 3 KEYNOTE-564 study, showing the efficacy of adjuvant therapy with pembrolizumab and immune checkpoint inhibitor in patients with renal cell carcinoma. And this study led to the approval of pembrolizumab this morning. So, please tell us more about the study design and why did you do this study.
Dr. Toni Choueiri: Thank you, Neeraj. And thank you, really, ASCO for this wonderful podcast series. And a big hit, I always listen to them when I'm driving or jogging. And really, thanks for this opportunity because kidney cancer adjuvant therapy has been something like a holy grail we're trying to find for a long, long time.
The first adjuvant trial, a randomized trial, in renal cell cancer was in 1973 with radiation therapy. And since that time, all the trials except for one have been a complete failure in a way. And the first adjuvant immunotherapy trial was with old immunotherapy cytokine that we don't use much anymore and was in 1992. I was not done with medical school. I was not actually done with high school at that time, let alone medical school.
And now that we have, as we all know, a revolution in the oncology field through these immune checkpoint inhibitors that reinvented immunotherapy in cancer, and now that pembrolizumab has shown activity in patients with more advanced disease, we thought about taking this into the adjuvant setting, a setting of patients where they were subjected to surgery. But on the pathology report, we knew that their risk of this cancer coming back, of recurrence, is somewhat intermediate high or high.
These are patients that have stage 2 but grade 4, stage 3, D3, D4. These are patients that had node-positive resected. And we took even patients where the kidney is out, but, also, they had a removal of a metastatic site--let's say a lung metastasis--within a year of removing the kidney. And we know these patients we refer to as M1NED are at quite high risk of recurrence.
And we randomly assigned 994 patients to receive pembrolizumab for a year versus placebo. And after a median follow-up of only 2 years--so I want to insist here that this is short for any trial in general--we saw a decrease in the risk of recurrence or death. The hazard ratio for disease-free survival was 0.68. So, a 32% decrease in the risk of recurrence or death.
We looked at safety, and we already are familiar in the field of GU oncology with pembrolizumab. And we didn't see when we looked at the safety profile any surprises, any enhanced toxicity. Of course, immune-related adverse events are the number one concern with pembrolizumab. There were no deaths on trial related to pembrolizumab. We saw around 7% of patients needing high dose steroid to medicate these immune-related adverse event, and some patients had to come off therapy for that.
We also took a look, Neeraj, an early look, at overall survival. We only had 25% of events, 51 deaths. And we did not meet the very rigorous statistical significance that is needed to say that study is positive for overall survival. But the hazard ratio was 0.54, a 46% decrease in the risk of death, which is kind of encouraging. And after a year, the curve starts to separate. Before a year, they're not separating. And that is consistent with prior studies in general.
Dr. Neeraj Agarwal: This is a very interesting point you just raised, that DFS, disease-free survival, is strongly positive. And even overall survival is trending in the right direction, right?
Dr. Toni Choueiri: Correct.
Dr. Neeraj Agarwal: That's great. So obviously, I would like to raise another point here. When we talk about adjuvant study, we usually think about a localized kidney cancer, which is removed by the surgeon, and then [the] patient is coming to see us for treatment in adjuvant setting. But this study, I would like to highlight, as you said, also included patients who had oligometastatic disease, had successful surgical removal of the oligometastatic disease, and they were also eligible for this trial.
Dr. Toni Choueiri: Yes, absolutely. And I think this is somewhat on the recent side in clinical trials in kidney cancer. The reason for that is that, in practice, we see those patients. And we even had two small trials in the TKI era with sorafenib and pazopanib, small studies, were also completely negative. So, we thought here that we should not exclude these patients. They end up being 6%, 7% of all participants, but this remains an area of unmet medical need.
Dr. Neeraj Agarwal: So, how is the hazard ratio in those patients who had metastatic disease removed and then treated with pembrolizumab?
Dr. Toni Choueiri: Yeah, it was very low. It was 0.2, so 0.29. And this was great to see. I don't want to go into really over-interpreting these results. All the hazard ratio--when you look at subgroup analysis or in the forest plot, all the hazard ratio are less than 1. We didn't see something--let's say 1.5--in favor of pembrolizumab.
Now you go into a smaller subgroup, then your confidence intervals are very large and hard to interpret, except that to say, look, on average there could be a significant benefit here, but we can't tell.
Dr. Neeraj Agarwal: Sure, absolutely. I agree with you. So, how this is going to affect the current treatment paradigm, which is for patients with newly diagnosed metastatic RCC, where combination of VEGF-TKI plus immunotherapies (IOs) or IO/IO combinations have become standard of care or treatment paradigm?
Dr. Toni Choueiri: I do believe it will be a standard of care currently in the right population. There are a lot of unanswered questions, but that will be answered hopefully with more follow up. We have already, beside these results, reported--so these results were reported in the plenary session at the 2021 ASCO [Annual Meeting]. But later on, another analysis dealing with patient-reported outcome and quality of life was reported at ESMO and also showed no detriment in quality of life--that's the voice of the patient--no detriment with pembrolizumab (pembro).
There is a lot still to do and a lot of unanswered questions, such as the non-clear cell histology, those patients who had surgery of their metastatic disease more than a year. But most important, I think, two questions. One, how can you know from the get-go who are the patients that need adjuvant pembrolizumab? We do not have any valid ctDNA.
And I know Dr. Pal was involved with a lot of these type of research. We don't have any ctDNA test that is really that faithful and sensitive in the MRD space in renal cell. Many of us are working, so we don't know. We may end up over-treating patients that need surgery only. And actually, we may end up under-treating patients that need, perhaps, pembro, and another drug.
And the second thing in those patients--and I hope it does not happen, but unfortunately, it will to some extent--whose tumor progress on adjuvant pembrolizumab, what do you do? What's the treatment paradigm? And actually, there is no data. This is a data-free zone. And I would think somebody whose tumor progressed, tumor continued to grow or grows, while they're actively on pembrolizumab, on IO, is way different than someone whose tumor comes back after 2 or 3 years from stopping the drug.
Should we treat them with the same drug? Should we treat them with the TKI plus IO? Luckily, there are trials that are ongoing in patients whose tumor progressed after PD-1/PD-L1 inhibitor to give them a TKI as a control arm, or a TKI plus an immune checkpoint inhibitor. And I know Dr. Pal is very heavily involved with such trials. So, hopefully, we will answer this question, but not anytime soon.
Dr. Neeraj Agarwal: Very interesting, and definitely new results are posing new challenges in how we practice medicine here in the coming future. So, Monty, you are leading a trial with a very similar trial with atezolizumab. And I'm really hoping, we are all really hoping, that we see the other trial being positive, so we have more treatment options for our patients.
Dr. Monty Pal: I couldn't agree with you more. I mean, I definitely think that Toni's study really adds a lot of fuel to the fire suggesting that this strategy of adjuvant immunotherapy may be successful in localized renal cell.
Dr. Neeraj Agarwal: And I'm not going to really delve into the side effects of pembrolizumab and atezolizumab because these drugs are used quite often. They are in widespread use for different types of cancer. But just a quick question, any safety signal, Toni? Did you see any safety signal with pembrolizumab in this patient population?
Dr. Toni Choueiri: Yeah, this is an excellent question. So, nothing that would be different than using pembrolizumab overall knowing in other diseases as a single agent. So, this drug not first in human, as you know, and it's been approved in combination or as a single agent in many diseases. A tumor that the three of us treat is bladder cancer, and we know from another study how to use pembrolizumab.
I think that the use of corticosteroid is somewhat of an objective way, at least to me, in looking at immune-related adverse event. And it has been between 5% to 10%, so we're not way off here. But there is no doubt that there are patients that we had no death on trial attributed to drug that may have, with pembrolizumab, some serious toxicities. We had patients that had autoimmune diabetes, hypophysitis, pneumonitis--quite uncommon, but not impossible.
Dr. Neeraj Agarwal: We'll still need to keep an eye for that, basically.
Dr. Toni Choueiri: No doubt.
Dr. Neeraj Agarwal: Yes. So, changing gears, let's talk to you, Monty. You recently presented the primary results of the SWOG 1500 trial in patients with metastatic non-clear cell renal cell carcinoma. Could you please tell us why you did this study and how this study's design was unique compared to similar studies in this setting?
Dr. Monty Pal: Yeah. No, absolutely. Toni did a great job of outlining areas that are sort of free of data in the adjuvant space, particularly with immunotherapy. I think that data-free area for us in kidney cancer for a long time has been non-clear cell histology. We just don't really know how to treat them.
And I actually got advice from Toni when I was devising SWOG 1500. We planned it out as a very simple study comparing sunitinib and cabozantinib. And Toni will remember this history well. It sort of went through several iterations. The study blossomed into a six-arm trial. Ultimately, it turned into a four-arm study, looking at sunitinib versus cabozantinib versus two other MET inhibitors--savolitinib and crizotinib.
And ultimately, the study was boiled down to essentially what we'd originally proposed. Two of the MET inhibitors--savolitinib and crizotinib--failed to surpass that initial analysis for PFS. So, ultimately, we demonstrated a superiority with cabozantinib over sunitinib for progression-free survival.
Dr. Neeraj Agarwal: So, what is the current treatment paradigm for patients who have newly diagnosed metastatic papillary RCC now?
Dr. Monty Pal: I think for patients who don't have genomic selection, I think that cabozantinib remains the standard. I really want to champion- and maybe Toni can talk a little bit more about this--a study that Toni is leading called the SAMETA trial, which I think has a really innovative design. And it's going to be genomically characterizing patients and randomizing to savolitinib with durvalumab or sunitinib. Tell me, Toni, if I have the design right there.
Dr. Toni Choueiri: Yes. Actually, this is a specific study in a specific population. It's not in papillary RCC as much as in those 30%, 40% of papillary RCC that have MET-driven tumors, so MET alteration, whether through chromosome 7 duplication, through chromosome 7 trisomy, through mutation or amplification.
These patients will get either control arm or they will get savolitinib, which is a pure MET inhibitor that is devoid of VEGF-related toxicities, savolitinib plus durvalumab, or durvalumab alone. So, two experimental arms and one control. And the reason for this is we saw activity and quite a good toxicity profile with savolitinib, a pure MET inhibitor, over sunitinib in an earlier trial that was sunitinib against savolitinib in selected patient populations. The study had to close early. So, despite the numerical difference, this was not statistically significant.
And then in another study led by Dr. Powles and colleagues, there was also some interesting activity how durvalumab could augment that activity. So, we're launching a phase 3 trial with three arms that you described very well.
Dr. Neeraj Agarwal: That's wonderful. So, what are the next steps, Monty? I mean, this is amazing to see you designing an investigator-initiated trial. This was your concept. You designed it. You built this to be a huge multicenter trial, which was open across the country, funded by the National Cancer Institute.
And congratulations for making that happen. It's rare for us to see these trials going from a concept stage to a national trial, and then changing the standard of care. So, what are the next steps now for you and your team in SWOG for papillary RCC or metastatic papillary RCC? How do you build out further with the backbone of cabozantinib?
Dr. Monty Pal: I really appreciate the question, Neeraj. It's so critical to understand that we're just not quite done yet. Toni's study, as I've mentioned, is incredibly innovative. I'm also really thrilled to be working with someone who you've mentored so well, Ben Maughan, at the Huntsman Cancer Institute in Utah. And he's actually designed a brilliant study, which we're going to be leading together, which looks at cabozantinib with or without atezolizumab.
Recently, in a study that you and I and Toni were a part of that we just published in JCO, we actually saw quite impressive response rates with the combination of cabozantinib and atezolizumab in patients with papillary RCC, around 47%. Those response rates were actually replicated in a separate study run by Joe Lee at Memorial Sloan Kettering. In the context of papillary disease response rates were again above a threshold of around 40%.
So, I think there's something to it. But until we really subject this to randomization, I think we're not going to know whether or not cabo plus IO is standard. So, I encourage everyone to consider Toni's study. I encourage everyone to look out for our trial of cabo plus or minus atezo, which should be rolling out next year.
Dr. Neeraj Agarwal: What is the name of the trial, or the number, for our audience?
Dr. Monty Pal: Yeah, we lucked out with another great number. We got 1500 for the first trial. This is going to be SWOG 2200. So SWOG 2200, and I think it's due to open maybe in the first quarter of 2022.
Dr. Neeraj Agarwal: That's fantastic news. Any new signal? We know cabozantinib is already approved for our patients with metastatic RCC, courtesy METEOR trial led by Dr. Choueiri. Toni, it's amazing to see how many times you have changed standard of care for our patients with metastatic RCC. So, any new safety signal of cabozantinib in this patient population with metastatic papillary RCC?
Dr. Monty Pal: Nothing that appreciated. The toxicity profile was pretty much on par with what you'd anticipate for cabozantinib in the setting. Major side effects were hypertension, hand-foot syndrome, [and] diarrhea. Nothing that really sort of stood out relative to what we would expect in a clear cell population of patients.
Dr. Neeraj Agarwal: That's great. Any final messages for our patients, for our audience, for our listeners?
Dr. Toni Choueiri: Well, let me start, and maybe Monty can add. It's been, and it hopefully will continue to be, this humbling experience, where median survival from metastatic RCC in mid-2000--not long time ago during our training--has been 1 year. And now in metastatic disease, it's 4 to 5 years. And that is only going to get better.
And then it's even more humbling to be in a time where you can talk about adjuvant treatment in this disease, renal cell cancer, that continues every year to kill, unfortunately, 14,000 Americans. That's just in the U.S. alone. So, we have to continue in getting more targets, more drugs, more reasonable combination, and the right patient, whether through specific biomarker that are tissue or blood-based or specific liquid biopsies that can tell you who has and who doesn't have cancer at the microscopic levels.
Dr. Neeraj Agarwal: Thank you. How about you, Monty? Any final message for our audience?
Dr. Monty Pal: I couldn't have summarized it better than Toni, just such a wonderful statement around optimism for what we've achieved so far and what's yet to come. And if I could emphasize to anyone in the audience today the need to keep progressing the field further with clinical trials, I think that would be my underlying message.
Dr. Neeraj Agarwal: Thank you again, Toni, Monty, for your valuable insights and thoughts. Thank you for all the inspiration. This is indeed so inspiring to see your work, which is changing the lives of our patients on a daily basis. Our listeners will find links to your studies in the transcript of this episode. I wish you all the best.
Dr. Toni Choueiri: Thank you.
Dr. Neeraj Agarwal: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you so much.
Disclosures:
Dr. Neeraj Agarwal:
Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Pfizer, Merck , Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Foundation Medicine, Gilead Sciences
Research Funding (inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, crispr therapeutics, and Arvinas
Dr. Sumanta (Monty) Pal:
Consulting or Advisory Role: F. Hoffmann LaRoche, F. Hoffman
Research Funding (inst.): Eisai, Genentech, Roche, Exelixis, Pfizer
Travel, Accommodations, Expenses: Genentech, Seattle Genetics
Dr. Toni Choueiri:
Employment: Dana Farber Cancer Hospital
Leadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCO, ESMO
Stock and Other Ownership Interests: Pionyr, TEMPEST
Honoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group,
AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck , Novartis, Peloton Therapeutics , Pfizer, Corvus Pharmaceuticals, Ipsen,
Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Healthcare, Kidney Cancer Journal, Exelixis, Prometheus, Lpath, NEJM, Lancet Oncology, Cerulean Pharma, alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQvia, Aveo, and NCI.
Consulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus Laboratories, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis,
Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, Paltform Q, Navinata Healthcare, Harborside Press, ASCO, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, and Aravive
Research Funding (inst.): Pfizer, Novartis, Merck, Exelixis , TRACON Pharma, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Astellas, Bayer, Foundation Medicine, Roche, Calithera Biosciences, Analysis Group, NCI, GATEWAY for Cancer Research, and Congressionally Directed Medical Research Programs (DOD)
Patents, Royalties, Other Intellectual Property (inst.): International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response
Patents, Royalties, Other Intellectual Property: ctDNA technologies
Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Journal, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Healthcare, NEJM, Lancet Oncology, EMD Serono, HERON, Lilly, and ESMO
Other Relationship: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel
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