OncLive On Air™ is a podcast from OncLive , which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.
Today, we had the pleasure of speaking with Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, and Robert J. Motzer, MD, the Kidney Cancer section head in the genitourinary oncology service and Jack and Dorothy Byrne chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center.
Both Choueiri and Motzer were authors on the CheckMate-9ER study, results of which were recently published in the New England Journal of Medicine and were the basis for the January 2021 approval of nivolumab (Opdivo) and cabozantinib (Cabometyx) as a frontline treatment for patients with advanced renal cell carcinoma (RCC).
In the phase 3 CheckMate-9ER trial, investigators set out to examine the safety and efficacy of nivolumab/cabozantinib vs sunitinib (Sutent) as a frontline treatment in patients with advanced RCC with clear-cell histologic features.
Data showed that the combination of nivolumab and cabozantinib showcased significant benefit in terms of progression-free survival, overall survival, and responses vs sunitinib in the frontline treatment of patients with advanced RCC.
In our exclusive interview, Choueiri and Motzer discussed the clinical implications of the phase 3 CheckMate-9ER trial in advanced RCC and how to best use the combination in practice.
Welcome to only live on air. I'm your host today. Gina morrow on Clive on Air is a podcast from on Clive which provides oncology professionals with the resources and information they need to provide the best patient care in both digital and print formats on Clive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions. Today we had the pleasure of speaking with Tony estuary, MD, director of the Length center for genital urinary oncology, director of the kidney cancer center and senior physician at Dana Farber Cancer Institute, as well as the jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School and robert J. Mozer MD. The kidney cancer section, head in the genital urinary oncology service and Jack and Dorothy Byrne, Chair in clinical oncology at Memorial Sloan Kettering Cancer center. Both Dr Chu area and monster. Were authors on the Chuck made 90 are study results of which were recently published in the New England Journal of Medicine and were the basis for the january 2021 approval of novel a mob and cabos antonym as a frontline treatment for patients with advanced renal cell carcinoma. In the phase three checkmate nine er trial investigators set out to examine the safety and efficacy of novel a mob and cabos antonym versus a. Net. Net as a frontline treatment in patients with advanced RCC with clear cell histological features. Data showed that the combination of novel a madman caboose antonym shook a significant benefit in terms of progression free survival, overall survival and responses versus unit nib. In the front line setting. In our exclusive interview, both doctors, actuary and Monster discussed the clinical implications of the checkmate 90. Our data in advanced RCC and how to best use the combination in clinical practice. I'd love to know what did we learn from the publication of these data that we didn't previously know from other presentations of the study. There was a second update of the data that Dr Moser uh the colleague of the study gave, we during the G. U. Cancer symposium updated the survival was more follow up and we showed that the survival benefit though as uh you know has persisted. The PFS remain has a racial remain very very strong and both dr Moser and sell a also embarked on a much more elaborate and detailed exploration of the patient reported outcome and the quality of life during the asthma 2020 dr Moser and I reported on two metric the f. K. S. I. 19 and the F. K. S. I. The R. S. Which is a subset of f. K. S. I. 19. But during the G. O. Cancer symposium dr motor and seller reported on way more. And it was refreshing to see that the quality of life data, even with more reporting of metrics like time to treatment deterioration, the EQ five Dl and other remains strongly favoring the combination of kabul sentinel naval amount over segment. This was a phase three trial that dr Sherry and I I led, it was sponsored by uh bristol Myers Squibb and my excellent texas. It demonstrated a high level of efficacy for novel ahmad plus cabos over the standard of care. Senate. Both you know, novel a mob is approved in in a mono therapy. And patients who have progressed on Senate and caboose antonym showed a survival benefit in a large phase three trial that Tony and I also lead called the Meteor trial. Uh and this was really the first time that the two were combined And compared to Senate, which has been the standard of care for the last 15 years, it follows on an earlier trial that we both contributed to as well, which was the 2 1/4 trial that that showed a benefit for the Nevo. Compared to Senate Nip. It feels a gap by giving us additional regimen A t K II oh combination that is also Nevo based with a very effective TK i cabos and in first line therapy. Now this combination has recently gained approval in the front line setting. So how would you say that it's changed clinical practice already? How are you best using it? Well, I think overall we started just gained approval and at the time, you know, the drugs hit the system all that, but we're starting to to use it as one of the preferred veg F I. O combination. One of the things about the combination of kabul's intensive, any volume up here is that if you look at the baseline characteristic compared to other studies, it looks like overall the population is more so has more adverse risk. So it is the it's the study that has the least amount of patients with kidney out brian affected me. The patient with poor risk are more so and the favorites are less so than other VHF IO combination like liberalism and accepted them and you have the quality of life data that I believe is one of the most advanced with my GF IO combination. But what I don't know what bob and I are thinking now is is already the next step. And there is a study perhaps bob can talk about that him and I are co leading called Cosmic 313 were already if in the future. Yeah. What's happened in the paradigm is a few years back, Nevo plus mp should superiority over Senate. But there are certainly some gaps in patient care. Not all patients respond to Neiva hippie, some certain groups, uh you know, we are more inclined to treat with veg f target therapy. So I think that the, you know, the cab Geneva was a natural extension of our work together with TK I'll rather than I O I. O combination. And so, you know, the next step which which Tony has led is this cosmic 313 trial which compares the triplet of Nevo ipi plus cab oh two, Nevo epi plus placebo. And so I think it's my impression is it's the top priority. First line trial globally because uh, you know, we're really hoping it's kind of the home run and combines the best of both regiments, the knee vocab, oh and the nouveau hippy regimen and hopefully sustained benefit, long term benefit and crs to our patients. So that is a, you know, that is a trial that was conducted globally. I think it's just see the wrapped up a cruel or has is will be wrapping up a cruel very shortly and hopefully we'll have an answer to that trial sometime next year. There's also a companion trial that's being done through the cooperative group. That is also a a study that's looking at incorporating Cabot Santana with the Nevo and happy as well correct. One thing to say that the cosmic 313 is intermediate and poor risks of those 80% of patients because the control arm, the VP is approved an intermediate and poor. And the other thing is yet to remind everyone about academic alliance led trial uh, by the name pedigree. Where it asked a different question rather than putting all the drugs that have three verses to patients start by an evil hippie. And depending on their response they may or may not need Kabul's antonym. If they have a progression, they go to Kabul. If they have a cr they stay one year on evil. And if in those 70% of patients that don't have a cr don't have a P. D. Usually they get maintenance involvement but perhaps they need caboose internet. So that's where the organization will happen with an OS primary endpoint I think you know, it's a very strategic trial to not answer the question is three superior to do but it's three superior to do in a certain sequence. And this trial is uh accruing actually pretty well. And through Alliance open at many sites in the United States, it definitely speaks to this precision oncology which were very much involved and very much in right now but really carries on that trend into the future. And tailoring to these specific patients novella magma composition is not the only, you know, TK a combination that we have available. Right. So how does this compare do you think in your own personal opinion with volumetric sittin in Pembroke city neb? How are you deciding, you know which patients should get which combination? And is there a really kind of optimal sequence? Can you go with one and then use another a combination in the second or third line. Besides involvement. People in Pembroke based combination Pembroke taxi or pam Roland have an overall survival benefit. And we've seen with dr Moser leading the Pembroke land the clear study there is quite an intriguing efficacy parameter with the cr of 16% and a P. F. S The only Pff over 20 months. So this is very interesting. The one thing with pam Brooklyn, it seems that you know, there are a bit more favor risk on the trial but and there is no quality of life yet. Hopefully the quality of life data, you know, comes in. But it's certainly a very important option if this is to be, you know, provided and I can Commend whether one over the other because they haven't been compared to each other. They were against an intuitive and I wouldn't say it's the same population simply because not looking at the baseline characteristic, but looking at the performance of selective in each arm which ranges between eight and 11 months. So, you know that that's because the characteristic or you could look at the Cr eight for Senate and on each arm. So, you know that baseline, they're different trial per se in terms of your question could remove from, from one combination to another. I think the problem the biggest problem here these are PT one and PT L. One based combination. So if the patient tumor progress on first line let's say caboose entities and the volume A. Should and then they get the T. K. I. Should. The third line or a second line beep embolism. A. Blood and lymphatic. What is the data of using A. P. D. One pd L. One after progression on Pd one pd L. One. This is not you know I don't want to say these are packaged together as frontline untreated patient. It doesn't mean they could be or they should be given later to that end. There are two studies here that were involved in perhaps dr Moser can talk about where the experimental arm is continuing the checkpoint inhibitor. The other thing is is I think there's really three stand out I O T. K. I combinations. Uh You know, I think they're the embolism. Ob executive keynote 4 26. The lymphatic embolism mob and the cowboys and the NovoLOG from our new England Journal of Medicine publication. They all showed improvement in response PFS and overall survival compared to synonyms. So I think to a certain extent, you know, they have distinguished themselves from a value modern exhibit. We really can't make cross study comparisons to pick the winner. I believe they're all very effective. So I mean I kind of look upon it as they them all being confirmatory for the approach of TK IO efficacy and first line therapy. Uh And in terms of choice for one over another. I mean I think it's going to depend on the level of comfort with the prescribing physician. I think it's going to be familiarity with one drug or another. What's what combination is kind of easiest to give, What what's the best experience that the physician the community has with one one program over another. In terms of you know, follow up therapy. I mean there was a large trial single arm study that we did that looked at live at pembroke oh and patients who had progressed on prior cryotherapy that showed a a you know a high response rate. Pretty good progression free survival in that population. But the question really is unanswered in terms of whether there is a benefit for continued iO therapy in patients who have progressed on first line, I'll regimen and particularly an I. O. T. K. I. And so there is one study that is open. It's called the contact trial DR XU areas, the leader that were participating in that M. S. K. As well. And that and that is looking at Cabot Santana. And it is Elizabeth versus caboose and have been patients who have progressed on first line i. O therapy. So I I think that the that remains kind of an open question. True. That's true. So there is this study which I call it with dr multiple and there's another study that I actually call it with with Dr Mozer which is looking at a new drug that just got approved by the name. Even if it's a clean VHF T. K. I that has a story in renal cell. A very very long story initiatives. Dr Moser with steve 01 But now it got approved as a monotherapy in third line versus our affinity. And now we're taking this doctor was on to the next step to combine it with the volume um versus divas alone in patients whose tumors progressed on prior bio based therapy. And that study is gonna, you know, it didn't open yet, but there was a press release a couple of days ago that, so it's in the public domain that it's being planned. So we're both very excited about that trial. I think one of the several aspects of that is to positive is not, it's not used in first line in the United States. And so patients will not have had to vote on a prior. I think one of the limiting factors for some of the, you know, the caboose and a second or third line trials is now it's a first line program, but none of the patients who have gotten to those in the first line. So it's really kind of a fresh approach. And there's really been a lot of excitement around to bozo because it's, it's a very well tolerated compound that we've really hoped would be available for our patients for a long time. And with this recent approval, it's, you know, it will be. And so I think it's a very exciting trial. It will be one that patients will really seek out and uh, and want to be treated on that program. Going back to checkmate 90 are. This was a study that everybody was talking about on social media. What what do you think it is about this combination that has garnered so much attention and traction amongst the community? There's been, you know, a lot of kind of favorable opinion about Cabazon Cabazon that came in a little late in RCC, our military. Um, but it's joan, really exceptional activity uh, in the meteor trial with the benefit and overall survival compared to ever lima's. It was really pretty striking benefits and overall survival have been elusive previously. And just about all our trials in RCC and so it also, and Tony letter trial called the Cabazon that should go to benefit and first line therapy compared to some negative. So I think for Cabot santa, it's all about efficacy. Uh it's very widely used by physicians. They're very comfortable using cameras and have been 2nd and 3rd line therapy. So it was no surprise that there was striking efficacy that we showed in 90 are in the new England Journal of publication. And I think it's it in certain ways it's a very it's a drug that we're very comfortable with giving. It's a flat dose in mono therapy at 60 mg, but in the combination it's 40 mg and you know, dose reduction to 20 or even 20 other every other day. So I think it's it's a very easy program for people to give. And RCC. Oncologists are very familiar with That drug based on its extensive use in second 3rd line therapy. The one thing is if we, you know, there's a lot of pre clinical rationale for caboose internet because of the immune modifying behaviour of the caboose internet targeting kindnesses like veg F. R. Which we know that but also met. Extell attire A. Three, you know, murder. How it helps how Jeff inhibit budget by itself. Inhibit demonstration of dendritic cell and reduces lymphocyte infiltration and also the release of A. G. F. And the met activation that drives Pd L. One expression and the role of Excel all to play a negative role if you want in uh in the immune system fighting the cancer. So caboose Anthony comes here and it does have this immune permissive you know, properties here overall by targeting all these uh kinesis and there's a lot of clinical pre clinical data around it now. How that is that only all these properties contributed to compose Anthony efficacy or simply because it's a better version of R two, we don't know, but it is believed if you look at the pre clinical that that matter, same thing a bit with limb botany. The talk in addition to veg f r f G f R which is involved in resistance to Jeff inhibitor, but also in some, you know, immune model battery effect. Is there anything else about checkmate 90 are that you want the community to know about? It's a very effective regimen. It's a regimen that's easy to give. And the, you know, the study suggested that it's a fairly tolerable regiment and I think that part of the tolerable. Itty, the good tolerable if he was the choice of the caboose antenna, but a slightly lower dose that scene in monotherapy. I agree. I think also it will be good to look at further subgroup analysis and more updated results. One of the things with all these red ref IO, we need to know how that has a ratio for Os uh stays and uh and we have two updates I think with Keynote 4 26 and two updates for 90 are and that has a ratio for us is persistent. Um, so we have will continue also looking at this and challenging the dogma from 1 to 2 to drugs combination. Hopefully to three drug combination obviously cost matters and we have to take that in perspective. Tolerable. Itty is very, very, very important. So we have to look at that extremely closely because common sense three drugs are more toxic than to but how much what's the balance and we're gonna continue this exciting field of renal cell cancer. That's all we have for today. Thank you for listening to this episode of on Clive on air. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field. And recapture mercy to the science summits and institutional perspectives in cancer webinars. More updates and oncology. Be sure to visit www dot on Clive dot com and sign up for our e newsletters on Clive is also on social media on twitter, follow said on Clive and on Clive S O. S s on facebook like I said on Clive and enclave state of the Science summit and follow her on club page on linked in if you like. Today's episode of enclave on air is consider subscribing to our podcast on apple podcasts or Spotify. 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