CheckMate 9ER: Extended Follow-Up Reveals Long-Term Benefits of Cabozantinib-Nivolumab Combo for Advanced Renal Cell Carcinoma - Toni Choueiri

December 7, 2022

In this conversation, Pedro Barata hosts Toni Choueiri to discuss a significant paper that he published on the CheckMate 9ER trial, which has established the combination of cabozantinib-nivolumab as a new standard of care for patients with advanced renal cell carcinoma. The extended follow-up analysis of about 33 months showed statistically significant and clinically relevant progression-free survival, overall survival response rates, and decreased risk of death compared to sunitinib monotherapy. Dr. Choueiri also addressed the promising benefits of this treatment across various subgroups, including patients with sarcomatoid features, bone metastasis, and kidney involvement. The discussion then shifted toward the future prospects of triple therapy treatments, emphasizing the importance of clinical relevance, toxicity, and quality of life when evaluating these new combinations.


Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute

Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH

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Pedro Barata: Hi, I'm Pedro Barata. I'm a GU medical oncologist at Tulane Medical School in New Orleans, Louisiana. It's a really a privilege to have here with me, colleague, mentor, friend, Dr. Toni Choueiri. He's the Director of Lank Center of GU Oncology Dana-Farber Cancer Institute, the co-leader of the Kidney Cancer Program at Dana-Farber and Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School. Thank you so much, Dr. Choueiri, for joining us today.

Toni Choueiri: Oh, thank you. Thank you Pedro, and thank you UroToday for always being in the forefront of information in oncology.

Pedro Barata: Now, that's great. First of all, let me congratulate you for the very important paper that came out recently, we're talking about, of course, CheckMate 9ER, that established cabozantinib-nivolumab combination as a new standard of care for patients with advanced renal cell carcinoma. You basically got an extended follow up analysis close to 33 months, I believe, and you basically report the activity of the data from that trial with a longer follow up. And so, again, congrats for that. That's an important paper to be out there for us to have access to. Maybe I should start by asking you, can you give us the highlights of these updated analysis with these extended follow up of over 32 months?

Toni Choueiri: Yeah, absolutely. You referred to a paper from this month in Lancet Oncology looking at long-term follow up from the doublet, the nivolumab-cabozantinib versus sunitinib. Doublets now in advanced metastatic renal cell carcinoma are standards. In this study, in this phase III trial, we randomized patients to the combination of nivolumab and cabozantinib at 40 milligram once a day. So this is an important distinction that we didn't go for the 60 milligram once a day that is approved as a starting dose in monotherapy. Here it was 40 milligram once a day with nivolumab, the PD-1 inhibitor, versus sunitinib at the standard dose. And this is one of the studies of many against sunitinib, a standard of care in metastatic clear cell RC we do not recognize anymore.

What we did here, initially, we presented during ESMO, the first time ESMO 2020, believe it or not, 2 years ago, the first result during the planetary session. The follow up was 18 months only, and we published concomitantly in the New England Journal of Medicine. Response rate, PFS, OS were all improved versus sunitinib. Now, what we did is that we did have almost 33 months or follow up, and with 33 months of follow up, the progression-free survival, overall survival response rate remained statistically significance and clinically relevant. There was 30% decrease in the risk of that with the combination compared to single-agent sunitinib. We also looked at updated toxicity and there was no difference from the first paper and the first results. Also important is to look at several subgroups, and perhaps we can discuss that next, and what subgroups can bring to the table.

Pedro Barata: Yeah, no, thank you for that, because that's kind of my follow up question and thank you for this beautiful overview of the development of Cabo-Nivo. I think you're absolutely right. When we look at the baseline characteristics, and we cannot compare across style trials Because all the patient populations are different, but if we were to say this particular trial, I think, enrolled more real-world data, or patients, if you will, they're kind of sicker, more poor risk, or with less nephrectomy, percentage-wise at least, that we normally see in other large trials out there. But, despite that, you've shown the benefit of Cabo-Nivo in those special groups, and also patients with difficult patient and disease characteristics like liver mats, bone mats, tumors with sarcomatoid features. How do you think it's important for the treating physician out there to see the activity of these agents in these special patient populations?

Toni Choueiri: Yeah, no, I think this is a very good point you make. We included trial like Nivo-Cabo, Pembro-Len, Pembro-Axi, Atezo-Bev, all these phase III trials we are open for all risk groups, but what you end up with is you end up with, so Cabo-Nivo, CheckMate 9ER, ended up with the least amount of favorable IMDC prognostic patients. Everything else was over 30%, Pembro-Len, Pembro-Axi, here it's 23%. If you look at patients with kidney in place, they were also higher in the Cabo-Nivo. So, even with that, the benefit persisted with more follow up. The hazard ratio for overall survival, got, if you want, less than the original data. And that's something we're seeing with all VEGF IO combination with follow up that we are not seeing with CheckMate 214, nivolumab and ipilimumab. Maybe the durability of responses are not as good if you don't have a CTLA-4. We don't know. We need more follow up. The only study that has significant follow up to 4 or 5 years is CheckMate 214. All the VEGF IOs, Axi-avelumab and Axi-Pembro happen, and shortly after the other one, Cabo-Nivo and Pembro-Len. So we need to wait.

But, but, but some encouraging thing is the rate of complete responses. And we know now from the presentation of Dr. Cristina Suarez at ASCO 2022, that complete responses and deep responses associated with overall survival, the complete responses are up to 12% in Cabo-Nivo. We looked also at some analysis that are important, because you rarely have a clinical trial dedicated to patients, for example, that have bone metastasis. Although we are starting to have patients with sarcomatoid features, et cetera, and the survival was superior. And I want to highlight the post-hoc analysis. It's exploratory, just to be clear here, that look at depth of response by organ site, still a higher proportion of patients had target lesion shrinkage with Nivo-Cabo than with sunitinib, including in the primary. So those are very important extra information for this study.

Pedro Barata: Now, this is fantastic. I really appreciate it, and how you bring all the data together and tell the story around that, that's really helpful for us. I'll get you a challenge question here as well. I have to say, I think it's beautiful to see the development of cabozantinib, either monotherapy and combination, in the RCC arena. I still go back, met your time with Cabo established as a second-line preferred regimen in the refractory setting, then Cabo-Sun that you led those efforts for front-line, also in the non-clear cell histologies with [inaudible 00:08:03], establishing it as a superior TKI against sunitinib, for example. And now we have, obviously, combination, not only CheckMate 9ER that we're just talking about, but also, I'm thinking data in the non-clear cell. That colleagues have published that data.

My point is, we clearly see an activity of these combination regiment across multiple RCC subtypes, if you will. And my next question is, we are awaiting for triple therapy data. We don't know what it's going to look like, but we are waiting for that. My question, and kind of challenge would be, given the fact that these Cabo-Nivo combo is so active, how do you see, or what do you'd like to see with a triple therapy, whether it's Cabo-Ipi-Nivo or a different triplet, to make you change your practice? Or do you actually believe that in 2 years from now we are going to be in a position where we are going to pick a doublet for some patients in a triplet for other patients? What are your thoughts about a triple in the context of the very active doublets that we have, including Cabo-Nivo, of course.

Toni Choueiri: I think, Pedro, this is a very fair question. You know how my my favorite series, Game of Thrones, winter is coming. I say in my thoughts, triplets are coming. But I don't know about that. I think they're coming, meaning we are doing the studies. Merck is embarking on a large program with triplets, where the control arm is VEGF IO. Excels embarked already, finished the study, where the control arm is Nivo-Ipi and they add Cabo to that.

Now, I can tell you that I think when you add the drugs, you have to always, always, first and foremost, think about patients. Most important. And what's in for patient and if you can achieve more or same with less drugs, that means less toxicity, less hassle. So when you add the drugs and when you go establish two is better than one. There are some exceptions. Some non-clear cell, maybe the favorable risk, those 20%, still controversial to some, not too many, because it's OS that is not, but PFS response rate are clearly favoring combo.

But I think with triplet, especially that the triplet is involving, in many studies, the CTLA-4, which has its own toxicity, I think you have to start seeing more convincing signals. So what are the signals for me? Let's take and dissect COSMIC-313. Important study, over 800 patients, Nivo-Ipi versus Nivo-Ipi-Cabo at 40. The first thing, which is quite important, the study was done in intermediate and poor, so it excluded good risk. I think that's great in a way, because it takes those patients that really need treatment those 75%, 80%, that probably need treatment. Knowing, in theory, you and I know that the IMDC risk scores are not completely a hundred percent perfect. You can see a favorable risk when you see them in clinic, they need therapy. And you can see someone with poor risk, they meet and you say, "Wait a second, this person is oligometastatic. I don't want therapy." Now, this is very uncommon.

The first thing is triplet is in intermediate poor if the study is positive. Second, despite the primary endpoint is progression-free survival, I think we need to look very carefully at overall survival. If the progression-free survival is positive statistically, how clinically relevant, especially if the OS hazard ratio, let's say, is 1 or 1.05? I like to see an OS benefit with triplet. The third thing we are saying is that CTLA-4 is what drive a durable response. Where, with Cabo-Nivo, we're seeing now after longer follow up, and we won't have that with 313, a CR rate of 12%. Those are the best actors. Okay, great. I want to see, now that I'm adding a CTLA-4, assuming it's the same risk criteria because 9ER is an all-risk, I want to see a CR rate over 12% for patients. I want to look at the toxicity and the quality of life. I want to see how many patient discontinued therapy.

So, luckily COSMIC-313 is not a small study. It will be a huge problem if it was like a randomized phase II of 200, 300 patients, because these are the studies that will be hard to interpret unless they're slam dunked. Like with Cabo-Sun, response rate PFS favored Cabo, there was an independent center review, there was a lot of analysis. It's a small study, but it all went the same direction, and OS hazard ratio was less than 1.8. So I'm glad it's a large study. Many of us involved in will be very important to see, in the right population, if triplet is going to make it, but the stakes are high.

Pedro Barata: Well, this was absolutely fantastic. Thank you for that. We started at, at 9ER extended follow up analysis and wind up kind of predicting the future, if you will. And also, thank you for lecturing us also on the importance of what elements from a clinical trial we like to look at and how we take that to our clinical practice. I'm looking forward to the future. I'm looking forward to more conversations with you, of course. It's such a privilege to be able to chat for these few minutes on the data. And finally, congratulations again for this very important, important paper to be out there. And so, with that, thank you so much, Dr. Choueiri, it was a pleasure to have you here today.

Toni Choueiri: Thank you, Pedro. Thank you UroToday. It's always a teamwork and hopefully we will see you soon live, not just by Zoom.