ESMO 2020: CheckMate-9ER Study of Nivolumab Combined With Cabozantinib Vs. Sunitinib in Participants With Previously Untreated mRCC - Toni Choueiri

September 28, 2020

Following the Presidential Symposium presentation at the European Society of Medical Oncology (ESMO) 2020 Virtual Annual Meeting, Toni Choueiri, MD, joins Alicia Morgans, MD, MPH and discusses the CheckMate—9ER phase III, open-label, international randomized controlled trial among patients with previously untreated, histologically confirmed advanced or metastatic renal cell carcinoma with a clear cell component. The primary outcome was progression-free survival and patients were randomized in a 1:1 fashion to receive nivolumab combined with cabozantinib versus sunitinib in participants with previously untreated advanced or metastatic renal cell carcinoma. Dr. Choueiri shares highlights of the study.


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

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans:  Hi, this is Alicia Morgans, GU Medical Oncologist, and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, a friend and colleague, Dr. Toni Choueiri, who is a Professor of Medicine at the Harvard Medical School, as well as being the Director of the Lank Center for GU Medical Oncology and Oncology overall at the Dana-Farber Cancer Institute in Boston. Thank you so much for being here with me today, Dr. Choueiri.

Toni Choueiri:  Thank you very much, Dr. Morgans.

Alicia Morgans:  Wonderful. So, Toni, you presented some really exciting data on first-line treatment for metastatic renal cell carcinoma at the European Society for Medical Oncology ESMO. I'd love to hear your overview of what was this checkmate study, and how did you plan it, and how did it run?

Toni Choueiri:  Yeah. So we now know that we have five years' experience with nivolumab single agent, cabozantinib single agent, plus TKI, two Phase 3 trials, both with an overall survival benefit. So instead of asking ourselves, should it be nivolumab, cabozantinib? I think the natural thing is to combine both. Dr. Apolo ran a phase 1 trial that was just published in the Journal of Clinical Oncology, combining nivo with cabo and the nivo-ipi with cabo. And we learned about the toxicity, we learned about the dosage and there was activity in renal cell cancer patients. So we took this around the same time, to a phase 3 trial against sunitinib, Checkmate-9ER, or the combination of nivolumab and cabozantinib at 40 milligrams per dose. The primary endpoint was progression-free survival response rate, overall survival was a secondary endpoint. And we really did some focus on health-related quality of life.

And the primary endpoint was met. It's quite easily, double the PFS. So 8.3 multiplied by 2, 16.6 months, hazard ratio 0.51, and investigator-assessed PFS, even the hazard ratio is 0.46.  The response rate-independent review, or investigator-assessed were also doubled. And the overall survival benefit, to be honest with you, we were a bit worried initially, this combination coming a bit later.  It's good to have other options, but how that impacts the overall survival and actually the overall survival hazard ratio was 0.6, 40% decrease in the risk of death. And the toxicity was manageable on both arms, quite similar, a bit more LFTs ASDNLP toxicity in the combination. Immune-related adverse events did happen and some needed steroids, but there were very few percentages of patients that needed Corticosteroid of 40 milligrams or more, more than 30 days was quite low.

And the treatment discontinuation due to AEs, is for both nivo plus cabozantinib was less than 5%. Now, one thing I want to add is, we had a slide about health-related quality of life. We use FKSI-19, and that's FKSIDRS, which is a subset of the FKSI-19. And we saw in both at most, time point is statistical significance, favoring, actually the combination over sunitinib. So quite pleased with the result. I think this is another option that will hopefully be available soon for our patients. And I'm glad ESMO leadership and Doctor Professor Peters put it in the presidential session.

 Alicia Morgans:  So all of this is amazing and fantastic. And I'd like to just dig in a little bit regarding who these patients are. Was there a subset that seemed to benefit most? And how did the inclusion criteria for this trial, how are they similar or different from other first-line Metastatic RCC studies that we've seen?

 Toni Choueiri:  I mean, that's very insightful. This is a great question. So these were untreated patients that had to have a clear cell component in their tumor. We know clear cell histology is by far the most common. They were all risk at low. So this, unlike nivo, it being a checkmate 214, where the primary endpoint in the patient was intermediate progress. The study here, the endpoint is an all-risk groups. And that, if you look at the baseline characteristics, they were balanced in both arms, but the favorable risk was around 20, 22% lower than keynote 426, for example, another study that we usually compare to. On the other hand, the rate of nephrectomy, because the trial happened around the same time CARMENA was reading, the rate of nephrectomy was lower on 9ER. So you wonder, did that make the responses even lower because it's hard to achieve a response in a big primary. They were quite noticeably lower than the trials that were reported in the past, against sunitinib, pembro-axi, avelumab-axi, and nivo-ipi, but the baseline characteristics were balanced between both arms.

 Alicia Morgans:  So I think that's all really important. And as you mentioned we have nivo-ipi, we have pembro-axi, and nivo-ipi we're going to usually use in those core and intermediate-risk groups pembro-axi seemed to benefit across the spectrum. What are your thoughts in terms of where cabo-nivo actually is going to fit into this paradigm, knowing that we have multiple other options for this first-line metastatic setting?

 Toni Choueiri:  Yeah, I think this is a fair question. I think cabo-nivo data is robust across all endpoints. You don't have that with every combination. I think the quality of life data, it's the only IOTKI combination that has a quality of life superiority over sunitinib. So I think these would be quite differentiated among other IOTKI. The comparison, I have to say with nivo-ipi is a bit difficult, because that study checkmate-9ER has significantly more prolong the median followup. So it's a bit hard. And the other thing was the combination of IOIO renal cell cancer remains that you have proven disease and in very, very large part. So you do have patients that unfortunately, when you give them IO only regimen, they blow through therapy and that is captured by the PD as a best response on nivo-ipi while on cabo-nivo, it's 5%.

 So these are going to be subtle, but very important differences. I think, honestly, I personally, in a way, my mind has moved to the next thing. Cosmic-313 is a study that is accruing, where it uses a modern control arm with nivo-ipi and add cabo to it, three versus two. We have the Alliance meeting you and I are part of the Alliance for Clinical Trial in Oncology with Dr. Michael Morris and many others. And we have the PDIGREE study, which sequences cabozantinib, so after it's a response at active study. So after the nivo-ipi response, you introduce cabo. If you have a progression or stable disease, and if you have a partial response you randomize, and these are going to be the next generation of trials.

 Alicia Morgans:  So speaking of the next generation of trials, were there patients allowed in a study if they had a non-clear cell component to their tumor?  And either way, what are you thinking about for non-clear cell patients, just in general, not related to this trial necessarily.

 Toni Choueiri:  The patient was sarcomatoid in histology, which is not as pure histology actually were allowed. And each patient does respond quite well to checkpoint inhibitors. But on the other hand, no, papillary renal cell cancer, chromophore, we're not allowed. We do have smaller studies that are coming.  One study here to be led by Dr. McGregor from our institution, it's a triplet of cabozantinib and nivolumab ipilimumab in this really rare variant histology. We have also a phase three coming in the post IO setting by the named CONTACT-03 that will give a patient cabozantinib versus cabozantinib plus atezolizumab and that study allows non-clear cell histology.

We have a study with our colleague, Dr. McKay from UCSD through the Alliance, also, specifically in bone metastases, which also is hard to treat the problem with cabozantinib building on cabozantinib that allows non-clear cell RCC and the experimental arm at radium-223 that could have at all there based on prior results from our center. So I think there's a lot to look for in the future. I think this is a good time for RCC, and I think hopefully we're going to still push the envelope further for survival,

 Alicia Morgans:  Absolutely. And for quality of life too. And I'm glad that you and the team incorporated that on the front-end and really could strengthen that survival data if it needed strengthening, which it probably didn't, but from a patient perspective, to strengthen that survival data and say, actually, you're going to feel better as well, you're not just gonna-

 Toni Choueiri:  Absolutely. We want patients to live better, to feel better. I know this is an area of active research. You're an international leader, Dr. Morgans in this area, very important to focus on it. Very important, also to focus on survival so that, these patients experience survivorship at some point, something, we never thought about that would happen in renal cell cancer, but I remain hopeful.

 Alicia Morgans:  Wonderful. Well, on that note, what is your final message for the viewers? The final take-home point, if you had to give them one from this work, from this study, as we look at the sea of options available to us in the metastatic renal cell carcinoma setting.

 Toni Choueiri:  I think with that combination, patients are living longer and living better when you put the survival, the overall survival benefit, and the quality of life benefit. And this is good news for the practitioner, this is good news for a provider, and this is really good news for patients. So onward and renal cell cancer till one day hopefully we cure this disease. Why not?

 Alicia Morgans:  Wonderful. I think that's the goal for all of us. And I look forward to hearing more about studies like this and other things from you. I know you and the team, both at the Dana-Farber and around the world are trying to push the envelope and cure this disease. And we love to see each step that you take in the right direction. So thank you so much for taking the time today and thank you for your work.

Toni Choueiri:  Thank you. And thank you, UroToday, as usual, trailblazing the field. Thank you.