Advancing Therapeutic Approaches in Sarcomatoid Renal Cell Carcinoma: Lessons from CheckMate 214 - Nizar Tannir

December 19, 2022

Pedro Barata and Nizar Tannir explore updated findings from the CheckMate 214 study, with a focus on sarcomatoid renal cell carcinoma (RCC) patients. They note that despite an improvement in patient outcomes due to nivolumab/ipilimumab (nivo/ipi) treatment, 20% of patients still progress, underscoring the need for ongoing research. The study showed significantly improved response rates and overall survival with nivo/ipi compared to sunitinib, transforming the prognosis for these historically hard-to-treat patients. With the promising results from nivo/ipi and other trials, they delve into the potential of further enhancing treatment effectiveness by combining additional drugs with nivo/ipi, a strategy needing more robust clinical data for support. Dr. Tannir expresses optimism for these potential combinations, urging the medical community to strive for better solutions to meet unmet patient needs.


Nizar Tannir, MD, FACP, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston TX

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: Hello, everyone. Welcome. My name is Pedro Barata. I'm a GU Medical Oncologist and Associate Professor of Medicine at Case Western, the Seidman Cancer Center in Cleveland, Ohio. It is my true privilege to be joined today by Dr. Nizar Tannir. He's a Professor at the Department of GU Oncology at MD Anderson Cancer Center, Houston, Texas, he’s also a friend. Thank you, Dr. Tannir, for joining us today.

Nizar Tannir: Thank you, Pedro. It's a pleasure to be with you as always and thank you for the opportunity to discuss the updated results of CheckMate 214 with respect to the sarcomatoid cohort in that study.

Pedro Barata: Absolutely. First, we're here after the great meeting we had in Austin, IKCS, the North American meeting. It's a fantastic meeting, a lot of interesting data presented, including your data. So today we're going to be chatting a little bit about the long-term follow-up there for sarcomatoid RCC in the CheckMate 214, as you said. And this is very, very important data. I really think we should highlight it for folks out there. And maybe we'll start right there, so when you put these data together, for the community who's listening to us, how important do you think it is to have extended follow-up data, number one? Number two, specifically for tumors with sarcomatoid features? How important that means to the treating physician out there?

Nizar Tannir: Of course. Thanks, Pedro. I think, we have always recognized that patients with renal cell carcinoma who have sarcomatoid features in their tumors have had a poor prognosis over the years, when we treated them with target therapies, the approved VEGFR-TKI, as well as the mTOR inhibitors. So for years, this was an unmet need to find effective and safe therapies to treat those patients.

And if you look at the history of the treatment of these patients, the median overall survival of patients with sarcomatoid RCC was 14 months. And until the launch and the approval of immune checkpoint inhibitor-based therapy, the median always remained 14 months. And you can look at different data sets. Our own dataset from MD Anderson, which were published in the Journal of Urology a few years ago with sunitinib and other target agents, it was 14 months, cytokines and all the target therapies we just discussed. And other data sets, including the IMDC, they published that also, and in patients with sarcomatoid RCC had a prognosis that was poor in their dataset, it was also, the median survival was about a year or less.

So it was important to look at the outcome of these patients in CheckMate 214. And again, to just remind our viewers, our audience, about CheckMate 214, this was a large phase 3 trial of 1,096 patients who were randomized to nivo/ipi or sunitinib. This was a first-line therapy, of course, clear-cell RCC and typical eligibility criteria that other phase 3 trials also followed. The certification was by IMDC's risk, favorable, intermediate, or poor risk, and geographical location. And I'm not going to go through the dose and schedule of nivo/ipi and sunitinib, we all know those things.

There were three co-primary endpoints: OS, PFS, and objective response rate. And then this was in intermediate and poor risk, because that was the primary population recruited to the program: intermediate risk, poor risk by IMDC. Secondary endpoints, again, and the restructured endpoint with favorable risk cohort.

So it was important to look at the sarcomatoid, again, because of the rationale, the reason why it's important to really see if this therapy, nivo/ipi, did revolutionize the outcome of these patients. And the methodology we used was, we looked at actually all the reports that came from the sites that participated in the trial where there was any mention of sarcomatoid, whether it was by reviewing the nephrectomy specimens, and of course, around 80% of patients had prior nephrectomy, or by biopsy of a metastatic site. So these were reviewed.

But we also collected, when we were able to collect slides, archived material from CheckMate 214, in both treatment arms, and there was a central pathology review by a colleague and friend, Dr. Sabina Signoretti from the Dana-Farber Cancer Institute. And these were reviewed and annotated. And the definition of sarcomatoid was any amount or percentage of sarcomatoid features in that tumor. Some pathologists like to call this sarcomatoid differentiation, some would like to call it, as we do at MD Anderson, our pathologists like to refer to it as sarcomatoid dedifferentiation.

So we looked at the outcomes of those patients with a minimum five years, and asked the question, how important is time? Well, of course, I think what's on everybody's mind is, if we achieve a good response in these patients with any particular therapy, is this response durable? What's the outcome of these patients as we follow these patients? So I think it's important when we look at a therapy, we look at, does the patient respond early on, and then, is this therapy durable? And then, of course, you brought up the issue of tail at the end of the curve, or shoulder at the end of the curve, as some people would like to refer to it. So I think that basically tells us whether we can hope, and of course, patients want to hope, that if they achieve a major response, a complete response in some patients, whether this is durable?

So I can get now to the updated results with a minimum five years of follow up on CheckMate 214. There were 139 patients who fit in or met the definition of sarcomatoid, as I said, by central pathology review by Sabina Signoretti and her team, or by local pathology report. And if you look at, we mentioned about the three core primary endpoints, so let's start with objective response rate with nivo/ipi versus sunitinib, again, in these patients who had intermediate or poor risk RCC and sarcomatoid features. The objective response rate with nivo/ipi was 61% versus 23% with sunitinib. Second, complete response rate, 23% of patients achieved a complete response with nivo/ipi versus 6% with sunitinib.

Then when you come to median OS and PFS, the median OS was 48 months, so four years compared to 14 months with sunitinib, 48 months versus 14 months. If you recall, I mentioned that, historically, the median OS of patients treated with target therapy, patients who had sarcomatoid features, was 14 months. And in the CheckMate 214, it was exactly 14 months. Amazing reproduction, consistent results with target therapy, almost more than threefold, or close to fourfold the median OS. And when you look at the hazard ratio for OS between the two treatment arms, 0.46. You look at PFS now, 26 months median PFS with nivo/ipi versus 5.6 months with sunitinib. And you look at hazard ratio for PFS between two treatment arms, 0.5. So impressive results, safety consistent with what were previously reported with CheckMate 214 with the two treatment regimens.

I have to mention that, you and I, Pedro, we talk about this all the time, we look at, of course, it's important to look at tumor regression response rate. By the way, when we mention or ORR and PFS, we're talking about blinded, independent... Well, it wasn't a blinded, because nivo/ipi and sunitinib...

Pedro Barata: Right.

Nizar Tannir: But we talk about independent radiology review. Okay? So by independent central review, the PFS and ORR. We mentioned that it's important to look at ORR, PFS, CR, but also looking at the progressive disease rate, because I think that's an important aspect. And I think it's interesting to note to you, Pedro, that the progressive disease rate with nivo/ipi in patients with intermediate risk who had sarcomatoid features was 20%. So there's still an unmet need. I would not sit on our laurels and say that nivo/ipi is going to cure every single patient with sarcomatoid clear cell RCC who has intermediate risk or poor risk, because we still have 20% of the patients whose best overall response is going to be progressive disease. One in five patients do not respond at all, in fact, have progressive disease with nivo/ipi. So our work is still cut out for us.

But this is the best data for the worst, in terms of most aggressive, worst tumor type you can think of in RCC, the sarcomatoid. So we still have to improve this data, but when you look at the totality of this data and data from other trials with immune checkpoint inhibitors, anti-PD-1 antibodies, plus VEGFR-TKI, the nivo/cabo, the pembro/axi and pembro/len, there the follow ups are still shorter than the follow up in CheckMate 214, so we still have to wait and see over longer follow up, five years minimum from these other trials, the KEYNOTE-426, the CheckMate 9ER, and the CLEAR study, we need to see what happens to these patients, not just the sarcomatoid patients, but overall patients, we need to see if there is a tail at the end of the curve, as you had mentioned.

But I can tell you, there is a tail at the end of the curve when it comes to progression-free survival for patients treated with nivolumab and ipilimumab in the intermediate risk for risk. And at five years, there is wide, wide separation of the curves with no tail at end curve for sunitinib of course, and a tail at the end curve for nivo/ipi.

Interestingly, patients with sarcomatoid dedifferentiation have a higher PD-L1 expression in their tumor cells compared to patients with intermediate risk who do not have sarcomatoid features. So in the CheckMate 214, nivo/ipi, around 28% had PD-L1 positive tumor defined by a greater or equal 1%, using the Checkmate 214 nivo around 28% had PD-L1 positive tumor defined by a greater or equal 1% using the Hi-C assay. So in non-sarcomatoid tumors, 28% or so had PD-L1 positive tumors; sarcomatoid tumors, 51% PD-L1 positive. When you look at patients who had PD-L1 positive tumors and intermediate risk scores, the CR rate is 25% with nivo/ipi, 25%.

So I think this is, again, we talk all the time about not comparing with other trials, because obviously, different trials, different patient population, different recruitment, different countries where these patients are recruited from, different treatment design, et cetera, et cetera. But at the end, you want to say, okay, patients with sarcomatoid RCC, 25% PD-L1 positive, 23% overall achieving CR, with a tail at the end of the curve, a plateau, and median OS of four years, when sunitinib and other agents, none in your checkpoint, have reduced only little over a year of median OS. That, I believe, is practice-changing. That, I believe, should be the preferred therapy for first line for patients with clear cell RCC who have sarcomatoid features in their tumors.

Pedro Barata: That was a beautiful summary. So as you said, sarcomatoid RCC or RCC with sarcomatoid features, it's, at the same time, a poor prognostic factor, but based on these data, very good predictive value for ipi/nivo, right? So it's almost like, at some point you almost want to have sarcomatoid features, because you can now do something about them. And obviously, ipi/nivo, I agree with you, is the standard of care, should be considered standard of care for this patient population. What is interesting about these data that you quote us is, actually, the numbers are remarkably good, and we put the general population with IO-TKIs in some of these endpoints, the numbers numerically look even better, right? Over two years of progression-free survival, CR rate over 20%, to your point, 23, 25%. I mean, those are remarkable numbers.

But I really think it's super important what you mentioned, we still see, about one out of five patients will not respond. In other words, it will progress as best response to this therapy. And I think it's an important point. So using that number, assuming we got to do better and we should not stop here, let me throw a little bit more data for me to formulate the question. We just saw data from COSMIC-313 that for some of us was a little bit underwhelming and I think there's more work to do. I guess the question that I have for you is, at least for patients with sarcomatoid RCC, the question is, is that it for ipi/nivo? Or you think there's a role for bringing perhaps another partner to join ipi/nivo and perhaps explore further combinations, perhaps a triplet, for this patient population? Do you think there's room for that? Of course, safety is always a concern. I'm wondering your thoughts about, where can we go from here, leveraging on this great data from 214 for sarcomatoid RCC?

Nizar Tannir: Well, I think, of course, we didn't cure germ cell tumors, we didn't cure leukemias and lymphomas and Hodgkin's disease with single agents or two agents. And most of these tumors became curable when we combined. So I am all for adding agents, combining agents that have different mechanism of actions and non-overlapping toxicity. And also, very importantly, I think we need to combine them in a rational way based on strong, robust clinical data in RCC. So if we're talking about clear cell RCC, I think we need to find these agents, and also look for at least additive, if not better, synergistic.

So do we have today a triplet that I can say we should use? I'm afraid to say the jury is still out and I don't think we can say now. Moving forward, what are other therapies that we can add to nivo/ipi as a backbone? I mean, obviously, this is an area of intense investigation. There are some other triplets as well. We can mention here the trial that's sponsored by Merck, that is very ambitious and bold. We discussed that at our board, if you recall. Looking at a triplet of anti-CTLA-4 given every six weeks plus pembro and lenvatinib in that trial, versus belzutifan plus pembro/len, versus pembro/len. And of course, there the bar is very high with pembro/len, and the toxicity is also not for the faint heart, because pembro/len can produce a high rate of dose reduction and discontinuation.

Well, there are others, there is adenosine pathway inhibitors. We'll see if this will pan out. There are other agents that people are looking at including CAR T-cell therapy here. So I think we'll wait to see. We're hopeful that we will be able to come up with a triplet or maybe even a quadruplet in the future, like we did in the past in germ cell lymphoma, leukemia. And then we can increase the CR rate, and of course, break the cure barrier.

Pedro Barata: That's wonderful. And I actually love the fact that we are general oncologists before specializing in one area, right? So sometimes we try not to invent the wheel and we go and copy the good ideas that others have explored in other tumors and try to see if they are applicable to GU tumors. So I love the fact that you brought knowledge from germ cell tumors, hematologic malignancies, et cetera, et cetera, because we try to do that all the time, right? We look at melanoma, we look at breast, we look at other tumors and see what we can use and learn from them to apply in GU tumors.

Wonderful discussion, Dr. Tannir, wonderful time as always. Thank you for being generous with us and spending time with us and chatting about the specific data for the 214 CheckMate trial. Congratulations again for your fantastic presentation. It was great to see you again and I'm looking forward to chat with you in the near future.

Nizar Tannir: Thank you, Pedro, it was a pleasure to be with you as always. You're a rising superstar in the field and I think you're making me famous here to be with you on these and I'm really happy to share our data, and again, to engage with you on a very vibrant, productive, illuminating, I hope, for our audience and our colleagues who may not see as many patients as you and I see who have RCC. I know this is a great platform for education for the healthcare providers, oncologists, as well as advanced practice providers. So thank you again. It was great to see you at the IKCS in Austin. Look forward to more of these interviews, interactions. It's a learning experience because I'd like to see also how other people think and how they interpret the data. So thanks again. Have a wonderful evening.