The Landscape of Systemic Therapy for Metastatic Renal Cell Carcinoma - Petros Grivas

June 24, 2019

Monty Pal joins Petros Grivas to share highlights from his ASCO 2019 presentation on IMmotion150, a phase two clinical trial in kidney cancer looking at patient-reported outcomes, that compared monotherapy with atezolizumab, to sunitinib, to the combination of bevacizumab with atezolizumab, a unique opportunity to look at monotherapy in this setting.


Sumanta Kumar Pal, MD, Associate Professor, Department of Medical Oncology and Therapeutics Research, Co-Director, Kidney Cancer Program, City of Hope

Petros Grivas, MD, Ph.D., Clinical Director, Genitourinary Cancers Program, University of Washington Medicine Associate Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine

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Petros Grivas: Hello. I'm Petros Grivas. I'm a medical oncologist at the Seattle Cancer Care Alliance, associate professor at the University of Washington, and an associate member of the Fred Hutchinson Cancer Research Center. I'm really thrilled today and honored, to host Dr. Sumanta Pal who is an associate professor at the City of Hope Comprehensive Cancer Center, and the co-director for the kidney cancer program there. Monty, welcome.

Sumanta Pal: Thank you. You think you're honored? I'm honored.

Petros Grivas: It's fantastic to have you here, my friend. You have done such great work in the field, across genitourinary cancers, in particular in kidney cancer. So, I would like to pick your brain a little bit about emerging data and the data you're presenting specifically with an IMmotion150 in the phase two clinical trial in kidney cancer. Tell us a little bit more of atezolizumab versus sunitinib. 

Sumanta Pal: So I was really thrilled that the committee selected it this year for poster discussion. 

Petros Grivas: This is important work.

Sumanta Pal: Oh, thank you. I appreciate that. But I have to tell you, this is a unique opportunity for us. It actually took a look at patient-reported outcomes, or PROs, in this phase two study, as you'd mentioned, that compared monotherapy with atezolizumab, to sunitinib, to the combination of bevacizumab with atezolizumab. So I think the uniqueness here derives from the fact that it's one of our few opportunities to look at monotherapy and do a deep dive in a randomized trial. I can't think of any other examples of this in renal cell. And if you look across the PROs for patients receiving sunitinib and atezolizumab, there's a clear difference there. Patients with atezolizumab certainly had less in the way of symptom interference. They did better in terms of their general quality of life. They did far better in terms of toxicity, as well. I think all data speaks to that.

Petros Grivas: It's interesting because quality of life metrics and patient-reported outcomes are very relevant decision making in clinic, and having some data sets like this one, with three different arms, is very, very important. And any other comments regarding the overall impact of quality of life metrics in the clinical decision making, do you have to make?

Sumanta Pal: Well, you see now what's interesting is I don't think we're going to see many trials moving forward comparing monotherapy with IO frontline to targeted therapy. I think the field has kind of moved past that, and skipped over it in some regards, right, we're looking at combinations of VEG-F plus IO versus VEG-F instead. What I do think this is going to be helpful in though, is in this emerging area of adjuvant studies in renal cells, so, as you know I'm chairing IMmotion010, which is a very critical trial that's going to look at atezolizumab versus placebo in patients with resected disease. Now, I think that this study that we're presenting here is important, because if, for instance, IMmotion010 is positive if adjuvant atezolizumab becomes an option, the question people are going to be asking is, “Should we give adjuvant sunitinib, or should we give adjuvant atezo?”. When you see this degree of quality of life and balance between the two regimens, I think it clearly favors an adjuvant IO regimen, of course, if the clinical the data speaks to that. 

Petros Grivas: I think it's a very important point because cross-trial comparisons are very difficult to make, especially when there is no direct comparison between two agents. So, having these data sets in the background can potentially form decisions like this, down the road, and I agree with you, the field is moving to the combination of VGFTKI and immunotherapy in the first-line setting of advanced kidney cancer. Any comments on this involving landscape data from the KEYNOTE-426 trial, from the JAVELIN 101 trial. How do you see this evolving field in the context of the Ipi/Nivo data from last year? 

Sumanta Pal: Yeah so, my paradigm has been shifting a lot recently. You know, for the good-risk patients, I'm just really concerned that we might be over-treating them. The data from KEYNOTE, the data from JAVELIN, is very, very compelling, but good risk patients are a good risk because they're going to do great and be on therapy for a very long time, and the prospect of giving them doublets for protracted periods scares me a little bit. So for that population, I'm actually still tempted to give them VEG-F inhibitors front line and give them other agents if, in the event, they progress. But you know, I think you and I probably both have these good risk patients at our practices who actually sustain on VEG-F inhibitors for years, right? 

Petros Grivas: These people exist and it's interesting how the biology of the disease of the good risk might potentially differ from the biology of intermitted and poor-risk disease based on the MSKCC criteria. And there was some work by Dr. David McDermott in that regard, from the IMmotion study, the phase two trial that you are part of, looking at this distinct biology. Patients who had a better response to sunitinib and had this angiogenesis signature, while patients who response to IO therapy, had a different expression profiling. Do you see this distinct biology explaining the discordance between good risk and intermittent poor-risk patients even with Ipi/Nivo data?

Sumanta Pal: Yeah, I think in the context of Ipi/Nivo, hard to say. But at this meeting, Toni Choueiri presented an update from JAVELIN 101. Fascinating data set. You've got to applaud him for doing this massive amount of work with Pfizer, actually looking at this combination versus sunitinib, axitinib avelumab versus sunitinib. And doing exome sequencing, RNA sequence, a whole barrage of very interesting biologic studies.

What really stood out to me though is that elements like KDR-2 or VEG-F receptor two really seemed to serve as predictors of response to sunitinib therapy. I don't know why that wouldn't hold for the combination of axitinib avelumab, you see what I'm saying? It should have probably predicted response to both. You know, so the curiosities like that I think emerge from the data set. Having said that, it is just an amazing achievement to have done that the phase three study, to have gone back and validated it as he did in the phase one B experience with axitinib avelumab.

When it comes to these intermediate and poor-risk patients, I think the approach that I'm generally taking offering Nivo/Ipi upfront. I will tell you why. The vast majority of folks that I see in that category have de novo metastatic disease. And if they do fall to that cohort, it allows me an opportunity to sit and think about this decision around cytoreductive nephrectomy. If I don't have to take the kidney out, I prefer not to, but I think that most patients that primary tumor can be symptomatic. It can result in bleeding, pain, et cetera. And I don't find that the responses are as robust. So, if I start with Nivo and Ipi, I can have my surgeon operate whenever he sees fit. If I start with the TKI, then a lot of other considerations come into play. So that's become my standard practice. 

Petros Grivas: Interesting, so the consideration of nephrectomy, cytoreductive nephrectomy, more palliative nephrectomy might appear to influence your decision in that particular context. 

Sumanta Pal: Absolutely. Absolutely. And it is important to know that I think that it does cross the board for oncologists when you are dealing with upfront de novo metastatic disease. And to that end, Ulka Vaishampayan and Hyung Kim have designed what I think is a very interesting study. It's going through the cooperative group mechanisms right now, it's called the PROBE trial. And it's going to take patients with de novo mets and actually treat them with Nivo and Ipi, and then randomize them at a later time point to And later randomized them to cytoreductive nephrectomy or not. 

Petros Grivas: Interesting. 

Sumanta Pal: So I think it's a really pragmatic take on CARMENA. It's a reiteration of that study with very, very different questions in mind.

Petros Grivas: Of course and they think having the CARMENA data in mind, I think having the opportunity to test this hypothesis in the context, the modern era of immunotherapy, I think it's very practical and relevant, and I agree with you. At the same time, someone can argue that they are pembrolizumab axitinib or avelumab axitinib benefit, seems to be in regarded as there are criteria by Hyung. or PDL1 status, and some people might use VEG-F TKI-IO combination across risk groups. Any comment on that or you think that the option of potential surgery might still impact your decision?

Sumanta Pal: Yes, so you know, good risk patients inherently don't have de novo metastatic disease, right? Because in the de novo metastatic patients you're getting systemic therapy going right away. So, they autonomically have one of these Hyung risk criteria they're called, right? So, autonomically that question of surgery falls out of the form for patients with good risk disease. And again, I hang on to that tenet of not wanting to over treat these patients. That's really why I'm really thinking VEG-F inhibitor, monotherapy, in most cases upfront. For the immediate and poor-risk patient who has de novo mets, again there. 

And I have just to tell you that if you start an agent like axitinib and avelumab, you're going to shut that axitinib off a couple of days ahead of surgery, and you are not going to put that patient back on for about four to six weeks thereafter. So, you are giving them the monotherapy for a very, very long stretch. And I think the data really speaks to that potentially being an inferior approach. 

Petros Grivas: And that's interesting because we don't have any direct comparison between singlet and checkpoint inhibitor, and IO VEGF TKI in a comparative phase three trial in the first line setting. There is some data from the KEYNOTE-427 trial that shows pembroluzimab having some response rates in the 37, 38 percent. In terms of numerically, it's close to what you see with Ipi/Nivo. However, it's much lower compared to what you see in the pembro/axi avelumab/axitinib data, but we don't have that comparison head-to-head with singlets and IO. 

Sumanta Pal: And this kind of takes us full circle back to IMmotion150, right? Because that is one of the few randomized comparisons we have of monotherapy against VEG-F, plus IO. And there, and I think most would agree, it looks as though the data for the combination is more compelling.

Petros Grivas: It's interesting. So the data, as you said with the full cycle we did, of the IMmotion150 is relevant, and to look forward to your poster in this meeting. Let me actually ask you a little bit more beyond the current existing landscape. What other combinations are out there? I know you are working on a very important trial along with Dr. Agarwal, looking at cabozantinib and atezolizumab and combination of angiogenesis and IO [inaudible 00:09:41]different to TKI. Tell us a little bit more about that. 

Sumanta Pal: Yeah, what a thoughtful way to conclude this. So you know we've talked about bevatizo. I think that the next generation is going to try to pair the best VEG-F inhibitor we have with IO, and I truly have felt for a long time that best VEG-F inhibitor we have is cabozantinib. So I was really excited to test the combination of cabo and atezo. We have a front line data set that we reported out last year at the Kidney Cancer Association Meeting where 100 percent of patients drive clinical benefit. We saw response rates upwards of 40 to 50 percent. You know, I think with a data like that, combinations that are cabozantinib based may actually reflect the wave of the future in the front line setting. 

Petros Grivas: I think it's a very exciting trial, and having the experience of VEG-F TKI and IO being so prominent, I think this new trial is going to shed more light, and I want to congratulate you for the important work in this trial, as well as the huge work you have done in the field of kidney cancer. And I'm looking forward to more practicing data from your work.

Sumanta Pal: I appreciate that. Thanks Dr. Grivas. 

Petros Grivas: Great to have you here today, Monty, and thank you so much for your attention today.