Rapidly Evolving Landscape in Metastatic Renal Cell Carcinoma- Rana McKay

May 25, 2019

Rana McKay, MD reviews the evolving landscape for the frontline treatment of metastatic RCC.  Historically, patients were treated with first-line TKIs although the paradigm has been shifting over the past two years including, VEGF targeted therapy with immunotherapy and IO-IO combinations.  Dr. McKay reviews the data from KEYNOTE 426 with pembrolizumab plus axitinib which demonstrated a survival benefit over sunitinib monotherapy. Importantly, Dr.McKay raises the point of how to find the 10-15% of patients that will have a dramatic response with deep, durable responses and potential cure.  Looking at multiple combination therapies in head to head trials will end up being practice transforming as we determine which combinations are suitable for specific patients.  Dr. McKay and Dr. Pal also discuss the OMNIVORE trial which is now completely accrued and will report data on the use of nivolumab with the ability to stop therapy after 4-6 months in patients with a confirmed CR or PR and in other patients who do not have a confirmed response then ipilimumab can be added as salvage therapy.  The standard for response is getting higher and higher for metastatic RCC with the combinatorial approach to treatment along with IO-IO combinations.


Rana R. McKay, MD, Medical Oncologist, Assistant Professor of Medicine, UC San Diego Health

Sumanta Kumar Pal, MD Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research, Co-director, Kidney Cancer Program, Medical Oncologist, City of Hope
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Monty Pal: Welcome to UroToday. My name's Dr. Monty Pal. I'm a Medical Oncologist at The City of Hope Comprehensive Cancer Center. And today I'm delighted to have Dr. Rana McKay, who's an Assistant Professor at the University of California, San Diego School of Medicine. And frankly, she's actually published more than most of the full professors that I know.

Rana, thanks for joining us.

Rana McKay: My dear, you're too kind. Thank you for having me today.

Monty Pal: No, I mean it.

Well, today I wanna probe you a little bit because we've had so many big data sets here at ASCO GU 2019, perhaps the biggest amongst them being the Keynote 426 data set. Can you tell our listeners a little bit about that trial and what it meant to you? 

Rana McKay: So specifically, the frontline space for metastatic RCC has just been rapidly evolving, where historically, these patients have been treated with frontline TKIs, over the last two years, we've really seen a shift in the paradigm in the frontline space for patients, and we're really trying to understand who is gonna benefit the most from which kind of therapy, and we're taking our therapies and combining them together. We're combining VEGF targeted therapy with immunotherapy. There's IO/IO combinations, and really the field is rapidly evolving. We're super excited to see the data come out about the combination of pembro/axi, and to see how that's gonna change the frontline space. How is it gonna pair up against the combination of nivo/ipi, how is the data gonna look for people with poor, intermediate and favorable risk disease? So I think the data that we're super excited to see, just how dramatic the benefits gonna be. The press release is that there's an OS benefit with a combo, and so I think seeing how that's gonna change the frontline space. It's not only what we're doing in the frontline, but also how is that now gonna effect what we do in the second line, 'cause we've just thrown a wrench into everything that we're doing frontline but don't really know now if we're setting a new standard in the frontline space, how that's gonna effect, trickle-down effect for what we do in the second line. 

I think the other thing, big questions that are being asked are deep responses, time to next therapy, durable remissions and though, for the overall population, the benefit may be low but can you find that 10 to 15 percent that's gonna have a dramatic benefit or near-cure, dare we say it, in this population? So I think it's super exciting to see how the field is changing and to kinda put the combinatorial frontline trials against one another head to head and see what's gonna actually end up changing practice and informing what we do. 

Monty Pal: That's very well said. I'm intrigued by a lot of what you brought up, but in particular, I think you've been a little bit ahead of the curve in terms of thinking about that question around what we're gonna approach patients with next, so we've had nivo and ipi at our disposal for a little while now. I know you've been involved in some trials that look at second-line therapy formally. Can you tell us a little bit about that? 

Rana McKay: So, we're specifically looking at a trial called OMNIVORE. I don't know if that's what you were referencing. 

Monty Pal: That's it. That's it. 

Rana McKay: Where we actually are modifying, tailoring somebody's approach to therapy based on their response, so we're recognizing that maybe not everybody needs the combo of nivo/ipi. Maybe not everybody needs to be subjected to that, but is there a way to actually tailor therapy based on someone's early and immediate response, or lack thereof? So OMNIVORE is now fully accrued, and hopefully will make a splash about the first data set later this year, but the concept of that trial is that patients in the frontline or really any line space with metastatic RCC, without any preference with regards to underlying histology, would all enroll, would get upfront nivolumab, and in the context of their response at four to six months from treatment initiation, if they had a CR that was confirmed or a PR that was confirmed, they would actually stop nivo, which no trial at the present time is looking at answering the question of, "Can we safely stop therapy early on in a small subset of patients who have a dramatic early response?" And in people who actually are not able to have an objective response, either have SD or PD as their best response, actually adding ipilimumab to see if you can salvage those individuals. 

There are a couple of other trials that are designed with that kind of salvage approach, starting off with nivo and then adding ipi. There's another trial in the U.S. and the TITAN trial in the EU that's looking at specifically answering that question, but not everybody may need everything all at once, so trying to tease out the patient population is what we're trying to do with OMNIVORE. 

Monty Pal: That's brilliant, wow. And looking into the future, recognizing the design of OMNIVORE and recognizing that it is, nonetheless, maybe not as big as the experience in Checkmate 214 and so forth. Will we be able to push forward with frontline monotherapy given all the other tall trees out there? 

Rana McKay: It's a tough question, you know what I mean? With regards to frontline. 

Monty Pal: Yeah. 

Rana McKay: The standard is getting higher and higher and higher, and that bar is getting higher and higher, so I think with regards to frontline monotherapy, it's gotta be driven by biomarkers, and who's gonna be that patient that's gonna respond in the frontline space? I think the bar is getting so high with the combinatorial therapies and IO/IO combinations, that you really have to demonstrate a dramatic benefit over now what is becoming the standard, and I think the only way to be able to do that is in a specific population, a biomarker-positive population that's gonna reap that dramatic benefit. 

Monty Pal: That was a tough question. I think you answered it perfectly. It is so attractive to think of a potential opportunity to de-escalate therapy in a biomarker-selected population. 

Rana McKay: Yeah. 

Monty Pal: And I agree with you 100%. Well, Rana, thank you so much for joining us. 

Rana McKay: Oh, you're welcome. Thank you for having me. 

Monty Pal: And we're gonna have more with Dr. McKay later on UroToday. Please tune in soon. Thanks so much.