Novel Treatment Strategies in Non-Clear Cell Renal Cell Carcinoma


Before closing out there review of non–clear cell RCC management, expert oncologists highlight novel therapeutic strategies and ongoing clinical trials.


Thomas Powles, MBBS, MRCP, MD: Eric, can I come to you? There's a LITESPARK, a KEYNOTE study of lenvatinib and pembrolizumab in this space that's been presented. Do you want to just give an overview of some of the data associated [with] that? Then, Ulka, at the end I'm going to give you the very difficult task to try to summarize the whole situation; I know there's little bits and pieces of cabo-nivo [cabozantinib-nivolumab] data. Eric, [if you would speak on] some details to start.

Eric Jonasch, MD: This is a study that's presented at this ESMO (European Society for Medical Oncology). It's a fairly large, single-arm, 147 patient study, which is ruling non–clear cell renal cell carcinoma, which is including most, predominantly papillaries, there's some chromophobe, there is unclassified, as well as a smattering of others. The analysis that was presented, the first 82 patients, of which about two-thirds are papillary, then there are some chromophobe. The objective response rate's pretty interesting. It's 47%. We are seeing that these agents or this combination is active. Now, it's interesting then when you break it down, if you look at papillary versus chromophobe versus unclassified, as we saw with cabozantinib and nivolumab, chromophobe seems to be its own thing. It's an immunologically cold tumor where the objective response rates themselves were quite low. Papillary seems to do very well, unclassified seems to do very well. Again, [it is a] single-agent study, not large, but compared to historic data that this does look like it's a potential advance.

Thomas Powles, MBBS, MRCP, MD: There's some cabo-nivo data and we need to put that in context. Do you want to just stay where you are with your patients and how you approach them with, particularly with the data we've just seen right now, whether or not you think the fields are changing?

Ulka Nitin Vaishampayan, MD: I think there is efficacy shown with single-agent VEGF-TKI (vascular endothelial growth factor-tyrosine kinase inhibitor) and with IO (immuno-oncology) single agent. There is promising activity now with combination of VEGF-TKI and IO. In terms of the MET amplification in papillary, the pure MET inhibitors have not shown efficacy. That's been a disappointing biomarker to use for biomarker-directed therapy in papillary. I think Ben's trial that will be activated later this year, which compares single-agent VEGF-TKI cabozantinib +/- atezolizumab, so [this] gives you the chance to answer the question of whether we use combination immunotherapy plus VEGF-TKI or if we need to just do single agent.

Thomas Powles, MBBS, MRCP, MD: Does anyone on the group want to make a big shoutout for the combination? Forty-seven percent seems high to me. Single-agent sunitinib back in the day, I think there was a study from (the University of Texas) MD Anderson (Cancer Center) that showed 0% response rate, but correct me if I'm wrong.

Eric Jonasch, MD: Slightly higher than that, but not much.

Thomas Powles, MBBS, MRCP, MD: It does seem we've moved on; have we moved on? Should we be changing the guidelines to recommend the combination? Or do we need to just wait a little before we run?

Eric Jonasch, MD: I think the answer is yes to both. When I have a patient sitting in front of me and we're having a conversation about treatment options, I do believe that it's a reasonable thing to offer combination therapy after a discussion of the data. Having said that, I think supporting a trial like Ben's is critically important and we do need to have these types of objective data. This ends up creating a little bit of quandary. Because you say, "We have these single-arm studies, they're interesting, yet we want the science." So, how do we actually play that juggling act when we're in the room when we want to support the proper trial?

Thomas Powles, MBBS, MRCP, MD: There's a study called [INAUDIBLE] as well, looking at a combination of savolitinib, which is a MET inhibitor with pembrolizumab versus sunitinib. It's a randomized phase 3 personalized study. The response rate for the phase 2 data was about 50% in the MET-amplified population. That trial also looks of interest, I think. It's a personalized study, specific, so moving away from VEGF-targeted therapy. I think it's fair to say a couple of things in summary. The first is my hypotheses with the wrong group of doctors be treating this, and other people would've done better, I'm beginning to question that. Because it does look like some of these new combinations coming through have genuine activity and I'm delighted about that. I think we haven't done well selecting patients for therapy in this group and we probably should do a bit better. We do need to try in these studies. Ben, I hope that both you and others manage to get that off the ground, that might be the most exciting part of this. But it is an area of population I've always felt have been left behind. I'm beginning to feel we're catching up the loss of this population. We're never going to be able to do a thousand-patient randomized phase 3; as a group, we're going to have this work out slightly different parameters to move the drugs forward. We can’t just, as a guideline, say that it has to be randomized phase 3s. Because if that's the case, we're never going to get there. The other pieces we need to do are these investigator-initiated trials, to some extent, the drug development of VEGF-TKIs and PD-1s in clear cell renal cancer is plateauing a bit. That's probably accounting for the negative trials we're seeing. The investigator-initiated, the global community, the cooperative groups now have to grab this, and refine and improve the toxicity that you talked about. I think belzutifan is an exciting new drug we need to work on. I think we need to see more CT-LA4 data, there are beginning to be some question marks the back of my mind around that. But overall, I feel the renal cancer space is moving forward really nicely or has moved incredibly quickly and now we're assessing that data, but beginning to see some negative trials for the first time. That means we perhaps need to change our direction. As we change that direction, I think the academic community as well as, of course, the pharmacy industry, need to get direct together and work out what that is. My personal opinion of this is the biomarkers are going to turn out to be really important in the future.

Transcript edited for clarity.

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