Novel Doublet Combination Regimens in Frontline Advanced RCC


Panelists provide insight on ongoing studies evaluating doublet combinations in frontline advanced RCC.

Dr. Elizabeth Plimack: I thought maybe we could move on to novel doublet combinations. There are some exciting ones here. And so Bob, let me send this to you. LITESPARK-024, PIVOT-09, anything else you're excited about? We have an embarrassment of riches in some ways, but until we're curing everybody, we're going to keep looking, right?

Dr. Robert Motzer: I think that there's a number of different trials that are on the radar screen here. And I think that one of the group are those studies that are combining Belzutifan with systemic therapy. And that's being done in first, second, and in third line therapy. And so there's a large trial that Brian is the lead investigator on that's looking at that in first line therapy. And it's also being studied in adjuvant therapy. And in second line therapy, there was data to suggest that the combination of Lenvatinib plus Belzutifan in previously treated patients was promising. And similar phase one, phase two data with cabozantinib and belzutifan as presented previously and published by David McDermott and Toni Choueiri. It looks like an interesting combination and is moving forward in phase three trials. So hopefully we'll have an answer to that as well. Just getting back to the I think the data at ASCO with axitinib pembro and with Lenvatinib pembro was new. It was very interesting. And I think we covered CheckMate 214 a little earlier, but the other program that stands almost equal to the others is the CheckMate 9ER trial, which compared Cabo-Nivo to sunitinib and likewise showed a high response rate about double that of sunitinib as well as improvements in progression-free survival and overall survival. And this has been an important study that's had updates as well. And I was wondering if you, Brian, or Betsy, if you've had a experience with this one, and if you think that this is particularly attractive to certain subsets of patients.

Dr. Brian Rini: I've used Cabo-Nivo. We're using it in our optic trial and our biomarker trial. And again, I think it has the strengths and limitations of the other IO-TKIs, Cabo's obviously a great TKI. I still step 40 in this regimen, so it's more tolerable than the 60 monotherapy dose. I think we've only seen three-year minimum follow-up data and I assume at an upcoming meeting we'll see the four and five-year data. And again, I have a feeling the story's going to be the same as the other IO-TKIs. I don't think there's any reason to believe it's going to be better or worse. And then I also use it in non-clear cell. So there's a single-arm study and there's also some Len Pembro data presented at ASCO we can talk about, I think non-clear cell. I think we're doing a better job of doing trials in those patients and including those trials than we were five, 10 years ago. And I think we're starting to see results that look pretty good. Maybe not as robust as clear cell and we certainly don't have the big randomized trials, but I think IO-TKI and probably Len Pembro, Cabo-Nivo have the most data in non-clear cell, so that tends to be where I use it.

Dr. Elizabeth Plimack: I probably use it the least, although we have a homegrown, speaking of optimizing TKI therapy, we have a homegrown study of dose adjustments worth Cabo here at Fox Chase, and we're about to open the frontline arm for that. So I'm about to get more experience doing that in a dose-adjusted fashion with the Cabo. But I tend to go to Pembro-based combination, either Axi again per longer term gentler treatment and favorable risk or Len in the rest.

Dr. Robert Motzer: We talked a little bit about the side effects, so the adverse events with Len Pembro and Axi Pembro. And I don't know, in terms of the tolerability of the Cabo-Nivo, I've found some issues with, particularly with skin toxicity with a hand-foot syndrome with that particular regimen that's problematic. I don't know, you mentioned in terms of the tolerability, Betsy, is that the issue that if you've come across with Cabo-Nivo or has been other aspects of toxicity that you've seen with this combination?

Dr. Elizabeth Plimack: Sure. So obviously, the IO does its own thing and it's unpredictable. And we tell people, if nothing bad happens in the first six months, you're probably OK, but not necessarily, it could be at any time. And the TKI is all the caveats that we just talked about. I think our trial here is looking at either measuring AEs, deciding what warrants a dose hold, reduction, trying some every other day dosing. Because again, as you know, the drug comes in 20 milligram tabs, so you could do 20, 40, or 60, not a lot of options there and every other day regimen is one that we use. But I don't know that one is more toxic than the other, I just think the doses that we're supposed to start at are different and have different toxicities and our ability to minimally adjust them is limited by the strengths available. That's what I think.

Dr. Robert Motzer: And I think it's like one size doesn't fit all here. I think that some patients in terms of choosing a regimen based on the individual, the needs of the patient is important. So, for example, hypertension seems to be a predominant toxicity for Axitinib and Lenvatinib given with pembrolizumab, but I've found that the hypertension's probably a little lower with Cabo-Nivo. So in some patients, if hypertension is a real issue or poorly controlled or you're concerned about compliance, and then in that sort of scenario, I might choose Cabo-Nivo over the others. On the other hand, if the patient is very active, perhaps a runner or what have you, is very concerned about development of hand-foot syndrome, then I might steer away from the Cabo-Nivo combination. I guess the other issue with the Cabo-Nivo has always been this idea that it's better in bone than the others. And I don't know, Betsy or Brian, have you found that this is the best regimen for bone metastasis, or is that a theory that hasn't been proven out?

Dr. Elizabeth Plimack: I think it has this lore to it from that very first bone scan in the prostate studies that we all saw. Obviously, this isn't a drug for prostate cancer, so it didn't work in the end. But I think it has that reputation, I've not observed that clinically. And just to your point, I think since toxicities in a given patient are so unpredictable, I choose my regimen for efficacy, treat for efficacy, and manage whatever toxicity evolves. Because you don't know until you try. And it's surprising, some people get nothing and some people get one and not the other. So that's tended to be my approach. Brian.

Dr. Brian Rini: No, I agree with both those points. Some days I believe Cabo's better in bone, and others I think it's more marketing than science. And I'm not sure that's a critical feature. Nothing really works in bone, let's start there. None of the regimens are great in bone and we need to remember our ortho colleagues and radiation colleagues, to help manage those patients bisphosphonates if you believe in them. And we just need better treatments, right? And I know there's some novel bone targeting agents. I'm not personally involved, but I think hopefully when we're sitting here in three to five years, we're not debating this point. We're talking about some novel bone seeking agent like prostate has, etc. where we're really making a separate choice for those patients, not an empiric choice based on biases.

Dr. Robert Motzer: No, I agree. I think localized therapy is the best therapy for bone metastasis. So oftentimes I use a combined modality therapy with systemic therapy plus stereotactic radiation therapy to bone metastasis because I don't think the systemic therapy is the best.

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