Navigating Refractory RCC: Sequencing, Combinations, and Emerging Therapies

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a panel of experts discussed the latest research, emerging therapies, and best practices for treating renal cell carcinoma (RCC). Moderator Dr. Katy Beckermann of Tennessee Oncology was joined by Drs. David Braun, Matt Campbell, Brad McGregor, and Katie S. Murray in the discussion.

In the fifth segment of their conversation, the panel explores the evolving treatment landscape of refractory RCC, highlighting treatment sequencing, the role of combination therapies, and how novel agents like HIF-2 inhibitors and TKIs are being integrated into practice. The panelists address key considerations for optimizing patient outcomes while managing treatment-related toxicities.

View the previous segments.

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Dr. Beckermann: Alright, I got one last challenge for everybody here, thinking about refractory. How do we treat, how do we choose, how do we sequence? I’ll highlight that, I think, at this meeting there’s been similar to that wave of change that we saw in the frontline setting, going from single agent to dual agents, and now, it’s seeming to now happen kind of in the refractory phase. So we’re seeing updated data of cabozantinib plus belzutifan, as both an upfront and a refractory cohort. We’re seeing a presentation in a refractory patient population of lenvatinib and belzutifan and then we, kind of, know on the horizon that there’s a randomized phase three out there. So would love to hear your perspective on just how you all think about sequencing at our current standard practice and then what your take is on dose and novel combinations, I’ll say, I guess, in the refractory setting. So maybe Brad, I’ll let you start.

Dr. McGregor: Yeah, I mean, I think the refractory has certainly changed quite a bit and there’s no right answer. If you look at NCCN guidelines like in a patient of prior IO therapy, there’s no preferred regimen. I think there are some things that, I think, right now, are probably wrong to consider. And I think we have two randomized trials that show that in patients who progress on immunotherapy, VEGF blockade is not going to rescue an immunotherapy failure. So we have CODOT-III looking at cabozantinib with pembrolizumab versus cabozantinib, and Tinivo-2 looking at tivozanib-nivolumab versus tivozanib. Neither trial showed any benefit to giving IO with the TKI, but there are some differences overall. And I think in the cabo, a teaser trial CODOT-III, they optimized dose, so 60 milligrams in the cabo of both arms. TiNivo-2, given some concerns with the regulatory authorities, used a lower dose in the combination arm. So you look at CODOT-III, no difference in clinical outcomes, but actually worse toxicities with the addition of tislelizumab. And if you compare that to TiNivo-2, there’s actually no difference in toxicities, but there are numerically worse outcomes. We actually did a nice exposure response analysis in a poster, which showed that the dose of 1.34 is the right dose for tivozanib, and that certainly caused the best response. And actually, there’s no increased hypertension with a lower dose.

So I think those two trials, to me, say we really need to prioritize TKI dosing and giving the optimal dose. And so given the dose that’s in the study, be it 60, 154 if you’re using lenvatinib, 18, and I think the exciting data we see from the belzutifan combination is that belzutifan is a nice partner. So you can partner with TKIs and give the full dose. So we see some very nice safety data overall. That’s an option. So I think I look forward to those trials going forward.

Dr. Beckermann: Yeah.

Dr. Braun: I’m probably in the minority. I’m probably a little more of a skeptic when it comes to combination therapies in the refractory setting. And part of that is just to think about what the goals are. I think with upfront immunotherapy, again, the numbers might be small, but the hope is to get something really long-term, to get even that chance of cure. I think when we’re talking about targeted therapies in a refractory setting, that’s realistically, probably, not the goal at that point. It’s to help people live longer and feel better. And that really has to be taken into account with these combinations. And so I think that makes the bar different. With two targeted therapies, a HIF-2 blockade plus a TKI, I think response will be better. I think PFS will be better. These things will be true, but are you, actually, helping people to live longer and feel better?

And if the answer is no, then I think we have to pause a little bit and say, is that really the right thing to do, just because we’re getting these upfront response rates? And of course, there are exceptions to that, people who have rapidly progressive disease where response really matters. But for the majority of patients, I think that’s the sort of calculus I have to have in my mind.

Dr. Campbell: I think there’s just a tremendous amount of nuance to caring for patients with metastatic kidney cancer because every patient that’s coming in, you’re trying to evaluate what is their pace of disease? What are their sites of disease? And I think one of the things that we don’t often talk about as medical oncologists, but many of us are doing, is we do a lot of stereotactic radiation. We do a lot of ablation. We refer to great surgeons at times for oligometastatic disease. And we do a lot of, I would say, kind of touch-up work. And you’re not necessarily curing most patients with these efforts, but you’re certainly, potentially, resetting the biologic clock. You’re preventing, potentially, dangerous sites from having bad outcomes, like fracture or potential spinal cord issues or whether it’s liver compromise. And I think a lot of us are doing this around the edges.

From a systemic treatment standpoint, I’m always looking at how dangerous is the cancer at this time? What can I potentially get away with? And if I have a sense that I can get away with axitinib after nivo-ipi because the disease is not threatening because I know how cabo performs after a TKI, which is great, based on METEOR, or how lenvatinib-everolimus performs after TKI. Those are my two kind of go-to if I’m in a challenging scenario. But if I can get away with axitinib first, I have cabo. If patients do very well on axitinib for a long time, I think belzutifan in that subset of patients, probably, performs very well. And you start playing the chess game of how many lines of treatment might I try and when do I, actually, have to go for my biggest kind of multi-prong approach.

And so that’s the strategy that I’m playing, is when can I do cleanup work? How much can I get away with? How much risk am I putting a patient on from not going to my most active drug at that time? And it’s just kind of a stepwise approach, working with patients and trying to get as much as you can. It is clearly a marathon. The chances of cure are likely out the window and are you going to be on a tolerable therapy where patients can live with as high of quality of life for as long as they can?

Dr. Beckermann: And I’ll add the comment because I’ve thought a lot about this as well, and I think David, to your point, Matt, you’re hinting at this too, in the refractory setting, if we’re not achieving cure, if we’re adding toxicity, I recently saw in my practice someone who at time of progression was very symptomatic, just third-line setting and very symptomatic disease. And I think we do try to assess that. We try to say, okay, what is the pace or what’s the symptom burden, you know, all this. But sometimes, it’s just really hard and it’s hard to have that conversation with the patient. Do you say to them, “This might control your cancer for longer, maintain your current quality of life, ability to be active, keep that bony met from coming and accept a little more fatigue, more anemia?” It’s a hard question.

Dr. Braun: It’s a hard balance, yeah.

Dr. Katy Beckermann: So yeah, I’ll be curious to kind of see where some of these combination treatments end up. And Brad, I was going to ask you as well, we all have our way of thinking about sequencing. Do you think there’s a clinical trial design out there that will allow us to test this?

Dr. McGregor: I think it’s going to be incredibly challenging. Right. Because at the end of the day, I don’t think we have a right answer. I think if you look at, now, we have data for tivozanib post two lines of therapy, post-nivo-ipi, post-IO-TKI. We have cabo, we have len-niv. So we have so many different options. I think some of these trials combinations will actually be helpful too because it will give us some even on the monotherapy arm of those trials.

And I’m curious to see, I share the concerns that it may not pan out, but I do find the HIF-2 has a very unique… It’s not a TKI so it has a very unique side effect profile. Now, that can be challenge to manage, but it’s different to manage. And so I think that’s one thing I find exciting about this concept. I think we can maybe even have better different HIF-2 inhibitors. So I think there’s some really great data on casdatifan, which is another oral HIF-2 inhibitor, updated results showing that 100 milligrams daily seems to be the right dose and early numbers, but lower PD as best response with that. I think one of the concerns I have with belzutifan is this, in the phase two trial, over 30% of the patients experienced progressive disease, and that’s pretty high number, especially, if you start using that later lines of therapy. So I think it’d be really interesting to see how that drug moves forward. There’s trials ongoing combined with cabozantinib and others would be…

Dr. Campbell: If you find the belzutifan people, I think in my clinic, seven or eight out of 10 patients would say belzutifan is easier.

Dr. McGregor: A hundred percent.

Dr. Campbell: And you figure out the anemia, you manage the anemia, you manage, make sure they have a pulse oximeter. But if you can hit that 30%, those patients often do well for a good while. And so it’s just can we do a better job of identifying those patients and are there prognostic features or others that we can say, this is the group that we can go down this road.

Dr. McGregor: I would agree. Most patients love HIF 2 inhibitors. They’re like-

Dr. Braun: It’s a nice break.

Dr. McGregor: They’re like, it’s a break. I feel so much better. I can taste again. It’s fantastic.

Dr. Beckermann: And I love this idea because I think that monotherapy of belzutifan does give that treatment break, while everything else we’re talking about is, essentially, de-risking the belzutifan primary progressive response by adding in a TKI. I think though, we’re all very so specialized, we’re all very focused, we kind of try to do a little nuance. How’s the scan looking? Is this rapidly progressive? But I think too, to our community colleagues who are practicing and seeing three patients with kidney cancer, and so there I wonder if the benefit of having that high up front ORR in a refractory setting and then the long-term tail of belzutifan is going to end up winning out. It’s somewhat distressing because then we won’t get the break from the TKI, but perhaps then in the community also, that might be an easier thing to not have to make all those nuanced decisions and just know, “Hey, I’m going to have this combination of treatment options.”

I have really enjoyed this conversation today. I’ve grilled each of you, I think, and so it’s just truly been a pleasure. I want to thank the audience for joining us and hope you all have found this insightful round table discussion at GU ASCO. Thanks for joining us.