Thomas Powles, MD: Eric, when you look at this from a distance and you have, let's say, a patient who's progressed first on ipi-nivo [ipilimumab-nivolumab] and they had a modest response to therapy, and they did nicely. They’ve got lung metastases, a lymph node metastasis, and they've got intermediate risk disease. With an ipi-nivo patient, how are you discussing what they should have next?

Eric Jonasch, MD: The biggest challenge here is we know that a TKI [tyrosine kinase inhibitor] like cabozantinib, lenvatinib, and everolimus will probably do a good job in these individuals. For that matter, axitinib or sunitinib. There are some small studies that demonstrate that in individuals who are IO [immunotherapy] refractory that single agent TKI provides a benefit. Back to Rana's point, do we need to continue PD-1 blockade? I don't know. Right now, it ends up being, with a board answer, is that you would give those individuals a single agent TKI where IO or combination therapy, the temptation is to continue PD-1 blockade.

Thomas Powles, MD: Ulka, I want to ask this difficult question. Is there a difference, a relapse, after individual with IO/IO ipi-nivo compared to VEGF [vascular endothelial growth factor]-TKI/IO? Are you more confident around treating patients with IO/IO rather VEGF/TKI? Essentially, what I'm saying is have you used everything upfront or is there anything left in the cupboard?

Ulka Nitin Vaishampayan, MD: It depends on what combination of VEGF-TKI and IO you used. Obviously, IO/IO is pretty simple. You go to a VEGF/TKI because that's a VEGF-TKI naive population. You probably expect better response rates, but then, the toxicity and things have not quite been tested before. In terms of if you used a VEGF-TKI and IO combination upfront, then you're probably looking at slightly attenuated efficacy. But, if you are seeing efficacy post IO, the data is pretty limited. Though, even the TIVO study had very few patients who had prior IO. There were a ton of cabozantinib pretreated patients on the TIVO-3 study. However, it still showed benefits with use of tivozanib. That gives me comfort that you can use a VEGF-TKI cycling from one to another and continue to get a response, especially for the patients who've had a duration of remission on the first combination.

Thomas Powles, MD: With my experience, I don't think the huge difference between those patients to progress on the different regimes. I think the tragedy of progression of disease with those patients still don't do terrifically well. This is an area we need to focus on.

Ulka Nitin Vaishampayan, MD: Absolutely.

Thomas Powles, MD: I don't think that those patients who progressed after ipi-nivo have dramatic responses to VEGF-targeted therapy. There seems to be some cross resistance between those as is the case with VEGF-TKI/IO therapy. Perhaps, this is one of the triplet challenges with triplet therapies. When you give all 3, things are very difficult. Who knows? Let's wait and see the future. The question I'd like to ask you, Ben, before we wrap this session up is, what do we need to do next in this environment in patients whose cancers have progressed after first line immune therapy? How are we approaching that as a community?

Benjamin Maughan, MD: The thing that this group needs in the second-line plus is another therapy that's terrible. What we've seen from every front-line therapy, every combination front-line therapy is that they can be durable for a significant proportion of patients. As we've discussed, there are differences in that durability. But they're all somewhat nuanced; they all can provide durable responses. We don't have a treatment in the second-line plus that for a significant proportion of patients is durable. There is evidence of durability for these therapies in a minority in each of these studies; the cabozantinib data has some patients that have durable responses, the TIVO-3 shows some patients have durable responses but it's a minority. We need to find therapy that's durable for them. It gets challenging because the biology is becoming more complex. To Eric's point, we are not understanding that biology as well as we need.

Thomas Powles, MD: Let's wrap this session up with belzutifan. Eric, you did some work with VHL [gene] and belzutifan publication in journal medicine. Belzutifan strikes me as a quite specific VEGF-targeted therapy. We've got data on heavily pretreated patients. Those patients probably have less VEGF-driven tumors and perhaps some of the earlier disease. What's belzutifan? What is it showing us so far in pretreated VEGF-TKI clear cell renal cancer patients?

Eric Jonasch, MD: We published a paper last year. These individuals had a median of 3 prior therapies, most of them had received IO therapy-VEGF therapy combination.

Thomas Powles, MD: What is belzutifan?

Eric Jonasch, MD: It is an oral HIF2 alpha inhibitor. Basically, when you have broken VHL in a cell which occurs in the majority of clear cell renal cell carcinomas, VHL's job is to basically ubiquitinate and degrade HIF2 alpha, which is a transcription factor. If you don't have VHL, you get up regulation of this and you get transcription of a whole bunch of different things that aren't supposed to be transcribed at that point in time, including things that regulate cell cycle, cell survival, as well as angiogenesis. It's not just the angiogenic factors. Belzutifan will prevent HIF2 alpha from interacting with HIF1 data and then you block that. The study looked at 55 individuals, heavily pretreated as mentioned, and really, interestingly, showed an objective response rate which wasn't stellar but still good, of 25%. It showed a much more intriguing progression-free survival of 14.5 months. It also demonstrated good toxicity profile. The main toxicity is anemia, which is an on-targeted effect. You could see some fatigue and see some hypoxemia, which we don't fully understand. Also, we didn't see the hypertension; we didn't see some of the other TKI effects. This is more than just modulating the VEGF pathway in a slightly different way. Again, we don't fully understand it, but we do see that it's an active agent.

Thomas Powles, MD: There's a study, a randomized phase III trial, that is comparing everolimus with belzutifan. People feel there's a good chance that's going to be positive. It's a late line trial.

Ulka Nitin Vaishampayan, MD: Yeah.

Thomas Powles, MD: We're looking forward to the results of that. Belzutifan has also being actively pursued in an adjuvant study, but also, a front-line triplet trial. It's a study, as a new drug, it's an important drug, and we're going to hear a lot more about it in the future.

Transcript edited for clarity.