Combining Belzutifan Plus Cabozantinib in Advanced Clear Cell Renal Cell Carcinoma, Exploring Novel Therapy Options - Toni Choueiri
May 15, 2023
In this conversation, Pedro Barata interviews Toni Choueiri, discussing the combination of cabozantinib with belzutifan in patients with advanced clear cell renal cell carcinoma (RCC). The study focused on two cohorts: one in the refractory setting and the other in the treatment-naive setting. Dr. Choueiri explains the rationale behind combining a HIF-2 inhibitor with a TKI and why cabozantinib was chosen for the study. The results showed a 31% overall response rate and a progression-free survival of nearly 14 months in the refractory setting. Dr. Choueiri discusses the potential of leveraging the HIF-2 inhibitor further, including the possibility of triple therapy and ongoing phase III trials. He also emphasizes the importance of understanding the unique side effects associated with HIF-2 inhibitors and highlights the future prospects of this novel class of drugs.
Biographies:
Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA
Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH
Biographies:
Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA
Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH
Read the Full Video Transcript
Pedro Barata: Hi, and welcome. I'm Pedro Barata. I'm a GU oncologist at Seidman Cancer Center University Hospitals in Cleveland, Ohio. It's my distinct pleasure to be joined today by the only great Dr. Toni Choueiri. Dr. Choueiri is the director of the Lang Center for GU, the medical director of the International Strategic Initiatives at Dana-Farber Harvard Medical School in Boston. Dr. Choueiri, true pleasure to have you here. Thank you so much for joining.
Toni Choueiri: Oh, thank you for having me.
Pedro Barata: Absolutely. Again, congratulations. Another outstanding paper came out on Lancet Oncology on a great effort. This time you are exploring the combination of cabozantinib with belzutifan, a novel HIF-2 inhibitor, in patients with advanced RCC. And there's some nuances, I think, regarding that study because you had two cohorts and you are presenting one of the cohorts in this paper. Maybe I'll start by asking you, can you share with us the thought process? Why combining a HIF-2 inhibitor with a TKI? Why cabozantinib? And what were you thinking when you thought about doing it different disease settings, maybe treatment naive cohort one in the refractory setting, plus IO plus TKI in the cohort two?
Toni Choueiri: Yeah, no, thank you for having me again here. The whole idea is to combine a TKI plus a HIF-2 inhibitor. Two classes of agents. Each have a single-agent activity, so it does make sense to combine them. We don't know, but there could be also some synergistic activity hitting the HIF-2 VEGF pathway in a strong fashion. There could be, potentially, when we treat with VEGF-TKI overexpression of HIF-2 that could be driving the tumors. So that's also possible. It's another way to target this axis. So they do make sense to combine and HIF-2 inhibitors with belzutifan and have showed activity in the refractory setting in metastatic RCC.
On the other hand, cabozantinib is the only TKI that is approved as a single agent in untreated patients, intermediate and poor risk, and in previously treated patients, again as a single agent TKI, that is the CABOSUN in untreated and the METEOR trials in the previously treated patients. So it does make sense to combine with cabozantinib.
The first cohort, I'm not going to talk about untreated patients. We just presented early result at the 2022 ESMO and the publication here was in the previously treated patients, we enrolled in this phase two study at 10 sites overall in the United States. We enrolled patients that had measurable disease and had to have up two previous regimens, but the patients needed to have been on an immune checkpoint inhibitor here. We end up with 52 patients. We're able to combine cabozantinib after a safety run-in for 6 patients at the full dose of 60 and belzutifan at the full dose of 120 milligram. Now, patients did need dose reduction, of course. Some of them shortly after.
The overall response rate by RECIST was 31%. The majority were partial responses. But then if you look, only 3 patients, 6%, had PD as best response. So the majority of patients had some form of tumor shrinkage. PFS was encouraging, close to 14 months. Again, this is a single-arm studied, so always take it with a grain of salt. But overall, despite the side effects and despite the fact that most of the side effects were low grade, we're able to get this combination moving forward, not with Cabozantinib per se, but with another TKI, lenvatinib, and belzutifan versus cabozantinib. This is a phase III trial that is actually ongoing.
Pedro Barata: Right. Well, that's an outstanding summary. I was just looking into results. I think you published these results with a median of about 2 years or so. It's quite interesting to me that I think when we're reading this, one of the things that comes to mind is the METEOR, with Cabo refractory setting and kind of compare, although we shouldn't do that, but 30% response rate, to your point, 14 months or so mPFS. And so there's something unique about this HIF-2 inhibitor allowing us time without progression for these patients. How do you think we can leverage that further? Do you think that's something we could think, perhaps, about triple therapy that perhaps is being investigated also? Do you think the sweet spot for HIF-2 would be a combination with a TKI or would you think of an IO? Where are your mindsets in addition to the Lenv-belzutifan versus Cabo, which is a phase III trial also ongoing? What are your thoughts about that?
Toni Choueiri: Well, I think the field is moving forward very fast in all directions. Single-agent, combination, adjuvant, first-line, second-line, not non-clear cell, obviously, so the answer is happening everywhere. We're using it in the adjuvant setting because it's tolerated. We finished the trial in the third-line setting versus everolimus, and that study should report at some point. The study was done and accrued some time ago, and in the front-line setting is being combined with Pembro-Len as one of the arms of the 012 study. And this trial also is accruing.
So let's see where it hits. The first step that it does need to hit as a single agent against everolimus. This is a population post VEGF-TKI and post PD-1 inhibitor. We hope that this first shows a significant activity. The primary endpoint are both PFS, co-primary, and OS. That is a study known by 005, and hopefully we'll have results at some point.
Pedro Barata: Right. Well, that's wonderful. Kudos to you because you're leading the efforts with these new therapies. We've been screaming for novel targets and novel agents, and of course this is leveraged on the novel price, on this HIF-2. So it's amazing to see that, actually, you were able to bring this to clinical development. It sounds like we might have news soon. Probably good news for patients. Any final remarks you'd like to make about this particular combo or about your thoughts about where you're going to go in addition to, obviously, the trials you mentioned?
Toni Choueiri: Well, I think it's very important to get familiar with some of the side effects. Mostly VEGF-TKI and HIF-2 inhibitors, they don't have overlapping side effects. The anemia could be in both. There is some fatigue. But you don't see hypertension, diarrhea, thyroid dysfunction with HIF-2 inhibitors. You may see hypoxia. And we've seen it in previously treated patient that, to begin with, did not have great lung function, at least anecdotally. So that's something to be aware of, but the drug is tolerated. The other thing is also to remember that belzutifan is, one, it's the most advanced, by far, HIF-2 inhibitor. There are other HIF-2 inhibitors coming, hitting on that transcription factor HIF-2. So I think the future is bright, but first, let's see, in randomized trials, what happens.
Pedro Barata: Right. Amazing. Well, Dr. Choueiri, it's been a pleasure. Again, congratulations. Great effort. I feel that we're not going to stop here. We are probably going to be chatting soon about another set of great news.
Toni Choueiri: Thank you.
Pedro Barata: With that, thank you so much for taking the time and sitting down with us and walking us through the paper. Congrats.
Toni Choueiri: Thanks for having me.
Pedro Barata: Thank you.
Pedro Barata: Hi, and welcome. I'm Pedro Barata. I'm a GU oncologist at Seidman Cancer Center University Hospitals in Cleveland, Ohio. It's my distinct pleasure to be joined today by the only great Dr. Toni Choueiri. Dr. Choueiri is the director of the Lang Center for GU, the medical director of the International Strategic Initiatives at Dana-Farber Harvard Medical School in Boston. Dr. Choueiri, true pleasure to have you here. Thank you so much for joining.
Toni Choueiri: Oh, thank you for having me.
Pedro Barata: Absolutely. Again, congratulations. Another outstanding paper came out on Lancet Oncology on a great effort. This time you are exploring the combination of cabozantinib with belzutifan, a novel HIF-2 inhibitor, in patients with advanced RCC. And there's some nuances, I think, regarding that study because you had two cohorts and you are presenting one of the cohorts in this paper. Maybe I'll start by asking you, can you share with us the thought process? Why combining a HIF-2 inhibitor with a TKI? Why cabozantinib? And what were you thinking when you thought about doing it different disease settings, maybe treatment naive cohort one in the refractory setting, plus IO plus TKI in the cohort two?
Toni Choueiri: Yeah, no, thank you for having me again here. The whole idea is to combine a TKI plus a HIF-2 inhibitor. Two classes of agents. Each have a single-agent activity, so it does make sense to combine them. We don't know, but there could be also some synergistic activity hitting the HIF-2 VEGF pathway in a strong fashion. There could be, potentially, when we treat with VEGF-TKI overexpression of HIF-2 that could be driving the tumors. So that's also possible. It's another way to target this axis. So they do make sense to combine and HIF-2 inhibitors with belzutifan and have showed activity in the refractory setting in metastatic RCC.
On the other hand, cabozantinib is the only TKI that is approved as a single agent in untreated patients, intermediate and poor risk, and in previously treated patients, again as a single agent TKI, that is the CABOSUN in untreated and the METEOR trials in the previously treated patients. So it does make sense to combine with cabozantinib.
The first cohort, I'm not going to talk about untreated patients. We just presented early result at the 2022 ESMO and the publication here was in the previously treated patients, we enrolled in this phase two study at 10 sites overall in the United States. We enrolled patients that had measurable disease and had to have up two previous regimens, but the patients needed to have been on an immune checkpoint inhibitor here. We end up with 52 patients. We're able to combine cabozantinib after a safety run-in for 6 patients at the full dose of 60 and belzutifan at the full dose of 120 milligram. Now, patients did need dose reduction, of course. Some of them shortly after.
The overall response rate by RECIST was 31%. The majority were partial responses. But then if you look, only 3 patients, 6%, had PD as best response. So the majority of patients had some form of tumor shrinkage. PFS was encouraging, close to 14 months. Again, this is a single-arm studied, so always take it with a grain of salt. But overall, despite the side effects and despite the fact that most of the side effects were low grade, we're able to get this combination moving forward, not with Cabozantinib per se, but with another TKI, lenvatinib, and belzutifan versus cabozantinib. This is a phase III trial that is actually ongoing.
Pedro Barata: Right. Well, that's an outstanding summary. I was just looking into results. I think you published these results with a median of about 2 years or so. It's quite interesting to me that I think when we're reading this, one of the things that comes to mind is the METEOR, with Cabo refractory setting and kind of compare, although we shouldn't do that, but 30% response rate, to your point, 14 months or so mPFS. And so there's something unique about this HIF-2 inhibitor allowing us time without progression for these patients. How do you think we can leverage that further? Do you think that's something we could think, perhaps, about triple therapy that perhaps is being investigated also? Do you think the sweet spot for HIF-2 would be a combination with a TKI or would you think of an IO? Where are your mindsets in addition to the Lenv-belzutifan versus Cabo, which is a phase III trial also ongoing? What are your thoughts about that?
Toni Choueiri: Well, I think the field is moving forward very fast in all directions. Single-agent, combination, adjuvant, first-line, second-line, not non-clear cell, obviously, so the answer is happening everywhere. We're using it in the adjuvant setting because it's tolerated. We finished the trial in the third-line setting versus everolimus, and that study should report at some point. The study was done and accrued some time ago, and in the front-line setting is being combined with Pembro-Len as one of the arms of the 012 study. And this trial also is accruing.
So let's see where it hits. The first step that it does need to hit as a single agent against everolimus. This is a population post VEGF-TKI and post PD-1 inhibitor. We hope that this first shows a significant activity. The primary endpoint are both PFS, co-primary, and OS. That is a study known by 005, and hopefully we'll have results at some point.
Pedro Barata: Right. Well, that's wonderful. Kudos to you because you're leading the efforts with these new therapies. We've been screaming for novel targets and novel agents, and of course this is leveraged on the novel price, on this HIF-2. So it's amazing to see that, actually, you were able to bring this to clinical development. It sounds like we might have news soon. Probably good news for patients. Any final remarks you'd like to make about this particular combo or about your thoughts about where you're going to go in addition to, obviously, the trials you mentioned?
Toni Choueiri: Well, I think it's very important to get familiar with some of the side effects. Mostly VEGF-TKI and HIF-2 inhibitors, they don't have overlapping side effects. The anemia could be in both. There is some fatigue. But you don't see hypertension, diarrhea, thyroid dysfunction with HIF-2 inhibitors. You may see hypoxia. And we've seen it in previously treated patient that, to begin with, did not have great lung function, at least anecdotally. So that's something to be aware of, but the drug is tolerated. The other thing is also to remember that belzutifan is, one, it's the most advanced, by far, HIF-2 inhibitor. There are other HIF-2 inhibitors coming, hitting on that transcription factor HIF-2. So I think the future is bright, but first, let's see, in randomized trials, what happens.
Pedro Barata: Right. Amazing. Well, Dr. Choueiri, it's been a pleasure. Again, congratulations. Great effort. I feel that we're not going to stop here. We are probably going to be chatting soon about another set of great news.
Toni Choueiri: Thank you.
Pedro Barata: With that, thank you so much for taking the time and sitting down with us and walking us through the paper. Congrats.
Toni Choueiri: Thanks for having me.
Pedro Barata: Thank you.