The LITESPARK-013 Trial and Belzutifan's Optimal Dose for Treating Metastatic Renal Cell Carcinoma - Neeraj Agarwal
November 10, 2023
Neeraj Agarwal discusses the phase two LITESPARK-013 trial exploring the efficacy of belzutifan, a hypoxia-inducible transcription factor 2 alpha inhibitor, in treating metastatic renal cell carcinoma. The trial compares two doses of belzutifan (120 milligrams and 200 milligrams daily) in patients who have progressed on PD-1 axis inhibitors. The primary endpoint is the objective response rate, with progression-free survival and overall survival as secondary endpoints. The results indicate similar objective responses in both arms, with a time to response of 3.6 months. Side effects, predominantly anemia, hypoxia, and fatigue, were more frequent in the 200 milligram group, leading to more dose reductions and discontinuations. Ultimately, the study concludes that the 120 milligram dose of belzutifan is optimal, reaffirming its status as the standard treatment dose for metastatic renal cell carcinoma.
Biographies:
Neeraj Agarwal, MD, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT) at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Biographies:
Neeraj Agarwal, MD, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT) at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA
Read the Full Video Transcript
Alicia Morgans: Hi, I am so excited to be here today with Dr. Neeraj Agarwal, who is joining me from the Huntsman Cancer Institute and the University of Utah. Thank you so much for being here today.
Neeraj Agarwal: Thank you. It's always a pleasure.
Alicia Morgans: Wonderful. And I'm so excited to talk with you about belzutifan and the latest data from the LITESPARK-013 trial that you presented. This is a phase two that you presented at ESMO 2023.
Neeraj Agarwal: Yes. So just to take a step back, belzutifan is a hypoxia-inducible transcription factor 2 alpha inhibitors. This is a transcription factor inhibitor, a new class of drug for patients with metastatic renal cell carcinoma. And based on the results of the LITESPARK-001 trial, belzutifan got FDA approval for patients with VHL associated tumors, which were not there, which are not ready for surgery. So for example, hemangioblastoma or some pancreatic neuroendocrine cancers and also VHL associated renal cell carcinoma. And based on the larger LITESPARK-005 trial, which compared belzutifan with everolimus in a randomized fashion in a salvage therapy setting in patients with metastatic clear cell renal cell carcinoma, we expect belzutifan to be approved for a wider patient population who have metastatic renal cell carcinoma. Now, coming to the trial I presented, this was the LITESPARK-013 trial, which compared two doses of belzutifan, the currently approved dose of 120 milligrams daily versus a 200 milligram dose.
And the rationale for testing these two doses comes from the original LITESPARK-001 trial, where in the dose exploration phase, when different doses were compared or different doses were tested in patients from 20 milligrams daily to 240 milligrams daily, the maximum tolerated dose was not reached. So obviously 120 milligram dose was chosen by the investigators based on the totality of safety, PK and PD data. But there was always a lingering question as to whether patients could or can tolerate a higher dose which could be more efficacious. So that question was addressed in this LITESPARK-013 trial, which is a phase two trial of 150 patients who were randomized to receive belzutifan 120 milligrams daily versus belzutifan 200 milligrams daily. And these patients had to have disease progression on at least one PD-1 axis inhibitor, and most patients had received VEGF TKIs and other drugs.
Alicia Morgans: So this kind of work is so important though, Neeraj. We talked before we started filming about the way that we sometimes decide on these doses. And if you have an agent that has not reached an MTD, in oncology we are increasingly thinking about trying to not necessarily push it to a maximally tolerated dose, but a dose that is effective against the cancer while minimizing the side effects and perhaps there are other doses that we should use. So this is so important and is not new or specific to belzutifan and this program, but it's something that in oncology we're increasingly trying to do.
Neeraj Agarwal: Absolutely. That's such a great point you made. I'm so glad you brought that up because we have seen recent examples within metastatic RCC settings. Lenvatinib doses have been used in two different trials. Dr. Monte Pal led that study. And then we saw pembrolizumab after approval, even nivolumab after approval being tested in longer term doses. So three week dose versus six week dosing for nivolumab, two week dosing versus four week dosing. So I think this is not new, and we always aspire to get the best dose for our patients, which is more efficacious and equally well tolerated. So that was the premise for this trial. And to keep it simple, objective response rates were the primary endpoint and progression-free survival and overall survival were the secondary endpoints. And of course, side effects were the secondary endpoints. So objective responses were similar in both arms at 23%.
Time to response was 3.6 months, which is good, good to know that belzutifan, when it causes response, they're usually quick within the first scan. However, if you look at the progression-free survival and overall survival, there were numerical differences in progression-free survival, but statistically they were similar and overall survival had not been reached in either arm, but statistically they were similar. But then interestingly, if you look at the side effects... By the way, talking about the side effects, the most common side effects were anemia, hypoxia, and fatigue, which are so synonymous with belzutifan now. But the usual traditional side effects we see with TKIs, which more affect quality of life such as hand-foot syndrome, diarrhea and altered taste and dryness, peeling of skin, were non-existent in this trial.
So again, highlighting the major differences in the side effects of belzutifan. So even though those side effects were similar in terms of frequency, but then if you look deeper and look at how often patients were decreasing the dose or how often they had to discontinue the dose of belzutifan, those were more common in the belzutifan 200 milligram dose.
Alicia Morgans: This is so important because obviously the drug does not work if we are not continuing it for the patient. And so finding a drug that is going to be one that we can continue with fewer dose reductions and fewer discontinuations is really critical.
Neeraj Agarwal: Yes. So after establishing that there was no difference in overall objective responses, median PFS or OS, but patients had to discontinue or decrease the doses in 200 milligram, more often the decision was that 120 milligram dose should remain the standard dose and our patients should be treated with belzutifan at 120 milligram daily.
Alicia Morgans: Wonderful. So at this point, I imagine you and the investigators certainly feel reassured that the dose that was tested and then retested in these other clinical trials is the dose that should continue to remain the standard. And I imagine this is how things will move forward, as you said.
Neeraj Agarwal: Yes, which is great news for our patients. They have to take less dose.
Alicia Morgans: It is very much great news. So if you had to sum it up from LITESPARK-013, what's the message?
Neeraj Agarwal: The message is that belzutifan 120 milligram daily is the optimal dose for our patients and should be the starting dose when we are starting to treat our patients with belzutifan.
Alicia Morgans: Fantastic. Well, I so appreciate you sharing this and really making sure that as a field we clarify this particular aspect of care. It is so important for our patients, it's so important for us in clinic, and I appreciate your time and your expertise today.
Neeraj Agarwal: Thank you very much.
Alicia Morgans: Hi, I am so excited to be here today with Dr. Neeraj Agarwal, who is joining me from the Huntsman Cancer Institute and the University of Utah. Thank you so much for being here today.
Neeraj Agarwal: Thank you. It's always a pleasure.
Alicia Morgans: Wonderful. And I'm so excited to talk with you about belzutifan and the latest data from the LITESPARK-013 trial that you presented. This is a phase two that you presented at ESMO 2023.
Neeraj Agarwal: Yes. So just to take a step back, belzutifan is a hypoxia-inducible transcription factor 2 alpha inhibitors. This is a transcription factor inhibitor, a new class of drug for patients with metastatic renal cell carcinoma. And based on the results of the LITESPARK-001 trial, belzutifan got FDA approval for patients with VHL associated tumors, which were not there, which are not ready for surgery. So for example, hemangioblastoma or some pancreatic neuroendocrine cancers and also VHL associated renal cell carcinoma. And based on the larger LITESPARK-005 trial, which compared belzutifan with everolimus in a randomized fashion in a salvage therapy setting in patients with metastatic clear cell renal cell carcinoma, we expect belzutifan to be approved for a wider patient population who have metastatic renal cell carcinoma. Now, coming to the trial I presented, this was the LITESPARK-013 trial, which compared two doses of belzutifan, the currently approved dose of 120 milligrams daily versus a 200 milligram dose.
And the rationale for testing these two doses comes from the original LITESPARK-001 trial, where in the dose exploration phase, when different doses were compared or different doses were tested in patients from 20 milligrams daily to 240 milligrams daily, the maximum tolerated dose was not reached. So obviously 120 milligram dose was chosen by the investigators based on the totality of safety, PK and PD data. But there was always a lingering question as to whether patients could or can tolerate a higher dose which could be more efficacious. So that question was addressed in this LITESPARK-013 trial, which is a phase two trial of 150 patients who were randomized to receive belzutifan 120 milligrams daily versus belzutifan 200 milligrams daily. And these patients had to have disease progression on at least one PD-1 axis inhibitor, and most patients had received VEGF TKIs and other drugs.
Alicia Morgans: So this kind of work is so important though, Neeraj. We talked before we started filming about the way that we sometimes decide on these doses. And if you have an agent that has not reached an MTD, in oncology we are increasingly thinking about trying to not necessarily push it to a maximally tolerated dose, but a dose that is effective against the cancer while minimizing the side effects and perhaps there are other doses that we should use. So this is so important and is not new or specific to belzutifan and this program, but it's something that in oncology we're increasingly trying to do.
Neeraj Agarwal: Absolutely. That's such a great point you made. I'm so glad you brought that up because we have seen recent examples within metastatic RCC settings. Lenvatinib doses have been used in two different trials. Dr. Monte Pal led that study. And then we saw pembrolizumab after approval, even nivolumab after approval being tested in longer term doses. So three week dose versus six week dosing for nivolumab, two week dosing versus four week dosing. So I think this is not new, and we always aspire to get the best dose for our patients, which is more efficacious and equally well tolerated. So that was the premise for this trial. And to keep it simple, objective response rates were the primary endpoint and progression-free survival and overall survival were the secondary endpoints. And of course, side effects were the secondary endpoints. So objective responses were similar in both arms at 23%.
Time to response was 3.6 months, which is good, good to know that belzutifan, when it causes response, they're usually quick within the first scan. However, if you look at the progression-free survival and overall survival, there were numerical differences in progression-free survival, but statistically they were similar and overall survival had not been reached in either arm, but statistically they were similar. But then interestingly, if you look at the side effects... By the way, talking about the side effects, the most common side effects were anemia, hypoxia, and fatigue, which are so synonymous with belzutifan now. But the usual traditional side effects we see with TKIs, which more affect quality of life such as hand-foot syndrome, diarrhea and altered taste and dryness, peeling of skin, were non-existent in this trial.
So again, highlighting the major differences in the side effects of belzutifan. So even though those side effects were similar in terms of frequency, but then if you look deeper and look at how often patients were decreasing the dose or how often they had to discontinue the dose of belzutifan, those were more common in the belzutifan 200 milligram dose.
Alicia Morgans: This is so important because obviously the drug does not work if we are not continuing it for the patient. And so finding a drug that is going to be one that we can continue with fewer dose reductions and fewer discontinuations is really critical.
Neeraj Agarwal: Yes. So after establishing that there was no difference in overall objective responses, median PFS or OS, but patients had to discontinue or decrease the doses in 200 milligram, more often the decision was that 120 milligram dose should remain the standard dose and our patients should be treated with belzutifan at 120 milligram daily.
Alicia Morgans: Wonderful. So at this point, I imagine you and the investigators certainly feel reassured that the dose that was tested and then retested in these other clinical trials is the dose that should continue to remain the standard. And I imagine this is how things will move forward, as you said.
Neeraj Agarwal: Yes, which is great news for our patients. They have to take less dose.
Alicia Morgans: It is very much great news. So if you had to sum it up from LITESPARK-013, what's the message?
Neeraj Agarwal: The message is that belzutifan 120 milligram daily is the optimal dose for our patients and should be the starting dose when we are starting to treat our patients with belzutifan.
Alicia Morgans: Fantastic. Well, I so appreciate you sharing this and really making sure that as a field we clarify this particular aspect of care. It is so important for our patients, it's so important for us in clinic, and I appreciate your time and your expertise today.
Neeraj Agarwal: Thank you very much.