Managing Toxicity and Safety of Belzutifan in ccRCC

A recent development in the treatment of recurrent advanced clear cell renal cell carcinoma (ccRCC) is the approval of the HIF2α inhibitor belzutifan (Welireg). Sumanta K. Pal, MD, FASCO, professor, Department of Medical Oncology & Therapeutics Research, and codirector of the kidney cancer program at City of Hope in San Francisco, California, and participants at a virtual Case-Based Roundtable event discussed managing the toxicity and safety profile of belzutifan in patients who received multiple prior lines of therapy for ccRCC.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• What has been your experience with belzutifan for advanced/metastatic RCC?
• What are your reactions to the final data analysis of LITESPARK-005 (NCT04195750)?

Sumanta K. Pal, MD: There is no doubt in my mind that belzutifan is a well-tolerated drug. The main toxicities that we tend to look for are anemia and hypoxia.¹ Although these adverse events are challenging, I tell every patient who starts on belzutifan to purchase a pulse oximeter and begin a log of the readings to bring with you on your appointments. If the pulse is falling below 92%, I tell the patient to stop the drug. The hypoxia is reversible and has been shown to be grade 3 or 4 in clinical trials.¹

Anemia is also a real challenge, especially in the late setting. A patient who is on third- or fourth-line therapy usually has a hemoglobin reading from 12 to 16 g/dL. It’s typically going to dip down to a range of 8 to 10 g/dL. With belzutifan, you’ll almost immediately see a dip in hemoglobin levels.

I’ve recently become familiar with using growth factor support, although initially I was apprehensive about it. If you need to, you can use epoetin alfa [Procrit]. [Dr Moon], have you been doing something like this with your patients who are taking belzutifan?

Helen Moon, MD: I do have 2 patients on the agent. I have similar concerns, but I also have a concern about blood clots. It’s due to the lingering, but admittedly old concerns, about using growth factor.

Yu-Wei Chen, MD: In my practice, there are some patients who develop anemia, and sometimes the development of hypoxia without anemia. Your suggestion about using a pulse oximeter while using the drug to monitor hypoxia is a great one.

Li Zhang, MD: [Because of] anemia and hypoxia, for patients with heart failure, this can be a difficult drug to give. I have found that with peripheral edema, like massive weight gain, can be a problem for a patient with heart failure.

Pal: What are your reactions to the final analysis data from LITESPARK-005? Thomas, relative to some of the data we looked at previously, what are your thoughts on the belzutifan data in this study?

Thomas Spillane, MD: I think this is a situation where you’re running out of treatment options. So, you get what you get with these drugs. I had used this in a patient with von Hippel-Lindau disease, and I thought that this was limited to that group of patients. Can you use this in non-VHL patients?

Karo Arzoo, MD: Yes, it’s unlimited.²

Pal: Where might you sequence belzutifan in the [treatment] lineup?

Spillane: I have used tivozanib (Fotivda) and I like it because of its safety profile. I would probably use tivozanib before belzutifan.

Pal: How about you, [Dr Kouz]? Based on the datasets, where do you sequence these drugs?

Rafid Kouz, MD: I do pretty much the same thing. I have a heavily pretreated patient, and I ended up giving them belzutifan as a last resort, after treating with immunotherapy and tyrosine kinase inhibitor [IO/TKI], followed by tivozanib. Interestingly, the patient has been doing well on [belzutifan] with a very good response rate. The only challenge I’ve encountered is the need to give them regular blood transfusions. He is already on oxygen, so coupled with hypoxia, I’m not sure if this will be manageable. [Because] he was on oxygen, I don’t know if the medication caused hypoxia in him. I know that it’s caused anemia because I’ve had to transfuse him on a regular basis. The hypoxia alarms me, so that might be a question for you, [Dr Pal].

Pal: Yes, we can tackle that now. It’s very timely. I think it’s a risky business. You can possibly try belzutifan for a short term and see whether their oxygen requirement goes up or down.

Kouz: The patient is on oxygen for his heart condition, and I did not notice any drop in his oxygen because he’s on oxygen on a regular basis. But if he becomes hypoxic on the medication, would you stop it permanently?

Pal: Yes, it’s tough. Let’s just assume for the moment, that the patient has already been through TKI therapies, or that you don’t want to prescribe TKIs because of the cardiac risk involved. In this scenario, I would probably suggest monitoring the patient week by week, such as having them submit their oxygen values to your nurse practitioner. If you see the values dipping quickly, I would propose that you pause the drug.

Once it dips, you can give a lower dose, going from 120 mg to 80 mg. If the 80-mg dose is still having the same impact on oxygenation, go down to 40 mg because there is a possibility that at those lower doses you can avoid the effect of de-oxygenation. I would closely watch those oxygen levels and titrate down the drug dose.

Arzoo: If we have choices in our disposition, such as tivozanib, why would we contemplate this medication in a patient who is hypoxic or anemic? I assume we’ve chose belzutifan because there is a good reason, such as von Hippel-Lindau disease?

Pal: Yes, absolutely. I think [Dr Kouz] was mentioning a situation where a patient had been on prior TKIs and so forth.

Kouz: Yes, that’s exactly the situation with the patient. You can use this as a last resort, as I did in this case and I’m happy with the results of the drug, which I didn’t expect.

Arzoo: Have you tried a lower dose to see if the hypoxia improves?

Kouz: He’s currently doing well and he doesn’t have hypoxia, per se, because he’s on home care oxygen. I reduced the dose to 80 mg, but that was because he couldn’t tolerate other adverse events, particularly anemia. He has no major issues, other than the fatigue and tiredness, which I think all these TKIs and other medications can cause. But apart from that, I can keep him on that dose. He’s not quite at the level of being a candidate for a clinical trial, so I don’t have any other option now.

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_DISCLOSURES:

_{Sumanta K. Pal reports being a member of the speakers’ bureau of IntrinsiQ, MJH Life Sciences, and Peerview; support for travel, accommodations, and expenses from CRISPR Therapeutics, Exelixis, and Ipsen.}

_{Helen Moon has served in consulting or advisory roles for Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany; and has received funding for travel, accommodation, and expenses from Bayer. J.B. Aragon-Ching has served in consulting or advisory roles for Algeta/Bayer, Amgen, AstraZeneca, AstraZeneca/MedImmune, AVEO, Bayer, Dendreon, Exelixis, Immunomedics, Janssen Biotech, Merck & Co., Rahway, NJ, Pfizer, Pfizer/Myovant, Sanofi, Seagen, and the healthcare business of Merck KGaA, Darmstadt, Germany; reports speakers services for Astellas Pharma, Bristol Myers Squibb, Janssen-Ortho, and Seagen/Astellas Pharma; has received travel and accommodation expenses from Algeta/Bayer, Astellas Pharma, Bristol Myers Squibb, Dendreon, and the healthcare business of Merck KGaA, Darmstadt, Germany; and has received honoraria from Astellas Scientific and Medical Affairs Inc, Bristol Myers Squibb, Pfizer, and the healthcare business of Merck KGaA, Darmstadt, Germany.}

REFERENCE

1. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906

2. FDA approves belzutifan for advanced renal cell carcinoma. News release. December 14, 2023. Accessed February 3, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma