Managing Hypoxia, Anemia, and Cardiac Toxicity With Belzutifan Plus Lenvatinib

In an interview with CancerNetwork® following the 2026 European Society for Medical Oncology (ESMO) Congress, Daniel Y.C. Heng, MD, MPH, FRCPC, head of medical oncology at the Arthur J.E. Child Comprehensive Cancer Centre and clinical professor of medicine at the University of Calgary in Alberta, Canada, explained how he manages the adverse events (AEs) associated with belzutifan plus lenvatinib in advanced renal cell carcinoma (RCC).

In the final analysis of the phase 3 LITESPARK-011 trial (NCT04586231), which Heng presented at the meeting, belzutifan plus lenvatinib was compared with cabozantinib in patients with advanced clear cell RCC after anti–PD-(L)1 therapy.¹ Anemia occurred in 70.8% vs 27.0% of patients, hypoxia in 15.7% vs 0%, and cardiac dysfunction in 13.0% vs 8.1%, respectively. Serious treatment-related AEs occurred in 28.1% vs 17.8%. The frequency of ejection fraction monitoring was increased partway through the trial, which Heng said may have contributed to the higher cardiac dysfunction rate.

The FDA approved belzutifan plus lenvatinib for advanced RCC with a clear cell component in September 2026.²

Transcript:

CancerNetwork: Serious treatment-related AEs were more frequent with the combination, and cardiac concerns led to added cardiac monitoring partway through the trial. How do you manage anemia, hypoxia, and cardiac risk in practice?

Heng: With any combination therapy, there are more toxicities. We need to make them tolerable and manageable enough that people can live well on these therapies and maintain a good quality of life. Hypoxia and anemia are on-target AEs of belzutifan. If a patient develops anemia, I think that is a good thing; it means there is enough belzutifan in their body. It is important to monitor it and transfuse as necessary, and you usually start erythropoietin when the hemoglobin reaches 9 g/dL or 90 g/L, depending on the units you use.

For hypoxia, I have my patients buy an oxygen saturation monitor so that they can check their oxygen saturation at home. There was a learning curve for me. At first, I was scared whenever someone was hypoxic; if their oxygen saturation was 88%, I would send them to the emergency department. However, I have learned that belzutifan-induced hypoxia has a few characteristics. First, patients usually do not look dyspneic unless it is late. They do not look short of breath; they look fine. It is just that their oxygen saturation is a little low. Second, if they take deep breaths, the oxygen saturation usually rises back above 90%, whereas with a large pulmonary embolism or pneumonia, it might not.

Obviously, if your patient is very sick, they should go to the emergency department. However, if it is related to belzutifan, you can hold the belzutifan and see whether it improves, which usually happens within 7 days, and then reduce the dose from there. That is how I manage hypoxia. It took me a while to work through that learning curve, but it is manageable for most people.

The other interesting aspect of the data was the increase in cardiac toxicity. Partway through the trial, cardiac monitoring was increased, and there was a difference in cardiac toxicity of 15% vs 9% or so [13.0% vs 8.1%]. It is difficult to tease out exactly what the cardiac toxicity was because of the way the electronic case report forms are built in the clinical trial and how coordinators enter the data, so there is only so much we can glean.

However, I think most events are related to asymptomatic declines in ejection fraction. Remember that we used version 5 of the Common Terminology Criteria for Adverse Events [CTCAE] for cardiac toxicity. A decrease of 10% is grade 1, and a decrease of 20% is grade 2. It is not hard to qualify for cardiac toxicity based on asymptomatic ejection fraction declines, especially if you are performing multigated acquisition [MUGA] scans often. We want to study that further, but for the most part, I think these are asymptomatic ejection fraction declines.

References

1. Heng DYC, Schmidinger M, McDermott R, et al. Final prespecified analysis of the phase 3 LITESPARK-011 study: belzutifan plus lenvatinib versus cabozantinib for advanced renal cell carcinoma after anti–PD-(L)1 therapy. Ann Oncol. Published online October 25, 2026. doi:10.1016/j.annonc.2026.10.109
2. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. FDA. September 24, 2026. Accessed November 12, 2026. https://tinyurl.com/mckvxff