Daniel Heng, MD, on How Belzutifan/Lenvatinib Fills an Unmet Need After Immunotherapy in RCC

In an interview with Targeted Oncology^TM, Daniel Heng, MD, of the University of Calgary, discusses the recent FDA approval of belzutifan (Welireg) plus lenvatinib (Lenvima) for patients with advanced renal cell carcinoma (RCC) in the second- and third-line settings.

Heng explains that patients whose disease progressed on immunotherapy previously had limited options, with median progression-free survival (PFS) of about 6 to 7 months and response rates around 30%. In the phase 3 LITESPARK-011 trial, belzutifan plus lenvatinib was compared with cabozantinib (Cabometyx). The combination produced an overall response rate of 53% vs 40% with cabozantinib, and median PFS of more than 14 months vs 10 months. He noted that other therapies used in the real world can yield a PFS as low as 6 to 7 months.

Because this is a combination, Heng says clinicians should expect more toxicity than with a single agent. Belzutifan introduces hypoxia and anemia, which may require transfusions or erythropoietin. A cardiac toxicity signal was observed, but Heng says it was low and may reflect the more frequent echocardiograms performed in the trial. He shared practical tips for hypoxia: patients often do not look dyspneic despite a low oxygen saturation, and it can typically be managed by holding the drug for a week and then reducing the dose. Patients who are dyspneic, or in whom pulmonary embolism is a concern, should still be sent to the emergency department. Overall, he says oncologists are experienced with TKIs and that patients with few comorbidities and no severe COPD requiring oxygen are good candidates.

Looking ahead, Heng says real-world data are needed to see whether benchmarks for response, PFS, and overall survival hold up, along with further evaluation of cardiotoxicity. He also points to other HIF inhibitors in development and open questions about whether they are interchangeable or can be used sequentially.

Heng also emphasizes sequencing. He says first-line choices may shift in the US, where the combination is available now, but not in countries that adopt new drugs more slowly, such as Canada. Still, he stresses using the best first-line therapy first, since not every patient reaches second- or third-line treatment.