In a phase II trial (LITESPARK-003), reported in The Lancet Oncology, Choueiri et al found that the combination of belzutifan—a first-in-class HIF-2α inhibitor—and cabozantinib showed promising activity in the first-line treatment of patients with advanced clear cell renal cell carcinoma.
Study Details
In the U.S. multicenter trial, 50 patients were enrolled between September 2018 and January 2023. They received belzutifan at 120 mg once daily and cabozantinib at 60 mg once daily until disease progression or unacceptable toxicity. The primary outcome measure was investigator-assessed confirmed objective response.
Responses
At data cutoff (in May 2023), median follow-up was 24.3 months (interquartile range = 13.9–32.0 months). Confirmed objective response was observed in 35 of 50 patients (70%, 95% confidence interval [CI] = 55%–82%), with a complete response in 4 (8%). The disease control rate was 98%. At data cutoff, 24 patients (48%) had ongoing treatment. Median duration of response was 28.6 months (95% CI = 11.2 months to not reached).
Median progression-free survival was 30.3 months (95% CI = 16.6 months to not reached), with 12- and 24-month rates of 69% and 57%. Median overall survival was not reached (95% CI = not reached to not reached), with 12- and 24-month rates of 96% and 86%.
Adverse Events
Grade 3 treatment-related adverse events were reported in 44% of patients, with a grade 4 event in one patient. The most common grade 3 or 4 treatment-related adverse events were hypertension (12%), anemia (10%), and fatigue (8%). Serious treatment-related adverse events occurred in 14% of patients. Adverse events led to discontinuation of belzutifan in 10% and discontinuation of cabozantinib in 12% of patients. No treatment-related deaths occurred.
KEY POINTS
- Objective response was achieved in 70% of patients treated with belzutifan plus cabozantinib for advanced clear cell renal cell carcinoma.
- Median response duration was 28.6 months.
The investigators concluded: “Belzutifan plus cabozantinib has promising antitumor activity in treatment-naive patients with advanced clear cell renal cell carcinoma and further investigation of an HIF-2α inhibitor in combination with a multitargeted tyrosine kinase inhibitor as a treatment option in this population is warranted.”
Toni K. Choueiri, MD, FASCO, of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, and the National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.
