Combination treatment with belzutifan and cabozantinib has demonstrated antitumor activity in previously treated, advanced clear cell renal cell carcinoma (RCC), according to research published in The Lancet.

This is the first trial to show that the combination of a HIF-2α inhibitor and a tyrosine kinase inhibitor targeting VEGFR might offer more benefit than either drug alone, the researchers wrote.

They conducted this phase 2 trial ( Identifier: NCT03634540) in patients with previously treated or treatment-naïve, locally advanced or metastatic RCC. The current report includes only the previously treated patients.

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The 52 patients had a median age of 63 (range, 57.5-68.5) years. A majority were White (92%), and most were men (73%). The patients had received 1 (56%) or 2 (44%) prior lines of therapy. Treatment consisted of immunotherapy alone (54%) or in combination with anti-VEGF/VEGFR therapy (46%).

On study, the patients received belzutifan at 120 mg once daily and cabozantinib at 60 mg once daily until disease progression, unacceptable toxicity, or patient withdrawal.

The median follow-up was 24.6 months. The primary endpoint was the objective response rate, which was 30.8%. Among 16 responders, there was 1 complete response. The median time to response was 3.2 months, and the median duration of response was 18.6 months. 

The median progression-free survival was 13.8 months, and the median overall survival was 24.1 months. At 12 months, the progression-free survival rate was 56.2%, and the overall survival rate was 76.5%.

Grade 3 treatment-related adverse events (TRAEs) occurred in 63% of patients. The most common were hypertension (27%), anemia (15%), and fatigue (12%). There were no grade 4 TRAEs, but there was 1 grade 5 TRAE (respiratory failure).

“Belzutifan plus cabozantinib has promising antitumor activity in patients with pretreated clear cell renal cell carcinoma, and our findings provide rationale for further randomized trials with belzutifan in combination with a VEGFR tyrosine kinase inhibitor,” the researchers concluded. 

Disclosures: This research was partly supported by Merck Sharp & Dohme. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: An open-label, single-arm, phase 2 study. Lancet. Published online March 31, 2023. doi:10.1016/S1470-2045(23)00097-9