In a U.S. phase II trial reported in The Lancet Oncology, Toni K. Choueiri, MD, and colleagues found that the combination of the hypoxia-inducible factor 2α inhibitor belzutifan and the VEGFR kinase inhibitor cabozantinib showed promising activity in patients with advanced clear cell renal cell carcinoma who had received PD-1 or PD-L1 inhibitors.

Toni K. Choueiri, MD

Study Details

In the multicenter trial, 52 patients with locally advanced or metastatic disease who had received prior immunotherapy and up to two systemic treatment regimens were enrolled between September 2018 and July 2020. Patients received belzutifan at 120 mg once daily and cabozantinib at 60 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was confirmed investigator-assessed objective response.

Responses

Median follow-up at data cutoff (start of February 2022) was 24.6 months (interquartile range [IQR] = 22.1–32.2 months).

Confirmed objective response was observed in 16 (30.8%, 95% confidence interval [CI] = 18.7%–45.1%) of 52 patients, including complete response in 1 (2%). An additional 32 patients (62%) had stable disease. Overall, 48 patients (92.3%, 95% CI = 81.5%–97.9%) had an objective response or stable disease.

Median time to response was 3.2 months (IQR = 1.9–7.3 months). A total of 45 patients (87%) had reduction in the sum of diameters of target lesions. Median duration of response was 18.6 months (95% CI = 8.3-22.8 months), with nine patients having ongoing response at data cutoff.

Median progression-free survival was 13.8 months (95% CI = 9.2–19.4 months), with a 12-month rate of 56.2%. Median overall survival was 24.1 months (95% CI = 20.0–37.4 months), with a 12-month rate of 76.5%.

Adverse Events

Treatment-related grade 3 adverse events occurred in 33 patients (63%); no grade 4 events were observed and 1 grade 5 event (respiratory failure) was observed. The most common grade 3 events were hypertension (27%), anemia (15%), and fatigue (12%).

Serious treatment-related adverse events occurred in 29% of patients, most commonly acute kidney injury (n = 2, 4%). Adverse events led to discontinuation of belzutifan in 10 patients (19%), most commonly fatigue (4%), and to discontinuation of cabozantinib in 11 patients (21%), most commonly fatigue (4%) and increased alanine aminotransferase increase (4%).

The investigators concluded: “Belzutifan plus cabozantinib has promising antitumour activity in patients with pretreated clear cell renal cell carcinoma, and our findings provide rationale for further randomised trials with belzutifan in combination with a VEGFR tyrosine-kinase inhibitor.”

Dr. Choueiri, of Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme (a subsidiary of Merck & Co) and the National Cancer Institute. For full disclosures of the study authors, visit www.thelancet.com.