Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.
Nature medicine. 2021 Apr 22 [Epub ahead of print]
Toni K Choueiri, Todd M Bauer, Kyriakos P Papadopoulos, Elizabeth R Plimack, Jaime R Merchan, David F McDermott, M Dror Michaelson, Leonard J Appleman, Sanjay Thamake, Rodolfo F Perini, Naseem J Zojwalla, Eric Jonasch
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. ., Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA., South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA., Fox Chase Cancer Center, Philadelphia, PA, USA., University of Miami, Miami, FL, USA., Beth Israel Deaconess Medical Center, Boston, MA, USA., Massachusetts General Hospital, Boston, MA, USA., University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Merck & Co., Inc, Kenilworth, NJ, USA., The University of Texas MD Anderson Cancer Center, Houston, TX, USA. .