Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)802-805
Number of pages4
JournalNature medicine
Issue number5
StatePublished - May 2021

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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