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Choueiri TK , Bauer TM , Papadopoulos KP , Plimack ER , Merchan JR , McDermott DF , Michaelson MD , Appleman LJ , Thamake S , Perini RF , Zojwalla NJ , Jonasch E
Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis
Nat Med. 2021 May;27(5) :802-805
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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.
1546-170x Choueiri, Toni K Orcid: 0000-0002-9201-3217 Bauer, Todd M Papadopoulos, Kyriakos P Plimack, Elizabeth R Orcid: 0000-0002-7618-0744 Merchan, Jaime R McDermott, David F Orcid: 0000-0002-2675-5095 Michaelson, M Dror Orcid: 0000-0001-9249-6338 Appleman, Leonard J Thamake, Sanjay Perini, Rodolfo F Zojwalla, Naseem J Jonasch, Eric Orcid: 0000-0003-0943-2806 Journal Article United States Nat Med. 2021 Apr 22. doi: 10.1038/s41591-021-01324-7.