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

Abstract

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.

Extended Data Fig. 1 |. Patient disposition.

AE: adverse event; BID: twice daily; ccRCC: clear cell renal cell carcinoma; DLT: dose-limiting toxicity; QD: once daily; PD: progressive disease.

Extended Data Fig. 2 |. Mean (SD) plasma concentrations of belzutifan at (a) week 1, (b) week 3, and (c) all weeks.

BID: twice daily; QD: once daily; SD: standard deviation. n includes patients who had a predose assessment and at least one postdose assessment. Data are presented as mean values ± SD.

Extended Data Fig. 3 |. Mean (SD) plasma concentrations of PT3317 at (a) week 1, (b) week 3, and (c) all weeks.

BID: twice daily; QD: once daily; SD: standard deviation. n includes patients who had a predose assessment and at least one postdose assessment. Data are presented as mean values ± SD.

Extended Data Fig. 4 |. Mean (SD) percentage change in erythropoietin (mIu/ml) from baseline for the first 8 days.

BID: twice daily; QD: once daily; SD: standard deviation. n includes patients who had a predose assessment and at least one postdose assessment. *Erythropoietin concentration from baseline for the 160-mg QD dose cohort is based on the values after excluding one patient who had a very low erythropoietin baseline measurement of 2.8 mIU/ml, which is lower than the typical lower value of normal physiological reference range (3.5 mIU/ml) and very close to the lower limit of quantitation of 2.5 mIU/ml. This possibly erroneous low baseline value resulted in apparent large increases in percentage change from baseline in all the postbaseline values for this patient.

Fig. 1 |. Efficacy results of the ccRCC cohort.

a, Maximum change from baseline in target lesions. b, Duration of treatment. c, Kaplan–Meier estimate of progression-free survival. Data in a–c are in the ccRCC cohort; data in a includes patients who had a baseline and an evaluable post-baseline assessment (n = 52).