Exposure–Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia‐inducible factor‐2α inhibitor, recently approved in the United States for the treatment of von Hippel–Lindau (VHL) disease‐associated renal cell carcinoma (RCC) and other VHL disease‐associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation/expansion study in solid tumors and RCC and a Phase 2 study in VHL‐RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure–response (E‐R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression‐free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade ≥3 anemia, Grade ≥3 hypoxia, and time to first dose reduction/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time‐to‐event analyses. Efficacy E‐R was generally flat with non‐significant positive trends with exposure. The safety E‐R analyses demonstrated a lack of relationship for Grade ≥3 hypoxia and a positive relationship for Grade ≥3 anemia, with incidences also significantly dependent on baseline Hgb. Exposure‐dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit–risk assessment in VHL disease‐associated neoplasms using E‐R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit–risk profile of belzutifan 120 mg once daily dosing in patients with VHL‐RCC for labeling and the overall development program.