Table 3.

Overall benefit-risk assessment

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	• Patients with VHL disease have a genetic predisposition putting them at high risk for developing various tumors including RCC, CNS hemangioblastoma, pNET, and retinal hemangioblastoma.	Patients with VHL disease have a serious and potentially life-threatening condition with limited treatment options.
Current Treatment Options	• Surgery and other procedures may treat individual VHL disease associated tumors, often with substantial associated morbidity. • While small studies describe the use of kinase inhibitors to treat localized VHL disease associated RCC tumors, these data have not been FDA-reviewed and this represents off-label use. • Efficacy data for use of kinase inhibitors in other VHL disease associated tumors is even less well-characterized.	There are no approved therapies for VHL disease associated tumors despite an unmet medical need.
Benefit	• In a single-arm trial, the confirmed response rate by IRC for belzutifan in 61 patients with RCC evaluated at the proposed dose was 49% (95% CI: 36 to 62). The median duration of response was not reached (range 3+ to 22+ months). • Responses were also seen in other VHL-associated tumors, including an ORR of 83% (95% CI: 52 to 98) for 12 patients with evaluable pNET and an ORR of 63% (95% CI: 4 to 30) for 24 patients with evaluable CNS hemangioblastomas.	Belzutifan has demonstrated a substantial ORR and DOR for VHL disease associated RCC and other tumors that represents direct clinical benefit.
Risk and Risk Management	• The most commonly reported treatment emergent adverse events were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose and nausea. Anemia, Hypoxia, and Embryo-Fetal Toxicity are labeled as Warnings and Precautions. Embryo-Fetal Toxicity is also a boxed warning due to the young age of patients and long-term use in the otherwise relatively healthy approval population. • The Applicant will submit extended follow-up of patients on MK-6482-004 as post-marketing information to further characterize safety and describe efficacy. An additional study will further evaluate and describe efficacy of belzutifan in patients with VHL disease associated non-RCC tumors.	The risk-benefit profile of belzutifan is acceptable in the approved patient population. Additional post-marketing trial data may further inform belzutifan labeling.

Note: Table adapted from FDA’s Multi-Discipline Review; there are no restrictions on its use (14).