FDA Approves Belzutifan for Von-Hippel Lindau-Associated RCC

The FDA has approved belzutifan for the treatment of Von-Hippel Lindau-associated renal cell carcinoma treated in frontline setting.

The FDA has approved belzutifan (MK-6482) for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery, according to a press release by the FDA.

Belzutifan is a novel and potent selective HIF-2a inhibitor. When the tumor-suppressor protein VHL is inactive, hypoxia-inducible factor proteins such as HIF-2a can accumulate in patients. When not properly regulated this protein stimulates several different cellular proliferation, angiogenesis, and tumor growth-associated oncogenes. This can lead to the growth of both malignant and benign tumors. The inactivation of VHL has been observed in majority, 90%, or RCC tumors.1

The approval of this agent is based on a phase 2 study, which showed that the agent has long-term clinical activity in patients with VHL-associated RCC treated in the frontline setting.

Updated results for the study were presented during the 2021 American Society of Clinical Oncology Annual Meeting. Sixty-one patients with VHL disease who had at least 1 measurable RCC tumor, had not received any prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of 0 or 1 were evaluated. The primary end point of the study is objective response rate (ORR). Secondary outcomes include duration of response (DOR), time to response, progression-free survival (PFS), time to surgery, the number of participants experiencing adverse events (AEs), the number of patients experiencing a serious AE, belzutifan plasma concentration, and belzutifan metabolite plasma concentration.2

At baseline, the majority of patients in the study (82%), had an ECOG score of 0 and the median number of prior tumor reduction procedures per patient was 5. Additionally, 33% of patients had lesions outside the kidneys.

At a median follow-up was 69 weeks the ORR was 49% ( 95% CI:36, 62). There were an additional 7 unconfirmed responses, all of which were partial. The DOR was not reached, but 56% of responders had DOR ≥ 12 months and a median TTR of 8 months.The median time to relapse was 31 weeks.1 Ninety-two percent of patients had some reduction in the sum of all tumor lesion diameter. The PFS rate at week 52 was 98%.2

In the subgroup of patients with other VHL-associated non-RCC tumors, 24 patients with measurable central nervous system (CNS) hemangioblastomas achieved an ORR of 63% and 12 patients who had measurable pNET reached an ORR of 83%. The median DOR was not reached in these patients, with 73% and 50% of patients having response durations ≥ 12 months for CNS hemangioblastomas and pNET, respectively.

In terms of safety, AEs were reported in 20% of the patient who received belzutifan. The most common AEs were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Anemia and hypoxia from belzutifan use can be severe. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Patients should be transfused as clinically indicated. The use of erythropoiesis stimulating agents for treatment of anemia is not recommended in patients treated with belzutifan. In Study 004, hypoxia occurred in 1.6% of patients. Belzutifan can render some hormonal contraceptives ineffective, and belzutifan exposure during pregnancy can cause embryo-fetal harm.


1. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. August 13, 2021. Accessed August 13, 2021. https://bit.ly/2Xh7eqC
2. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39(suppl 15):4555. doi:10.1200/JCO.2021.39.15_suppl.4555
3. Merck Receives Priority review from FDA for new drug application for HIF-2α Inhibitor belzutifan (MK-6482). News release. Merck. March 16, 2021. Accessed June 7, 2021. https://bit.ly/38NLYM2