Frontline Belzutifan Associated with Meaningful Clinical Activity in Treatment of VHL-Associated RCC


A phase 2 study reported clinical efficacy from the use of frontline belzutifan in patients with Von-Hippel Lindau (VHL).

Updated findings from a phase 2 study (NCT03401788) presented during the 2021 ASCO Annual Meeting revealed that patients with Von-Hippel Lindau (VHL)-associated renal cell carcinoma (RCC), as well as other VHL-associated neoplasm, showed significant clinical responses to the hypoxia-inducible factor-2 alpha inhibitor belzutifan.1

“This update continues to demonstrate the activity of belzutifan in patients with VHL-associated renal and non-renal tumors accompanied by an acceptable safety profile,” said lead study author Ramaprasad Srinivasan, MD, PhD, head of the Molecular Cancer Therapeutics Section, Center for Cancer Research, National Cancer Institute.

Recently, the FDA granted belzutifan a priority review for the treatment of patients with VHL disease–associated RCC who do not require immediate surgery based on earlier results of this study.2

The open-label, single-arm study enrolled 61 patients who were diagnosed with VHL disease based on germline alteration 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. Patients were treated with 120 mg oral daily belzutifan as a potential systemic treatment for VHL-associated RCC and other VHL neoplasms.

Objective response rate (ORR) in RCC tumors per RECIST criteria by independent review committee was the primary end point and secondary end points included ORR in non-RCC neoplasms, duration of response (DOR), and safety.

The median age was 41 years (range, 19-66) at baseline and the majority of patients were male (52.5%) and had an ECOG performance status of 0 (82.0%). Pancreatic lesions were also reported in all patients, 36.1% of which were neuroendocrine; central nervous system (CNS) hemangioblastomas were reported in 82.0% of patients and retinal lesions in 26.2%.

As of data cutoff, a median of 21.8 months (range, 20.2-30.1) after enrollment, 88.5% of patients were still receiving treatment.

Responses in target RCC lesions were observed in 30 patients (49.2%; 95% CI, 36.1%-62.3%) of patients by independent review committee; all responses were partial responses (PRs), and another 4 patients had unconfirmed PRs. Stable disease was reported in 49.2% of patients and 1 patient was not evaluable. Ninety-two percent of patients had a decrease in target RCC lesion size.

The median time to response was 8.2 months (range, 2.7-19.1) and the duration of response was not reached (range, 2.8+ to 22.3+). Progression-free survival rate at 12 months was 98.3% and 96.5% at 24 months, and the median has not yet been reached.

In pancreatic lesions, responses were reported in 77.0% (95% CI, 64.5%-86.8%), with complete responses (CRs) in 9.8% and PRs in 67.2%. Among pancreatic neuroendocrine tumors, the ORR was

90.9% (95% CI, 70.8%-98.9%) with CRs in 13.6% and PRs in 77.3%. The ORR was 30.0% (95% CI, 17.9%-44.6%) in CNS hemangioblastomas with CRs in 6.0% and PRs in 24.0%.

Srinivasan noted that retinal hemangioblastomas were not amenable to classic response evaluation with RECIST criteria. Sixty-nine percent of retinal hemangioblastomas were improved and 31% were stable as best response.

All patients reported a treatment-related adverse event (TRAE) of any grade, grade 3 events were observed in 32.8% and grade 4 or 5 events in 14.8%. TRAEs led to discontinuation in 1.6% of patients and an adverse event led to death in 1 patient, but the event was not treatment related.

The most common AEs of any grade were anemia (90.2%), fatigue (65.6%), headache (41.0%), dizziness (39.3%), and nausea (34.4%). Most of the events were grade 1 or 2, but common grade 3 events were anemia (8.2%) and hypertension (8.2%). Srinivasan said that anemia was a predicted on-target effect of HIF-2–dependent downregulation of erythropoietin.


  1. 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
  2. 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.

This article was originally published on OncLive as “Frontline Belzutifan Showcases Significant Clinical Activity in VHL-Associated RCC”

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