Disclosures: Srinivasan reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Schmidinger reports no relevant financial disclosures.
November 24, 2021
2 min read

Belzutifan active in von Hippel-Lindau disease-associated renal cell carcinoma

Disclosures: Srinivasan reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Schmidinger reports no relevant financial disclosures.
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Belzutifan demonstrated clinical efficacy among patients with von Hippel-Lindau disease-associated renal cell carcinoma, according to results of a phase 2 study published in The New England Journal of Medicine.

Belzutifan (Welireg, Merck), a novel small-molecule inhibitor of hypoxia-inducible factor-2 alpha, became the first FDA-approved treatment for von Hippel-Lindau disease in August, based on results of the ongoing, open-label Study 004.

Infographic showing response rate with belzutifan

“Based on the results of this study and the subsequent FDA approval of belzutifan, we now have, for the first time, a systemic treatment option for patients with von Hippel-Lindau disease with certain tumors,” Ramaprasad Srinivasan, MD, PhD, researcher and head of the molecular cancer section at NCI’s Center for Cancer Research, told Healio. “Until now, surgery was their only option, but we now have a highly effective option that can complement surgery or in some cases delay or obviate the need for surgery. This is a game changer for these patients and will have a profound impact on how we manage them.”

The single-group trial included 61 adults across 11 centers in the U.S., Denmark, France and U.K. with a germline mutation diagnosis of von Hippel-Lindau disease, no prior systemic cancer therapy, measurable nonmetastatic renal cell carcinoma tumors and an ECOG performance status of 0 or 1.

Ramaprasad Srinivasan, MD, PhD
Ramaprasad Srinivasan

Patients received oral, once-daily belzutifan, dosed at 120 mg, until disease progression, unacceptable toxicity or decision to withdraw. Researchers evaluated tumor size at screening and every 12 weeks thereafter.

At a median follow-up of 21.8 months, results showed an objective response rate of 49% (95% CI, 36-62) among patients with renal cell carcinoma, and 92% of patients achieved a decrease in target lesion size. PFS was 96% (95% CI, 87-99) at 24 months.

At the most recent follow-up, no patients had experienced disease progression and 54 patients remained on study treatment, with zero deaths. Common grade 1 or grade 2 adverse events included anemia (90%) and fatigue (66%).

Researchers observed a treatment response in 77% of patients with von Hippel-Lindau disease-associated pancreatic lesions and in 30% of patients with von Hippel-Lindau disease-associated central nervous system hemangioblastomas, as well as improvement among all 12 patients with evaluable retinoblastomas.

“What has been achieved so far is a bright and promising beginning,” Srinivasan told Healio. “Key areas of interest for further research include understanding how best to use this agent and what the long-term benefits and side effects are for these patients. Our goal should be to maintain efficacy for as long as possible with as few side effects as possible. While we have shown activity at multiple organ sites, we still need to understand more about the efficacy of this drug against some of the manifestations of von Hippel-Lindau disease, such as retinal hemangioblastomas.”

Considering both the efficacy of the treatment among all patients with von Hippel-Lindau disease-associated tumors and the acceptable adverse-event profile, early and possibly even intermittent use of belzutifan may spare patients with von Hippel-Lindau disease-associated disease multiple surgeries, decrease their risk for loss of organ function and reduce their risk for death from metastatic renal cell carcinoma or CNS hemangioblastomas, according to an accompanying editorial by Manuela Schmidinger, MD, researcher in the department of urology at Medical University of Vienna.

“Finally, blocking hypoxia-inducible factor-2 alpha at the most proximal point in the pathway may represent another major step in oncology beyond the treatment of von Hippel-Lindau-associated tumors, since hypoxia-inducible factor-2 alpha, the target of belzutifan, controls multiple genes involved in cancer progression,” Schmidinger wrote. “Moreover, the immune response to cancer is strongly regulated by hypoxia, which in turn drives hypoxia-inducible factor accumulation. Thus, belzutifan is under investigation for use in the treatment of sporadic clear-cell renal cell carcinoma and other solid tumors, either as a single agent or in combination with tyrosine kinase inhibitors and immune checkpoint inhibitors.”


For more information:

Ramaprasad Srinivasan, MD, PhD, can be reached at NCI, Building 10, Room 2W-5940,10 Center Drive, Bethesda, MD 20892; email: ramasrin@mail.nih.gov.