Belzutifan for RCC and non-RCC Neoplasms Associated With von Hippel-Lindau Disease Shows Encouraging Clinical Activity

The phase 2 MK-6482-004 trial found that belzutifan produced positive response data for patients with renal cell carcinoma and non–renal cell carcinoma neoplasms associated with von Hippel-Lindau disease.

Belzutifan (MK-6482) showed encouraging clinical activity for patients with both renal cell carcinomas (RCCs) and non-RCC neoplasms associated with von Hippel-Lindau (VHL) disease, according to results from the phase 2 MK-6482-004 trial (NCT03401788) published in the New England Journal of Medicine.1

The objective response rate (ORR) in the RCC cohort was 49% (95% CI, 36%-62%) as assessed by independent central radiology review committee. Of note, the best response for an additional 49% of patients was stable disease, and 3% of patients experienced disease progression.

“Patients with von Hippel-Lindau disease are at risk of developing several types of cancer and require repeated surgical procedures to manage their tumors,” principal investigator Eric Jonasch, MD, professor of genitourinary medical oncology, said in a press release.2 “These results profoundly change the way we manage patients with VHL disease and will provide an impactful benefit to a majority of patients with VHL.”

Eligible patients were aged 18 years or older with VHL disease diagnosed on the basis of germline VHL alteration and a minimum of 1 measurable RCC tumors. Patients were also required to have an ECOG performance status of 0 or 1 and no RCC tumors larger than 3 cm. Between May 31, 2018, and March 29, 2019, the study enrolled patients across 11 centers in the United States, Denmark, France, and the United Kingdom.

Belzutifan was administered orally at 120 mg once daily via three 40 mg doses. The primary end point was ORR to treatment among patients with VHL disease–associated RCC. Key secondary end points included duration of response, time to response, and progression-free survival (PFS).

A total of 61 patients were enrolled on the study, with a median age among these patients was 41 years (range, 19-66). Fifty-two percent of patients were men, and 82% had an ECOG performance status of 0. All but 2 patients (97%) underwent a previous tumor reduction procedure.

The median follow-up time at the point of data cutoff was 21.8 months (range, 20.2-30.1), and median exposure was 21.7 months (range, 1.9-30.1). As of the cutoff data, 89% of patients continued to receive belzutifan treatment.

Responses were seen in patients who had pancreatic lesions (77%) and central nervous system hemangioblastomas (30%). Furthermore, the sum of all target lesion diameters was reduced in 92% of patients. The percentage of patients with PFS was 96% (95% CI, 87%-99%) at 24 months.

The median duration of response was not reached (range, 2.8+ to 22.3+ month), and median time to response was 8.2 months (range, 2.7-19.1).

At least 1 treatment-related adverse effect (AE) was observed in all 61 patients. Common any-cause AEs included anemia (90%), fatigue (66%), headache (41%), and dizziness (39%) Treatment interruptions were reported in 43% of patients, and dose reductions were seen in 15% of patients. Seven patients discontinued treatment.

Any-cause grade 3 or higher AEs were reported in 33% of patients. Common grade 3 or higher AEs included anemia (8%), hypertension (8%), and fatigue (5%). No treatment-related deaths were reported in this study.

“These data suggest HIF-2a inhibition offers an effective treatment option with manageable side effects for patients with VHL-associated renal cell carcinoma and other VHL-related tumors. I am excited to be able to provide this impactful therapy to patients who have waited a long time for new options,” Jonasch concluded.


  1. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036-2046. doi:10.1056/NEJMoa2103425
  2. Belzutifan induced strong responses in patients with von Hippel-Lindau disease-associated kidney cancer. News release. MD Anderson Cancer Center. November 24, 2021. Accessed November 30, 2021.