Belzutifan nears EU approval for advanced renal cell carcinoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use has issued a positive opinion recommending approval of belzutifan (Welireg) for adult patients with advanced clear cell renal cell carcinoma (RCC) that progressed following treatment with a PD-1 or PD-L1 inhibitor and at least 2 VEGF targeted therapies, Merck announced in a news release.¹

Belzutifan was approved by the FDA in December 2023 for advanced RCC.

The recommendation for approval of belzutifan also includes an indication for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated, localized RCC, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors.

A final decision on marketing authorization is anticipated for Q1 of 2025.

“Today’s positive CHMP opinion brings us closer to offering WELIREG, a first-in-class HIF-2α inhibitor, to certain patients in the European Union, in order to help address critical gaps in care for these patients,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in the news release.¹ “We are committed to providing innovative treatment options that address serious unmet needs for patients globally and look forward to the European Commission’s decision.”

Belzutifan was approved in the US for patients with VHL disease-associated tumors in August 2021 based on data from the phase 2 LITESPARK-004 trial (NCT03401788). In this study, belzutifan led to an objective response rate (ORR) of 49% in patients with VHL-associated RCC. All response were partial responses. The median duration of response has not yet been reached; 56% of respondents have maintained a response for 12 months or longer.

Belzutifan was also approved by the FDA in December 2023 for advanced RCC based on findings from the phase 3 LITESPARK-005 trial (NCT04195750). Data from the trial were recently published in The New England Journal of Medicine.²

Overall, belzutifan demonstrated superior progression-free survival (PFS) vs everolimus (Afinitor) in patients with advanced RCC whose tumors had progressed following treatment. Specifically, 24% of patients in the belzutifan arm vs 8.3% of patients in the everolimus arm were alive and free from progression at 18-month follow-up (P = .002). This translated to a 25% reduction in the risk of disease progression or death with belzutifan (HR, 0.75; 95% CI, 0.63-0.90; P = .0008). The median PFS was 5.6 months in both groups.

Additionally, the ORR was 21.9% (95% CI, 18-27) among patients who received belzutifan compared with 3.5% (95% CI, 2-6) among patients who received everolimus. In the belzutifan arm, the ORR consisted of a complete response rate of 3% (n = 10) and a partial response rate of 19% (n = 72). No patients achieved a complete response in the everolimus arm, and the partial response rate was 4% (n = 13).

At a median follow-up of 25.7 months, the median overall survival was 21.4 months in the belzutifan cohort and 18.1 months in the everolimus cohort. At 18 months, 55.2% of patients in the belzutifan group vs 50.6% of patients in the everolimus arm were alive (HR, 0.88; 95% CI, 0.73 to 1.07; P = .20).

Regarding safety, 61.8% of patients in the belzutifan arm and 62.5% of patients in the everolimus arm experienced a grade 3 or higher adverse event. Additionally, 5.9% of patients in the belzutifan cohort and 14.7% of patients in the everolimus cohort discontinued treatment due to AEs.

In total, the randomized, open-label, active-controlled phase 3 LITESPARK-005 trial enrolled 746 patients with unresectable, locally advanced, or metastatic RCC. Participants were randomly assigned 1:1 to receive 120 mg of belzutifan orally once daily (n = 374) or 10 mg of everolimus orally once daily (n = 372) until disease progression or unacceptable toxicity.

The primary end point was PFS, as determined by blinded independent central review per RECISTv1.1, and overall survival. Key secondary end points included ORR, duration of response, and safety/tolerability.³

References

1. Merck receives positive EU CHMP opinion for WELIREG (belzutifan) as treatment for adult patients with certain types of Von Hippel-Lindau Disease-associated tumors and for certain previously treated adult patients with advanced renal cell carcinoma. News release. Merck. Published online and accessed December 13, 2024. https://www.merck.com/news/merck-receives-positive-eu-chmp-opinion-for-welireg-belzutifan-as-treatment-for-adult-patients-with-certain-types-of-von-hippel-lindau-disease-associated-tumors-and-for-certain-previously-trea/

2. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906

3. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Last updated November 18, 2024. Accessed December 13, 2024. https://clinicaltrials.gov/study/NCT04195750