FDA approves belzutifan for advanced renal cell carcinoma

The FDA has approved belzutifan (Welireg) for the treatment of patients with advanced renal cell carcinoma (RCC) who have progressed following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TKI, announced Merck, the developer of the drug, in a news release.¹

This approval of belzutifan introduces a meaningful new treatment option for certain patients, as belzutifan reduced the risk of disease progression or death compared [with] everolimus,” said Toni K. Choueiri, MD.

The approval is supported by findings from the phase 3 LITESPARK-005 trial (NCT04195750), in which belzutifan demonstrated superior progression-free survival (PFS) vs everolimus in patients with advanced RCC whose tumors had progressed following treatment. Specifically, the risk of disease progression or death was reduced by 25% with belzutifan (HR, 0.75; 95% CI, 0.63-0.90; P = .0008). The objective response rate (ORR) among patients who received belzutifan was 22% (95% CI, 18-27), compared with 4% (95% CI, 2-6) among patients who received everolimus.

“Despite recent progress in the treatment of advanced RCC, there is yet to be an option specifically approved for patients whose disease progresses following a PD-1 or PD-L1 inhibitor and a TKI therapy,” Toni K. Choueiri, MD, LITESPARK-005 study chair, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and a Jerome and Nancy Kohlberg professor of medicine at Harvard Medical School, stated in the news release.¹ “This approval of belzutifan introduces a meaningful new treatment option for certain patients, as belzutifan reduced the risk of disease progression or death compared [with] everolimus.”

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). The median duration of exposure among patients who received belzutifan was 7.6 months (range, 0.1–28.5).

The primary end point was PFS, as determined by blinded independent central review based on RECISTv1.1, and overall survival. Key secondary end points included ORR, duration of response, and safety/tolerability.²

Median PFS among patients in the belzutifan cohort was 5.6 months (95% CI, 3.9-7.0) versus 5.6 months (95% CI, 4.8-5.8) for everolimus. In total, 82 patients (22%) in the belzutifan arm demonstrated a response, with a complete response (CR) rate of 3% (n = 10) and a partial response (PR) rate of 19% (n = 72). Among the 82 patients with a response in the belzutifan arm, 25 patients (30%) achieved a duration of response of at least 12 months. ORR among patients in the everolimus arm was 4%, with no patients achieving a CR and a PR rate of 4% (n = 13). Overall survival results were immature.

Regarding safety, 38% of patients who received belzutifan experienced a serious adverse event (AE), including hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%) and pleural effusion (2.2%). Fatal AEs occurred in 3.2% of patients, and 6% of patients discontinued treatment due to AEs. Dose interruptions due to AEs occurred in 39% of patients, and dose reductions due to AEs occurred in 13% of patients.

There is a boxed warning on the belzutifan label stating that exposure to belzutifan during pregnancy can cause embryo-fetal harm.

Marjorie Green, MD, senior vice president and head of late-stage oncology of global clinical development at Merck Research Laboratories, concluded in the news release, “In 2021, Welireg became the first HIF-2α inhibitor therapy approved in the U.S. for the treatment of adult patients with certain [von Hippel-Lindau] disease-associated tumors and is now approved for eligible patients with advanced RCC. This approval of Welireg marks the first new therapeutic class available for eligible patients with advanced RCC in nearly a decade and was based on the statistically significant progression-free survival benefit observed in patients following treatment with a PD-1 or PD-L1 inhibitor and a VEGF-TKI when compared to everolimus.”¹

References

1. FDA approves Merck’s WELIREG (belzutifan) for the treatment of patients with advanced renal cell carcinoma (RCC) following a PD-1 or PD-L1 inhibitor and a VEGF-TKI. News release. Merck. December 14, 2023. Accessed December 15, 2023. https://www.businesswire.com/news/home/20231214762284/en/FDA-Approves-Merck%E2%80%99s-WELIREG%C2%AE-belzutifan-for-the-Treatment-of-Patients-With-Advanced-Renal-Cell-Carcinoma-RCC-Following-a-PD-1-or-PD-L1-Inhibitor-and-a-VEGF-TKI

2. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Last updated August 1, 2022. Accessed December 15, 2023. https://clinicaltrials.gov/study/NCT04195750