FDA Approves Merck's Welireg With Keytruda After Surgery for High-Risk Kidney Cancer

The US Food and Drug Administration on June 12 approved Merck's belzutifan (Welireg) in combination with pembrolizumab (Keytruda) or its subcutaneous form (Keytruda Qlex) for the adjuvant treatment of adults with renal cell carcinoma with a clear cell component (ccRCC) at intermediate-high or high risk of recurrence after nephrectomy, or after nephrectomy and resection of metastatic lesions, according to the FDA's notice. The application had priority review.

Merck said in its announcement that the decision is the first approval for Welireg, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, in earlier-stage ccRCC, and the first approval of a combination of a PD-1 and a HIF-2α inhibitor. Welireg was previously approved for advanced ccRCC after earlier therapies, for tumors associated with von Hippel-Lindau disease, and for pheochromocytoma or paraganglioma.

The LITESPARK-022 trial

The approval rests on LITESPARK-022 (NCT05239728), a multicenter, randomized, double-blind Phase 3 trial that enrolled 1,841 patients who had undergone nephrectomy. Patients received belzutifan or placebo, each with pembrolizumab, for up to 54 weeks of belzutifan or 12 months of pembrolizumab.

At a prespecified interim analysis, investigator-assessed disease-free survival, the main efficacy measure, improved significantly, with 186 events in the belzutifan arm and 246 in the placebo arm (hazard ratio 0.72; 95% CI, 0.59 to 0.87; p=0.0003), the FDA said. Median disease-free survival was not reached in either arm, and overall survival data were not mature. Merck reported an estimated 24-month disease-free survival rate of 81% with the combination versus 74% with pembrolizumab plus placebo.

"The results of the LITESPARK-022 trial demonstrated the ability of pembrolizumab in combination with belzutifan to reduce the risk of disease recurrence, metastasis, or death by 28%, which represents an important new option for these patients to help keep their clear cell renal cell carcinoma from coming back," said Toni K. Choueiri of Dana-Farber Cancer Institute, in Merck's release.

Safety and dosing

Belzutifan's prescribing information carries a boxed warning for embryo-fetal toxicity and warnings for anemia and hypoxia. In the trial, serious adverse reactions occurred in 30% of patients on the combination and fatal adverse reactions in 1.1%, according to Merck. Belzutifan was permanently discontinued because of adverse reactions in 27% of patients, and decreased hemoglobin was reported in 95%.

The recommended belzutifan dose is 120 mg orally once daily alongside pembrolizumab, given intravenously every three or six weeks or subcutaneously as Keytruda Qlex every three or six weeks, according to the FDA. Treatment continues until recurrence or unacceptable toxicity, for up to 54 weeks of belzutifan or 12 months of pembrolizumab.

The FDA said the review was conducted under Project Orbis with Australia's Therapeutic Goods Administration and Health Canada, whose reviews are ongoing.