Merck wins FDA nod for Keytruda-Welireg combo in kidney cancer

Key Takeaways:

FDA approved Keytruda plus Welireg for adjuvant ccRCC after nephrectomy
Phase 3 LITESPARK-022 trial showed 28% reduction in recurrence risk
First approved PD-1 and HIF-2alpha inhibitor combination regimen

The U.S. Food and Drug Administration approved Merck's Keytruda (pembrolizumab) in combination with Welireg (belzutifan) for the adjuvant treatment of patients with clear cell renal cell carcinoma at intermediate-high or high risk of recurrence following nephrectomy, the company said Friday.

The approval marks the first authorized combination of a PD-1 inhibitor and a hypoxia-inducible factor-2 alpha inhibitor, and the first approval for Welireg in earlier-stage ccRCC, Merck said.

"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," Dr. Toni K. Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, said.

The Phase 3 LITESPARK-022 trial enrolled 1,841 patients who were randomized to receive either Welireg (120 mg orally once daily) plus Keytruda (400 mg intravenously every six weeks) or Keytruda plus placebo for up to nine cycles. The combination reduced the risk of disease recurrence, metastasis or death by 28% compared with Keytruda plus placebo (HR=0.72; 95% CI 0.59-0.87; p=0.0003). The estimated 24-month disease-free survival rate was 81% in the combination arm versus 74% in the control arm. Median DFS was not reached in either group. Overall survival data were not yet mature at the interim analysis.

Serious adverse reactions occurred in 30% of patients receiving the combination, with the most common being pneumonia (2%), hypoxia (1.9%) and pneumonitis (1.6%). Fatal adverse reactions occurred in 1.1% of patients. The Welireg prescribing information carries a boxed warning for embryo-fetal toxicity, as well as warnings for severe anemia and hypoxia.

The FDA also approved Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph), a subcutaneous formulation, in combination with Welireg for the same indication. The recommended dosing is 120 mg of oral Welireg once daily with Keytruda or Keytruda Qlex until disease recurrence, unacceptable toxicity or for 54 weeks.

The approval expands Merck's oncology portfolio in kidney cancer, where Keytruda already holds approvals in the first-line advanced setting in combination with axitinib and as a monotherapy adjuvant treatment for RCC. Welireg, a first-in-class HIF-2alpha inhibitor, generated $892 million in sales in 2025, according to Merck's annual filing. The combination now competes in the adjuvant ccRCC market against standard surveillance and Keytruda monotherapy, which was approved for adjuvant RCC in 2021 based on the KEYNOTE-564 trial.

Merck shares closed at $119.05 Friday, down 1.42%, in line with a broader market decline.

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