FDA Approves Welireg plus Keytruda as Adjuvant Therapy for High-Risk Clear Cell Renal Cell Carcinoma
On June 12, 2026, the FDA approved Merck's Welireg (belzutifan)—a first-in-class oral HIF-2α inhibitor—in combination with Keytruda (pembrolizumab) or its subcutaneous formulation Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) for the adjuvant treatment of adults with clear cell renal cell carcinoma (ccRCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
This approval marks a major expansion for Welireg, moving it from its previous 2023 approval in advanced/metastatic disease into earlier-stage, post-surgery adjuvant therapy where the goal is to prevent cancer from returning.1
Clinical Trial Data: LITESPARK-022
The approval was based on positive results from the Phase 3 LITESPARK-022 (NCT05239728) trial, a randomized, double-blind, multicenter study evaluating 1,841 patients. Key highlights include:
- Efficacy: A prespecified interim analysis demonstrated a statistically significant improvement in investigator-assessed disease-free survival (DFS) for the Welireg + Keytruda arm compared to the placebo + Keytruda arm.
- Hazard Ratio (HR): 0.72 (95% CI: 0.59, 0.87; p-value = 0.0003), representing a 28% reduction in the risk of disease recurrence, metastasis, or death.
- Events: There were 186 DFS events in the belzutifan + pembrolizumab arm compared to 246 events in the placebo + pembrolizumab arm.
- Median DFS: Not reached in either treatment arm.
- Overall Survival (OS): OS data was immature at the time of the interim analysis.
Administration and Companion Approvals
The recommended dosage is Welireg 120 mg orally once daily in combination with pembrolizumab (200 mg intravenously every three weeks or 400 mg every six weeks) or pembrolizumab/berahyaluronidase-pmph (395 mg/4,800 units subcutaneously every three weeks or 790 mg/9,600 units every six weeks) for up to 54 weeks of belzutifan or 12 months of pembrolizumab, or until disease recurrence or unacceptable toxicity.
The review was conducted under Project Orbis, a collaborative framework of the FDA Oncology Center of Excellence with international partners including Health Canada and the Australian Therapeutic Goods Administration (TGA).
-
An instance of Oncology blockbusters must target adjuvant settings to secure massive patient volumes. — To secure larger patient volumes and extend treatment windows, the drug is expanding from late-stage metastatic use into the post-surgical adjuvant setting. ↩︎