RAHWAY, N.J., June 12, 2026
The U.S. Food and Drug Administration (FDA) has approved KEYTRUDA® (pembrolizumab) and KEYTRUDA QLEX™ (pembrolizumab and berahyaluronidase alfa-pmph), each in combination with WELIREG® (belzutifan), for the adjuvant treatment of adult patients with clear cell renal cell carcinoma (ccRCC) at intermediate-high or high risk of recurrence following nephrectomy. The approval marks the first-ever FDA-approved combination of a PD-1 inhibitor and a HIF-2α inhibitor and introduces a new standard of care option for patients at risk of disease recurrence after surgery.
Phase 3 Trial Demonstrates Significant Reduction in Recurrence Risk
The FDA decision was supported by data from the pivotal Phase 3 LITESPARK-022 trial, which enrolled 1,841 patients with clear cell renal cell carcinoma. Results showed that KEYTRUDA combined with WELIREG reduced the risk of disease recurrence, metastasis, or death by 28% compared with KEYTRUDA plus placebo. The study achieved its primary endpoint of disease-free survival (DFS), with an estimated 24-month DFS rate of 81% in the combination arm versus 74% in the control group.
Notably, this represents the first global Phase 3 study to demonstrate improved disease-free survival beyond KEYTRUDA monotherapy in the adjuvant ccRCC setting. Researchers highlighted that many patients with earlier-stage kidney cancer remain vulnerable to relapse following surgery, making the new combination an important advancement in reducing recurrence risk and extending disease-free periods.
First PD-1 and HIF-2α Combination Opens New Treatment Era
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The approval establishes a new therapeutic approach by combining immune checkpoint inhibition with hypoxia-inducible factor (HIF-2α) blockade, targeting two distinct pathways involved in cancer progression. KEYTRUDA enhances the immune system’s ability to identify and attack tumor cells, while WELIREG inhibits HIF-2α signaling, a pathway associated with tumor growth, angiogenesis, and adaptation to low-oxygen environments.
The approval also marks the first indication for WELIREG in earlier-stage renal cell carcinoma, expanding its role beyond advanced disease and rare hereditary cancer syndromes. Experts involved in the study noted that the combination offers a promising strategy for preventing recurrence and improving long-term outcomes in patients with surgically treated kidney cancer.
Safety Profile and Clinical Significance
Safety findings from the LITESPARK-022 trial were generally consistent with the known profiles of the individual therapies. The most common serious adverse events observed in patients receiving the combination included pneumonia, hypoxia, pneumonitis, arrhythmia, diarrhea, and acute kidney injury. WELIREG carries a boxed warning regarding embryo-fetal toxicity, and healthcare providers are advised to monitor patients for anemia and hypoxia, two clinically significant risks associated with treatment. Despite these considerations, investigators emphasized that the substantial improvement in disease-free survival provides a meaningful benefit for patients facing a high risk of kidney cancer recurrence.
With kidney cancer accounting for approximately 435,000 new cases globally each year, and clear cell renal cell carcinoma representing about 70% of all RCC diagnoses, the approval offers a significant advancement in the evolving landscape of adjuvant cancer therapy and reinforces Merck’s leadership in immuno-oncology innovation.
Source: Merck press release
