FULL APPROVAL

FDA approves Keytruda plus Welireg as first adjuvant regimen in kidney cancer

The combination cut recurrence or death risk by 28% versus Keytruda alone, the first HIF-2α and PD-1 combination to reach approval in earlier-stage clear cell renal cell carcinoma.

By AppliedXLJune 12, 2026Trial NCT05239728

Executive Summary

The FDA approved Merck's Keytruda and Keytruda Qlex, each paired with Welireg, as the first adjuvant regimen combining a HIF-2α inhibitor with an anti-PD-1 antibody in clear cell renal cell carcinoma, arriving ahead of its target action date rather than on it.
The Phase 3 trial supporting approval showed the combination cut the risk of disease recurrence or death versus Keytruda alone, meeting its primary endpoint with a result well below conventional significance thresholds, while the overall-survival endpoint remains unresolved.
Welireg now moves from advanced and rare hereditary kidney cancer into earlier-stage adjuvant treatment, a setting where no other HIF-2α program has yet reached this evidentiary bar, even as several rivals in the same target class advance through their own Phase 3 trials.
The trial continues to follow patients for overall survival, the secondary endpoint that will determine whether the disease-free survival advantage converts into a durable clinical benefit.

The decision

Merck Sharp & Dohme LLC announced on June 12, 2026 that the FDA approved Keytruda (pembrolizumab) and Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph), each combined with Welireg (belzutifan), for adjuvant treatment of adult patients with clear cell renal cell carcinoma at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. The decision landed seven days before the FDA's June 19, 2026 target action date on a supplemental application that had been granted Priority Review. Merck called the approvals the first for Welireg in earlier-stage disease and the first for a PD-1 and HIF-2α inhibitor combination regimen. FDA+1

Probability of Success

Endpoint Met96%

Completes64%

Clinical Significance95%

Regulatory85%

The trial and the result

The approval rests on LITESPARK-022 (NCT05239728), a randomized, triple-masked, placebo-controlled Phase 3 trial that enrolled 1,841 patients and compared Keytruda plus Welireg against Keytruda plus placebo, with disease-free survival as the primary endpoint. At a pre-specified interim analysis with a median follow-up of 28.4 months, the combination reduced the risk of disease recurrence, metastasis or death by 28% (hazard ratio 0.72, 95% CI 0.59-0.87, p=0.0003). The estimated 24-month disease-free survival rate was 81% for the combination versus 74% for Keytruda alone, and median disease-free survival was not reached in either arm. Overall survival, a key secondary endpoint, remained immature at this interim analysis. Dr. Toni K. Choueiri of Dana-Farber Cancer Institute, an investigator quoted in Merck's release, said the combination is "the first ever regimen in the adjuvant setting for renal cell cancer to demonstrate an improvement in disease-free survival over pembrolizumab monotherapy". NCT05239728+2

Safety and tolerability

The safety profile of the combination was consistent with prior studies of both agents, and no new safety signals emerged. Grade 3 or higher treatment-emergent adverse events occurred in 52.1% of patients on the combination versus 30.2% on Keytruda alone, driven mainly by anemia (12.1% versus 0.5%), elevated liver enzymes (6.4% versus 2.0%) and hypoxia (4.6% versus 0%). Treatment completion rates were similar between arms, at 69.5% for the combination and 71.1% for Keytruda alone. Welireg's label carries a boxed warning for embryo-fetal harm, along with monitoring requirements for anemia and hypoxia. KEYTRUDA+1

Where Welireg sits in the field

Welireg's HIF-2α mechanism has drawn a small direct field: Arcus Biosciences' casdatifan and AstraZeneca's volrustomig are both in Phase 3 testing for renal cell carcinoma, and Merck itself runs an earlier Phase 3 trial of Welireg evaluating overall survival in a different renal cell carcinoma population. Two of eight trials pairing the HIF-2α target with clear cell renal cell carcinoma have completed, and neither was terminated, a track record with too few resolved trials to state as a rate. This approval is the first to combine that target class with an anti-PD-1 antibody, extending Welireg from its prior advanced-disease and Von Hippel-Lindau-associated indications into an adjuvant, potentially curative-intent setting for the first time. FDA

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