Merck’s Welireg and Keytruda combo gets FDA clearance as adjuvant for clear cell kidney cancer

Edited by Robert McTiernan··3 min read

The US FDA has approved Welireg (belzutifan) in combination with Keytruda (pembrolizumab) — and its subcutaneous equivalent 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. The decision marks the first approved PD-1 and HIF-2α inhibitor combination regimen and the first approval for belzutifan in earlier-stage ccRCC, extending Merck’s (NYSE: MRK) reach in kidney cancer beyond the advanced setting.

The approvals apply to patients who have undergone nephrectomy, or nephrectomy plus resection of metastatic lesions, and who had no prior systemic therapy for advanced RCC. Belzutifan is administered orally at 120 mg once daily alongside pembrolizumab 400 mg intravenously every six weeks, for up to nine cycles (54 weeks). Keytruda QLEX, a fixed combination of pembrolizumab and berahyaluronidase alfa — an enzyme that enables subcutaneous delivery — is administered as an injection into the thigh or abdomen over one to two minutes, offering an alternative to intravenous infusion. Its effectiveness in this indication was established by bridging pharmacokinetic and safety data from study MK-3475A-D77 alongside the pivotal LITESPARK-022 results.

Belzutifan blocks the interaction between HIF-2α and its dimerization partner HIF-1β, reducing transcription of target genes that drive angiogenesis, cellular proliferation, and tumor adaptation to hypoxic conditions — pathways particularly relevant in VHL-deficient ccRCC. Combining this mechanism with pembrolizumab’s PD-1 blockade, which restores T-cell–mediated anti-tumor immunity, provides a rationale for dual pathway inhibition in the adjuvant setting.

The Phase III LITESPARK-022 trial (NCT05239728) enrolled 1,841 patients randomized 1:1 to belzutifan plus pembrolizumab or placebo plus pembrolizumab. The primary endpoint was investigator-assessed disease-free survival (DFS). The combination demonstrated a statistically significant 28% reduction in the risk of disease recurrence, metastasis, or death compared with pembrolizumab monotherapy (HR=0.72 [95% CI 0.59–0.87]; p=0.0003). Estimated 24-month DFS rates were 81% versus 74%, respectively; median DFS was not reached in either arm. Overall survival data were not yet mature at the interim analysis.

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The safety profile of the combination reflected the known toxicities of both agents. Decreased hemoglobin occurred in 95% of patients receiving belzutifan plus pembrolizumab, with Grade 3 or higher events in 11%; anemia led to dose interruption in 25% and permanent discontinuation of belzutifan in 4%. Hypoxia occurred in 7% of patients, with Grade 3 or higher events in 5%. Serious adverse reactions were reported in 30% of patients, and fatal adverse reactions in 1.1%. Welireg carries a boxed warning for embryo-fetal toxicity; prescribers must verify pregnancy status prior to initiation and advise use of effective non-hormonal contraception, as belzutifan can render hormonal contraceptives ineffective.

The approval positions Merck’s combination as the only regimen demonstrated to improve DFS over pembrolizumab monotherapy in the adjuvant ccRCC setting — the active control arm in LITESPARK-022, itself approved for this indication since 2021 (KEYNOTE-564). The dual checkpoint approach of nivolumab plus ipilimumab, evaluated by Bristol Myers Squibb in CheckMate 914, failed to demonstrate a DFS benefit versus placebo in adjuvant ccRCC, leaving pembrolizumab monotherapy as the established standard against which the new combination was tested.

The HIF-2α inhibitor class is attracting competitive interest. Arcus Biosciences and Bristol Myers Squibb are evaluating casdatifan, a rival HIF-2α inhibitor, in combination with a PD-1 inhibitor in RCC — applying the same mechanistic logic as the belzutifan-pembrolizumab combination, though in earlier clinical development. The approval of belzutifan in the adjuvant setting also extends its label beyond advanced ccRCC and VHL disease-associated tumors, consolidating its position across the disease continuum.

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