Pembrolizumab plus lenvatinib with belzutifan or quavonlimab as first-line therapy for advanced renal-cell carcinoma: randomized open-label phase 3 LITESPARK-012 study.

Background

Pembrolizumab plus lenvatinib is a first-line standard of care for advanced clear-cell renal-cell carcinoma (ccRCC). The phase 3 LITESPARK-012 study (NCT04736706) evaluated efficacy and safety of adding belzutifan (HIF-2α inhibitor) or quavonlimab (anti-CTLA-4) to this regimen.

Participants

AND

Methods

Adults with previously untreated advanced ccRCC were randomized 1:1:1 to 400 mg pembrolizumab IV Q6W plus 20 mg lenvatinib orally daily and 120 mg belzutifan orally daily (Arm A); coformulated quavonlimab/pembrolizumab 25 mg/400 mg IV Q6W (collectively called MK-1308A) plus lenvatinib (Arm B); or standard-of-care pembrolizumab plus lenvatinib (Control). Treatment continued until progression, unacceptable toxicity, or withdrawal from study; pembrolizumab or quavonlimab/pembrolizumab were administered for a maximum of ∼2 years. Progression-free survival (PFS) by blinded independent central review and overall survival (OS) were dual primary endpoints, tested in all randomized participants for Arm A versus Control, and in participants with IMDC intermediate/poor risk or all participants for Arm B versus Control. Safety was a secondary endpoint.

Results

Overall, 560 participants were randomized to Arm A, 562 to Arm B, and 566 to Control. As of the data cutoff date (February 4, 2026), median follow-up was 43.6 months (range, 31.8-57.4). Among all participants, median PFS was 20.8 months in Arm A (HR vs Control: 1.08, 95%CI 0.93-1.26; P=0.8408), 20.7 months in Arm B (HR vs Control: 1.07, 95%CI 0.92-1.25; nominal P=0.8174), and 23.7 months in the Control arm; median OS was 52.0 months in Arm A (HR vs Control: 1.04, 95%CI 0.87-1.25; P=0.6622), not reached (NR) in Arm B (HR vs Control: 1.12, 95%CI 0.94-1.35; nominal P=0.8955), and NR in the Control arm. Among participants with intermediate/poor risk, median PFS was 20.5 months in Arm B and 23.5 months in the Control arm (HR 1.12, 95%CI 0.94-1.33; P=0.8954); median OS was 39.1 versus 46.2 months (HR 1.17, 95%CI 0.96-1.42; P=0.9419). Any-grade all-cause adverse events led to any-drug discontinuation in 51.6%, 51.4%, and 36.2% of participants in the A, B, and Control arms.

Conclusions

Neither addition of the HIF-2α inhibitor belzutifan nor the CTLA-4 inhibitor quavonlimab to pembrolizumab plus lenvatinib improved outcomes in participants with previously untreated advanced RCC versus pembrolizumab and lenvatinib alone. Higher drug discontinuation rates due to adverse events occurred in the investigational arms. Efficacy and safety of standard-of-care pembrolizumab plus lenvatinib was consistent with prior reports.