First-line triplet therapy may expand clinical benefit for advanced clear cell renal cell carcinoma (ccRCC). The phase Ib/II KEYMAKER-U03 Substudy 03A (NCT04626479) investigated novel pembrolizumab (pembro)-based regimens in this setting.
Participants with advanced ccRCC and no prior systemic therapy were randomized 2:1 to quavonlimab (qmab)/pembro plus lenvatinib (lenva), favezelimab (fave)/pembro plus lenva, pembro plus lenva plus belzutifan (bel), and vibostolimab (vibo)/pembro plus bel or a concurrent reference treatment (pembro plus lenva). A safety lead-in of ∼10 participants occurred for all investigative treatments before randomization. Primary endpoints were objective response rate (ORR) per RECIST v1.1 by blinded independent central review in all randomized participants (excluding safety lead-in), and safety in all treated participants. Secondary endpoints included progression-free survival (PFS) and overall survival (OS).
As of March 31, 2025, 393 participants were enrolled. Median follow-up for randomized participants across the 5 cohorts ranged between 16 and 39 months. ORR (95% CI) was 80.6% (68.6-89.6) with pembro plus lenva, 71.3% (60.0-80.8) with qmab/pembro plus lenva, 62.7% (48.1-75.9) with fave/pembro plus lenva, 77.5% (66.8-86.1) with pembro plus lenva plus bel, and 42.5% (31.5-54.1) with vibo/pembro plus bel. Median PFS (95% CI) in months was 26.3 (15.3-39.8) with pembro plus lenva, 18.0 (11.6-34.3) with qmab/pembro plus lenva, 26.0 (8.2-31.8) with fave/pembro plus lenva, 31.8 (26.3-NR) with pembro plus lenva plus bel, and 15.2 (12.4-NR) with vibo/pembro plus bel. Median OS was not reached in any arm. Grade ≥3 treatment-related adverse events occurred in 71.0% (44/62) of participants treated with pembro plus lenva, 73.3% (66/90) with qmab/pembro plus lenva, 86.9% (53/61) with fave/pembro plus lenva, 70.0% (63/90) with pembro plus lenva plus bel, and 68.9% (62/90) with vibo/pembro plus bel.
Observed efficacy and safety of pembro plus lenva were confirmatory of prior observations for this combination. ORR was similar to reference for pembro plus lenva plus bel and qmab/pembro plus lenva, but not the other investigative arms. Further investigation of pembro plus lenva plus bel and qmab/pembro plus lenva versus pembro plus lenva is ongoing in the phase 3 LITESPARK-012 study.
Annals of oncology : official journal of the European Society for Medical Oncology. 2025 Oct 18 [Epub ahead of print]
C Suarez, C Rojas, S J Shin, P Yanez Weber, L Albiges, R Motzer, H Hammers, A Peer, J-L Lee, W H Miller, T Waddell, V Neiman, D Keizman, A Zwenger Kloster, A Weickhardt, R Dziadziuszko, L Suttner, M Sharma, J E Burgents, T Powles
Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Electronic address: ., Bradford Hill Investigación Clínica and Universidad Finis Terrae, Santiago, Chile., Severance Hospital, Yonsei University Health System, Seoul, South Korea., Universidad de La Frontera, James Lind Cancer Research Center, Temuco, Chile., Gustave Roussy, Université Paris-Saclay, Villejuif, France., Memorial Sloan Kettering Cancer Center, New York, NY, USA., University of Texas Southwestern Medical Center, Dallas, TX, USA., Rambam Health Care Campus, Haifa, Israel., Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Jewish General Hospital, McGill University, Montréal, Québec, Canada., The Christie NHS Foundation Trust, Manchester, United Kingdom., Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel., Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel., Oncovida Cancer Center, Providencia, Santiago, Chile., Olivia Newton-John Cancer and Wellness Centre, Austin Hospital, Melbourne, Australia., Medical University of Gdansk Clinical Centre, Gdansk, Poland., Merck & Co., Inc., Rahway, NJ, USA., Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/41115468
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