Novel pembrolizumab-based treatments as first-line therapy in advanced clear cell renal cell carcinoma: Substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial
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Authors
Suarez C.
Rojas C.
Shin S.J.
Weber P.Y.
Albiges L.
Motzer R.
Hammers H.
Peer A.
Lee J.L.
Miller W.H.
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2025
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Abstract
BACKGROUND: 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. METHOD(S): 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). RESULT(S): 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. CONCLUSION(S): 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. Copyright © 2025. Published by Elsevier Ltd.
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Annals of oncology : official journal of the European Society for Medical Oncology