KEYMAKER-U03 Substudy 03B: Pembrolizumab (pembro) and novel immunotherapy agents for advanced clear cell renal cell carcinoma (ccRCC).
Authors: Cristina Suárez, Laurence Albiges, Katy Beckermann, Hans J. Hammers, Walter Michael Stadler, Wilson H. Miller, Carlos Rojas, Avivit Peer, Jeffrey C. Goh, Se Hoon Park, Tom Waddell, Philippe Barthelemy, Pablo Gajate, Andrew Weickhardt, Guy Faust, Rodolfo F. Perini, Lockman Bousserouel, Ding Wang, Robert J. Motzer, Thomas Powles
Journal: Journal of Clinical Oncology (2025)

552 Background: Substudy 03B of the phase 1/2 KEYMAKER-U03 trial (NCT04626518) was designed to evaluate combination treatments with pembro and investigational agents for previously treated ccRCC. We present results from arms containing only immunotherapy regimens: arm B1 (quavonlimab [qmab; anti–CTLA-4] coformulated with pembro), arm B2 (favezelimab [fave; anti–LAG-3] coformulated with pembro), and arm B3 (pembro + MK-4830 [anti-ILT4]), and the reference (ref) arm (pembro + lenvatinib). Methods: Adults with histologically confirmed ccRCC and disease progression on or after PD-(L)1 inhibitor and VEGF-TKI treatment were enrolled. Patients (pts) in arm B1 could not have received prior anti–CTLA-4 inhibitors. Pts were randomly assigned 1:1 to arms open for enrolment. Treatments were qmab/pembro 25 mg/400 mg IV Q6W in arm B1, fave/pembro 800 mg/200 mg IV Q3W in arm B2, pembro 200 mg IV Q3W + MK-4830 800 mg IV Q3W in arm B3, and pembro 400 mg IV Q6W + lenvatinib 20 mg PO QD in ref arm. Primary end points were safety and confirmed ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included CBR (CR + PR + SD ≥6 months), DOR, and PFS per RECIST v1.1 by BICR, and OS. End points were evaluated in each arm separately; no formal comparisons were made across arms. Efficacy was evaluated in all enrolled pts and safety was evaluated in all pts who received ≥1 dose of treatment. Enrollment was planned for 50 pts in each arm, although enrollment would be stopped if the 6-mo PFS rate was ≤40%. Results: Overall, 20 pts were assigned to arm B1, 20 to arm B2, 24 to arm B3, and 73 to ref arm. Median follow-up was approximately 2 years across arms (B1, 20.6 mo; B2, 23.3 mo; B3, 30.0 mo; ref, 19.4 mo). Efficacy is reported in the table. Grade 3 or 4 treatment-related AEs (TRAEs) were reported in 5/20 pts (25%) in arm B1, 2/19 pts (11%) in arm B2, 2/23 pts (9%) in arm B3, and 36/73 pts (49%) in the ref arm. No grade 5 TRAEs occurred. Conclusions: Preliminary data from qmab/pembro (arm B1) and pembro + lenvatinib (ref arm) showed antitumor activity in pts with ccRCC that progressed on anti–PD-(L)1 and VEGF-TKI therapy. Fave/pembro (arm B2) and pembro + MK-4830 (arm B3) arms did not show clinical activity in this setting. The safety profile of each arm was manageable. Additional arms containing targeted therapies will be reported separately. Clinical trial information: NCT04626518 . Arm B1Qmab/pembron = 20 Arm B2Fave/pembron = 20 Arm B3Pembro + MK-4830n = 24 Ref Pembro + lenvatinibn = 73 ORR (95% CI), % 30 (12-54) 0 (0-17) 0 (0-14) 40 (29-52) CR, n (%) 0 0 0 0 PR, n (%) 6 (30) 0 0 29 (40) CBR (95% CI), % 35 (15-59) 5 (0-25) 0 (0-14) 58 (45-69) DOR, median (range), mo Not reached(5.6+-19.4+) — — 8.3 (2.6+-25.6+) PFS, median (95% CI), mo 5.5(1.5-not reached) 1.6 (1.4-2.8) 1.5 (1.3-1.6) 9.4 (6.9-11.2) 6-mo PFS rate, % 45 20 4 67 OS, median (95% CI), mo Not reached(7.8-not reached) Not reached(9.4-not reached) 11 (7-18) Not reached(21.8-not reached) 12-mo OS rate, % 75 61 44 82