KEYMAKER-U03 Substudy 03B: Pembrolizumab (pembro) and targeted therapy combinations for advanced clear cell renal cell carcinoma (ccRCC).
Authors: Laurence Albiges, Cristina Suárez, Thomas Powles, Robert J. Motzer, 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, Hans J. Hammers, Katy Beckermann
Journal: Journal of Clinical Oncology (2025)

440 Background: The phase 1/2 KEYMAKER-U03 Substudy 03B (NCT04626518) is being conducted to evaluate combination treatments for previously treated advanced ccRCC. We present results for targeted therapy–containing regimens from arm B4 (pembro + belzutifan [HIF-2α inhibitor]), arm B5 (lenvatinib [VEGF-TKI] + belzutifan), and the reference (ref) arm (pembro + lenvatinib). Methods: Adults with histologically confirmed locally advanced/metastatic ccRCC and disease progression on or after PD-(L)1 inhibitor and VEGF-TKI treatment were randomly assigned 1:1 to arms open for enrollment. Arms B4 and B5 had a safety lead-in phase where ~10 patients (pts) were initially enrolled before randomization. Treatment doses were pembro 400 mg IV Q6W + belzutifan 120 mg PO QD (arm B4), lenvatinib 20 mg PO QD + belzutifan 120 mg PO QD (arm B5), or pembro 400 mg IV Q6W + lenvatinib 20 mg PO QD (ref arm). Primary end points were safety and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included DOR, clinical benefit rate (CBR; CR + PR + SD ≥6 months), and PFS per RECIST v1.1 by BICR, and OS. Efficacy was evaluated in all enrolled (allocated and randomized) pts; safety was evaluated in all pts who received ≥1 dose of treatment. No formal comparisons across arms occurred. Enrollment was planned for 50 pts in each arm, although enrollment would be stopped if the 6-mo PFS rate was ≤40%. Results: Overall, 62 pts were assigned to arm B4, 64 to arm B5, and 73 to the ref arm. Median (range) follow-up was 16.6 mo (6.5-38.7) in arm B4, 17.6 mo (6.5-35.9) in arm B5, and 19.4 mo (6.7-33.2) in the ref arm. Efficacy is reported in the table. Grade 3-5 treatment-related AEs (TRAEs) occurred in 26/62 pts (42%) in arm B4, 38/63 pts (60%) in arm B5, and 36/73 pts (49%) in the ref arm. TRAEs led to death in 2 pts in arm B5 (cerebral hemorrhage and intracranial hemorrhage) and 1 pt in the ref arm (esophageal perforation). Conclusions: Lenvatinib + belzutifan (arm B5) exhibited durable antitumor activity and a safety profile consistent with the individual profiles of the drugs. Results from Substudy-03B support further investigation of lenvatinib + belzutifan combination for pts with advanced RCC, as in LITESPARK-011. Clinical trial information: NCT04626518 . Arm B4Pembro + belzutifann = 62 Arm B5Lenvatinib + belzutifann = 64 Ref armPembro + lenvatinibn = 73 ORR (95% CI), % 19 (10-31) 47 (34-60) 40 (29-52) CR, n (%) 2 (3) 1 (2) 0 (0) PR, n (%) 10 (16) 29 (45) 29 (40) CBR (95% CI), % 32 (21-45) 59 (46-72) 58 (45-69) DOR, median (range), mo Not reached (1.4+-33.0+) 22.1 (1.4+-32.8+) 8.3 (2.6+-25.6+) PFS, median (95% CI), mo 5.4 (2.8-6.9) 12.5 (5.9-26.3) 9.4 (6.9-11.2) 6-mo PFS rate, % 42 63 67 OS, median (95% CI), mo 27.4 (12.6-not reached) 32.3 (22.4-not reached) Not reached (21.8-not reached) 12-mo OS rate, % 68 80 82