Botensilimab (BOT) ± balstilimab (BAL) in patients (pts) with advanced cutaneous melanoma (cMEL) refractory/resistant (R/R) to anti–PD-(L)1 ± CTLA-4: A phase 2 trial.

Abstract

9543 Background: Pts with advanced cMEL R/R to PD-(L)1–based therapy, including PD-(L)1+CTLA-4, have few treatment options. BOT (Fc-enhanced anti–CTLA-4) augments T-cell priming, depletes Tregs, and activates antigen-presenting cells to overcome immune checkpoint inhibitor (ICI) resistance. BOT ± BAL (anti–PD-1) has shown activity in ICI-R/R and cold tumors. Methods: The open-label, global phase 2 C-800-23 trial (NCT05529316) enrolled pts with cMEL (stage III unresectable or IV) R/R to prior anti–PD-(L)1 ± CTLA-4. Part 1: randomized 1:1 to BOT 50 mg or 150 mg every 3 weeks (Q3W; up to 4 doses). Part 2: BOT 75 mg Q3W (up to 4 doses) plus BAL 450 mg Q3W (up to 2 years). Endpoints included confirmed objective response rate (ORR; primary; RECIST 1.1), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety. Clinical benefit rate (CBR) was complete or partial response or stable disease for ≥24 weeks. Results: As of Dec 13, 2025, 138 pts received BOT monotherapy (median follow-up, 12.3 mo; range, 0.2–35+) and 36 pts received BOT+BAL (median follow-up, 13.8 mo; range, 2–26+). Overall, 51% had stage M1c or M1d disease, 29% had BRAF mutant disease, and 39% had LDH >ULN. In pts R/R to anti–PD-(L)1, 72% (60/83 with pre-trial data available) had primary resistance (best overall response of progressive disease [PD] or PD ≤6 mo from most recent course of respective ICI type). In pts R/R to anti–PD-(L)1+CTLA-4, 69% (61/88) had primary PD-(L)1 resistance and 69% (60/87) had primary CTLA-4 resistance. With BOT+BAL, ORR was 22% (95% CI, 10–39), CBR was 33% (95% CI, 19–51), median DOR was not reached (NR; 95% CI, 4.17–NR), 12-mo PFS was 29% (95% CI, 15–44), and median OS was 16.6 mo (95% CI, 9.1–NR; 24-mo OS, 46%; 95% CI, 29–61). ORR with BOT+BAL was numerically higher in PD-(L)1+CTLA-4 R/R pts (29%, 4/14; 95% CI, 8–58; 3/4 responders had primary ICI resistance) vs PD-(L)1–only R/R pts (18%, 4/22; 95% CI, 5–40; all responders had primary ICI resistance). With BOT alone, ORR was 6% (95% CI, 3–11), CBR was 14% (95% CI, 9–21), 12-mo PFS was 7% (95% CI, 3–13), and median OS was 12.9 mo (95% CI, 9.7–16.2; 24-mo OS, 28%; 95% CI, 20–36). Responses were irrespective of Fcγ receptor genotype. Treatment-related adverse events occurred in 81% (grade ≥3, 30%) with BOT alone and 94% (grade ≥3, 36%) with BOT+BAL; most common was diarrhea (BOT 33%; BOT+BAL 42%). One possibly treatment-related death was reported with BOT monotherapy (immune-mediated enterocolitis). No new safety signals occurred. Conclusions: In this ICI-R/R cMEL population enriched with primary ICI-resistant pts, BOT+BAL showed durable responses, encouraging survival, and a stronger signal in pts who had prior conventional anti–CTLA-4. BOT monotherapy also showed activity. This supports a differentiated mechanism for BOT and continued development of BOT+BAL, including for pts with dual ICI-R/R cMEL. Clinical trial information: NCT05529316 .