Botensilimab (Fc‑enhanced anti‑CTLA‑4) + balstilimab (anti‑PD‑1) delivers 22% ORR in dual ICI‑refractory cutaneous melanoma

Botensilimab (BOT) is an Fc‑engineered anti‑CTLA‑4 antibody designed to enhance T‑cell priming and Treg depletion, and balstilimab (BAL) is an anti‑PD‑1; both were evaluated in the open-label global Phase 2 C‑800‑23 trial (NCT05529316) in unresectable stage III/IV cutaneous melanoma refractory/resistant to prior anti–PD-(L)1 ± CTLA‑4. As of December 13, 2025, BOT+BAL showed ORR 22% (95% CI 10–39) and CBR 33% with median DOR not reached, 12‑mo PFS 29%, and median OS 16.6 mo in a heavily primary‑resistant population (n=36; 51% M1c/M1d; 39% LDH>ULN); BOT monotherapy produced ORR 6% and 12‑mo PFS 7% (n=138; median OS 12.9 mo). Grade ≥3 TRAEs were 36% with BOT+BAL (diarrhea 42%) and 30% with BOT alone (diarrhea 33%), with one possibly treatment-related death on BOT monotherapy (immune-mediated enterocolitis); in context, the approved post–PD‑1 option lifileucel has reported ~31.4% ORR in advanced melanoma after anti–PD‑1/PD‑L1 (and BRAF±MEK if BRAF V600+), albeit with very different logistics/toxicity expectations versus antibody therapy.