Brenetafusp (PRAME×CD3 ImmTAC) shows 17% ORR at 160µg in late-line melanoma, with mostly low-grade CRS and no irAE recurrence

Brenetafusp (IMC-F106C) is a PRAME-targeted ImmTAC bispecific (PRAME×CD3) designed to redirect polyclonal T cells into PRAME-expressing tumors; in this Phase 1 study (NCT04262466), HLA-A*02:01+ advanced melanoma patients who had exhausted standard options (median 2.5 prior lines; 100% prior anti–PD-1; 30% PD-1 refractory; 68% stage IVc/IVd) received weekly IV brenetafusp monotherapy across doses including 40µg (n=16) and 160µg (n=24), plus a small combination cohort of brenetafusp 160µg weekly + pembrolizumab 400mg Q6W (n=10). In the full monotherapy melanoma set (n=66), DCR was 52% with ORR 12%, 6-month OS 83%, and ctDNA molecular response 38% (ctDNA-evaluable n=50); by dose, 160µg trended higher than 40µg for DCR (67% vs 56%), ORR (17% vs 6%), and ctDNA response (33% vs 20%) despite baseline imbalances favoring the 40µg cohort, while PD-1–refractory patients still showed ORR 10% and ctDNA response 53% (ctDNA-evaluable n=15). Safety was characterized by Grade 1/2 CRS (56% at 40µg; 42% at 160µg) and rash (44% vs 42%), with Grade 3/4 AEs more frequent at 160µg (54% vs 25%) mainly due to transient lymphocyte decreases; notably, among 10 patients with prior ICI Grade 3/4 irAEs, none recurred, and the combo cohort showed DCR 70% and ORR 20% with no new signals—an AE profile that appears qualitatively different from CTLA-4–based salvage strategies where ≥Grade 3 toxicity is often a central limitation. For efficacy context post–anti–PD-1, published salvage outcomes with ipilimumab-based approaches are typically in the ~10–25% ORR range but with substantial ≥Grade 3 irAEs (often ~30%+; higher in many series), so a 17% ORR signal at 160µg lands “in-family” on response while potentially differentiating on irAE phenotype (needs confirmation in larger, controlled data).