Phase 1 evaluation of the PRAME-targeted ImmTAC brenetafusp in advanced melanoma (Mel).

9527 Background: Brenetafusp (brene) is an ImmTAC bispecific (PRAME × CD3) therapy that promotes T cell recruitment into tumors. Initial Phase (Ph) 1 data showed acceptable safety, robust T cell activation at target doses (TD) ≥ 20 mcg and promising clinical activity in multiple tumors including heavily pretreated cutaneous melanoma (CM) (Hamid 2022, 2024; NCT04262466]). We present updated monotherapy (mono) and PD1 immune checkpoint inhibitor (ICI) combination (combo) safety and efficacy results supporting brene dose selection in Mel (CM, mucosal [Mu] or acral [Ac]). Methods: HLA-A*02:01+ Mel patients (pts) who exhausted standard treatments were eligible. Primary objectives: safety and recommended dose; additional objectives included efficacy, biomarkers and ctDNA response. Brene mono was administered intravenously weekly (QW) with 1-2 step-up doses to TD; TD 40 and 160 mcg were evaluated in expansion. Combo was 160 mcg brene QW + 400 mg pembrolizumab (pembro) Q6W. Molecular response: ≥ 0.5 log [68%] ctDNA reduction by week 9 (Hamid 2024). T cell fitness defined as 3-gene (TESPA1, CD28 and GPR183) signature in blood (Sacco 2024). Tumor PD-L1 measured by immunohistochemistry, beta2 microglobulin (B2m) by immunofluorescence. Results: As of Oct 2025, 66 pts with Mel (median 2.5 prior lines, 100% prior PD1, 30% PD1 refractory [progression <6 mo post start of first anti-PD1], 68% St IV-c/IV-d) received brene mono (TD 40, n=16; TD 160, n=24; other TD 10-320 mcg, n=26). The 40-mcg cohort had more favorable baseline prognostic factors (ECOG PS, tumor burden, ctDNA, prior treatment) and T cell fitness. Ten pts (median 2.5 prior lines, 90% prior PD1, 50% prior BRAF/MEKi, 70% St IV-c/IV-d) received brene + pembro. Safety was similar at TD 40 and 160 mcg with Gr1/2 CRS (56% vs 42%) and rash (44% vs 42%) initially. Gr3/4 events occurred in 25% vs 54%: mainly transient lymphocyte decrease, consistent with mechanism. Of 10 pts with prior ICI Gr3/4 irAE, none had recurrence. Combo profile resembled each agent alone. No new safety signals observed. Disease control, RECISTv1.1 response and ctDNA molecular response rates were numerically higher at 160 vs 40 mcg (Table), with similar rates across subgroups typically less responsive to anti-PD1. Overall survival was associated with baseline T cell fitness and tumor B2m, but not with PD-L1 status. Conclusions: Brene shows promising monotherapy activity in late-line Mel, including difficult to treat populations, without causing ICI-like irAEs, and can be safely combined with pembro. Ph1 results support 160 mcg as the selected dose in the Ph3 PRISM-MEL trial evaluating brene with nivolumab versus standard nivolumab regimens (NCT06112314). Clinical trial information: NCT04262466 . N DCR% (PR + SD) ORR% 6mo OS% ctDNA-evaluableN ctDNA response% Brene mono 66 52 12 83 50 38 40 mcg 16 56 6 81 10 20 160 mcg 24 67 17 79 15 33 PD1 refractory 20 55 10 70 15 53 Ac / Mu 7 57 14 86 5 40 Sum target lesions >10 cm 25 44 12 80 19 32 Brene + pembro 10 70 20 80 5 40 PD1 refractory 6 67 33 67 2 50