What does this research mean for the field?

Brenetafusp demonstrates promising clinical activity and acceptable safety as both monotherapy and in combination with pembrolizumab in heavily pretreated advanced melanoma, supporting a 160 mcg dose for Phase 3 evaluation. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To evaluate the safety and efficacy of brenetafusp in patients with advanced melanoma.

May 29, 2026

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

Key Points

To evaluate the safety and efficacy of brenetafusp in patients with advanced melanoma.
Phase 1 trial with HLA-A*02:01+ patients after standard treatment failure.
Brenetafusp administered intravenously weekly with step-up doses, evaluated at 40 and 160 mcg.
Combination therapy with brenetafusp and pembrolizumab was also assessed.
Disease control and ctDNA response rates were numerically higher at 160 mcg compared to 40 mcg.
Overall survival correlated with baseline T cell fitness and B2m levels.
No new safety signals observed; adverse effects were consistent with expected profiles.

Abstract

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 10 cm 25 44 12 80 19 32 Brene + pembro 10 70 20 80 5 40 PD1 refractory 6 67 33 67 2 50

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

Key Points

Abstract

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