Patient-level clinical response dynamics in advanced melanoma with anzutresgene autoleucel (anzu-cel), a PRAME-directed T-cell receptor (TCR) T-cell therapy.

9508 Background: Pts with advanced melanoma frequently experience progressive disease (PD) with limited long-term survival following available therapies; there is a need for novel systemic treatments that can induce deep and durable responses. PRAME is a cancer-associated antigen expressed in >50 cancers, including melanoma. Anzu-cel (IMA203) is an autologous PRAME-directed TCR T-cell therapy engineered to recognize intracellular PRAME-derived peptides presented by HLA-A*02:01 and mediates a potent and specific anti-tumor immune response (Wermke et al. ASCO, 2025). A registration-directed phase 3 trial (SUPRAME; NCT06743126) is underway. Methods: IMA203-101 is an ongoing, multicenter, phase 1/2 trial evaluating anzu-cel in pts with advanced PRAME-positive solid tumors. Pts underwent lymphodepleting (LD) chemotherapy followed by a single infusion of anzu-cel +/- low-dose SUBQ IL-2. This analysis focuses on melanoma pts in phase 1b treated at RP2D. Data cutoff was Sep 24, 2025. Exploratory analyses evaluated lesion-level patterns of progression among pts evaluable per RECIST1.1. Results: As of data cutoff, 33 pts with melanoma were evaluable, incl. cutaneous (n=14), uveal (n=16), and other subtypes (n=3). Most frequent AEs were LD-related cytopenias. AEs of special interest included cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS) and hemophagocytic lymphohistiocytosis (HLH). CRS was predominantly low grade (G1: 36%, G2: 46%, G3: 18%) and occurred early after infusion, with incidence and severity decreasing over time. ICANS (G1: 6%, G3: 6%) and HLH (G2: 3%, G3: 3%) were infrequent. Confirmed ORR was 56% (cCR=1, cPR=17) and DCR was 91%. mDOR was 14.6 mos (4.2-38.2+), mPFS was 6.1 mos (1.4-39.6+), and mOS was 16.2 mos (2.4-39.6+). Responses were observed in target and nontarget lesions, with most pts demonstrating initial lesion responses within the first 6 weeks of treatment; median time to BOR of cPR/cCR was 1.4 mo (1.2-2.8). 25 pts were evaluable for patterns of PD. At the time of PD, 68% (17/25) developed new lesions (NL); 1 pt developed new central nervous system (CNS) lesions. PD via growth of existing lesions was observed in 56% (14/25); 24% (6/25) experienced PD by both growth of existing lesions and NLs. No specific pattern of PD was identifiable in those who achieved cPR compared to those who did not. Conclusions: Anzu-cel demonstrated favorable tolerability and induced clinically meaningful and durable responses. Exploratory analyses suggest that the CNS was not a common site for relapse. Future analyses will characterize response dynamics and progression patterns to better define scenarios in which progression following cPR remains clinically manageable, potentially supporting individualized decision-making regarding timing and necessity of subsequent systemic therapy. Clinical trial information: NCT06743126 .