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Background Outcomes in metastatic melanoma after failure of immune checkpoint inhibition are poor with limited long-term survival. There is an urgent need for therapies delivering more durable survival. PRAME is an intracellular protein presented on the surface of tumor cells that are targeted by T cell receptors (TCR); PRAME is expressed in 95% of cutaneous melanoma (CM) cells and PRAME expression has been associated with poorer prognosis and shorter survival. IMA203 is a PRAME-directed TCR T-cell therapy engineered to recognize intracellular PRAME-derived peptides presented by HLA-A*02:01 on the cell surface and initiate a potent and specific anti-tumor response. In the phase 1 trial ( NCT03686124), IMA203 exhibited favorable tolerability and encouraging anti-tumor activity in patients with advanced melanoma at RP2D. Confirmed ORR was 56% (18/32), mDOR was 12.1 months, mPFS was 6.1 months, and mOS was 15.9 months. Most frequent TEAEs in all indications (N=74) were lymphodepletion-related cytopenias (99%). CRS was mostly lower grade (84% G1/2; 11% G3; no ≥G4) and ICANS was infrequent (10% G1/2; 4% G3; no ≥G4).1 SUPRAME will evaluate IMA203 in advanced cutaneous melanoma after immune checkpoint inhibition.Methods SUPRAME ( NCT06743126) is a prospective, multicenter, open-label, randomized, actively controlled, phase 3 trial evaluating the efficacy and safety of IMA203 vs investigator’s choice in previously treated patients with unresectable or metastatic cutaneous melanoma (including acral melanoma). Eligible patients are ≥18 y, HLA-A*02:01+, measurable disease (RECIST v1.1), ECOG PS 0-1 and disease progression on or after ≥1 PD-1 inhibitor. Patients with BRAF mutation should have received 1 prior BRAF-directed therapy (± MEK inhibitor) at investigator discretion. Patients with active brain metastases, leptomeningeal disease or with primary mucosal, uveal melanoma and melanoma of unknown primary are excluded. Those with asymptomatic stable brain metastasis will be assessed for eligibility. The study will randomize 360 patients 1:1 who will undergo leukapheresis. Patients in the IMA203 arm will undergo lymphodepletion with Cy 500 mg/m2 and Flu 30 mg/m2 x 4 days, followed by a one-time infusion of IMA203 (1-10x 109 TCR T cells), and low-dose IL-2 (1 M IU QD x5 days, BID x5 days, SC). Patients in the control arm will receive nivolumab/relatlimab, nivolumab, ipilimumab, pembrolizumab, lifileucel (US), or chemotherapy. The primary endpoint is PFS. Secondary endpoints include OS, ORR, safety, and patient-reported outcomes. The trial is currently enrolling patients in the US and Germany and plans to enroll patients in France, the Netherlands, Canada, and the United Kingdom.Acknowledgements Study funding provided by Immatics US, Inc.Trial Registration NCT06743126Reference Wermke M, Alsdorf W, Araujo DM, et al. Phase 1 clinical update of IMA203, an autologous TCR-T targeting PRAME in patients with PD1 refractory metastatic melanoma. Abstract 2508. Presented at: ASCO Annual Meeting; June 2025; Chicago, IL.Ethics Approval The protocol and all amendments were approved by the appropriate institutional review board or independent ethics committee at each participating study site. The study is being conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.