Phase 1 clinical update of IMA203, an autologous TCR-T targeting PRAME in patients with PD1 refractory metastatic melanoma.

Abstract

2508 Background: Frequent recurrence and limited long-term survival in unresected or metastatic melanoma after relapse from 1L checkpoint inhibitor treatment highlight the critical need for new therapies that deliver deeper, more durable responses. ACTengine IMA203 is an autologous TCR-T targeting PRAME, an intracellular protein displayed as peptide antigen at high density on the surface of multiple solid tumors, including melanoma. Methods: Patients treated in this ongoing Ph1a/b trial (NCT03686124) are ≥18yo, HLA-A*02:01+, PRAME+, have recurrent and/or refractory solid tumors with no additional standard of care treatments available, measurable disease (RECIST1.1) and ECOG PS 0-1. Patients receive Cy/Flu (500 mg/m 2 & 30 mg/m 2 x4 d) lymphodepletion prior to infusion, followed by low-dose IL-2 for 10 days. Results: As of Aug 23, 2024: 70 heavily pretreated patients with solid tumors (median 3 prior systemic therapies) across all dose levels (median total infused dose 2.09x10 9 TCR-T cells (0.08-10.02x10 9 )) were enrolled and assessed for safety. Baseline tumor burden (median sum of diameter): 11.78 cm; LDH > 1 x ULN: 64% of patients. IMA203 had an overall favorable tolerability profile. Most common TEAEs: chemotherapy-related cytopenias (100%), mild to moderate CRS (G1-2: 83%, G3: 11%), infrequent ICANS (G1: 6%, G2: 4%, G3: 4%), no G5 events. Objective responses were observed in melanoma, ovarian cancer, synovial sarcoma, and other tumor types. Successful trafficking of IMA203 cells to various organs was evidenced by their ability to shrink metastatic tumor lesions in the lung, liver, pleura, peritoneum, skin, lymph nodes, adrenal gland, bladder, kidney, spleen, and muscle. Across patients treated in dose escalation and dose expansion, higher doses of IMA203 TCR-T cells were associated with a higher rate of confirmed responses (p = 0.018), whereas tolerability profile remained favorable. Exposure data (C max , AUC) demonstrated a clear dose-dependent improvement in clinical efficacy: Patients with confirmed PR had a higher concentration of IMA203 TCR-T cells in the periphery, compared to patients with unconfirmed PR, SD, and PD. In heavily pretreated patients (median 2 prior systemic therapies) with melanoma at RP2D (1-10x10 9 ) in Ph1b, cORR was 54% (14/26), with tumor shrinkage in 88% (23/26) of patients. Median DOR was 12.1 months with 7/14 confirmed responses ongoing (longest > 2 years). Median PFS was 6 months and median OS not reached at 8.6 months mFU. Updated data with longer follow-up will be presented. Conclusions: IMA203 TCR-T was well tolerated and showed durable objective responses in patients with advanced melanoma. Given its promising risk/benefit profile and high PRAME prevalence in melanoma, a registration-directed Phase 3 trial (SUPRAME; NCT06743126) is underway to further evaluate its efficacy in patients with previously treated (2L) advanced cutaneous melanoma. Clinical trial information: NCT03686124 .