2507 Background: IMA401 is a next-gen bispecific TCR-based T-cell engager designed to redirect T cells to antigen-positive cancer cells. It combines a high-affinity, highly specific TCR domain against an HLA-A*02:01-presented target peptide common to cancer-specific antigens MAGEA4 and MAGEA8 with a low-affinity T-cell–recruiting domain for improved tolerability and biodistribution, and an Fc part for half-life extension. IMA401-101 (NCT05359445) is a first-in-human phase 1a/b basket study evaluating IMA401 in pts with advanced solid tumors. Methods: Pts were ≥18 y, HLA-A*02:01+, MAGEA4+ and/or MAGEA8+, have R/R solid tumors, measurable disease (RECIST 1.1), ECOG performance status 0-2, and have exhausted SOC options. Dose escalation involved cohorts of 1-6 pts using adaptive design (BLRM). Doses ranged from 0.0066 mg - 2.5 mg IMA401 q2w (± pembrolizumab pembro q6w with 1.0 mg or 1.5 mg IMA401). Weekly step dosing of IMA401 was implemented for the first 2-3 doses at ≥1 mg . Primary endpoint was MTD assessed by BLRM and/or RP2D as monotherapy and in combination with pembro. Secondary endpoints included safety and initial antitumor activity (confirmed objective response rate cORR and disease control rate DCR). Results: As of Sep 26, 2025, 55 heavily pretreated pts across > 15 different tumor types with a median of 4 prior lines of therapy (range 1-9) received IMA401 ± pembro. Most frequent TRAEs were low-grade CRS (G1: 24%; G2: 11%; no ≥G3 events), expected and transient lymphopenia (any grade: 29%; ≥G3: 24% which typically improved within 1-3 days), and reversible neutropenia (any grade: 29%; ≥G3: 18%). No ICANS was observed. Tolerability of IMA401 + pembro (n = 9) was consistent with the IMA401 monotherapy safety profile. MTD was not reached (3 DLTs at 2.5 mg IMA401). RP2D range was determined to be 1-2 mg IMA401. Efficacy was evaluable in 38 pts receiving a target dose of ≥1 mg IMA401. Promising clinical activity was noted in pts with head and neck (HN) cancer (cORR: 25% 2/8; DCR: 63% 5/8) and melanoma (cORR: 29% 2/7; DCR: 57% 4/7) with duration of all confirmed responses beyond 6 months postinfusion. In squamous non-small cell lung cancer (sqNSCLC n = 3), 1 PR with reduction in all target lesions, 1 SD with OS of ~16 months and 1 PD with reduction in all liver target lesions were observed. After data cutoff, 2 more cPRs were observed in HN cancer resulting in a cORR of 33% (4/12). An updated full dataset will be presented. Conclusions: IMA401 demonstrated overall favorable tolerability without reaching formal MTD and encouraging antitumor activity in pts with HN cancer, melanoma, and sqNSCLC at RP2D range. Based on the promising results and preclinical proof of concept data, further development steps are being evaluated including a potentially synergistic combination with the PRAME-directed bispecific IMA402 in sqNSCLC and other solid tumor indications. Clinical trial information: NCT05359445 .
Wermke et al. (Wed,) studied this question.