IMA401 is a T cell receptor (TCR)-based next-generation bispecific T cell engaging receptor(TCER) targeting an HLA-A*02:01-presented peptide derived from MAGE-A4/MAGE-A8 with itshigh-affinity TCR-based domain, incorporating a low-affinity T-cell-recruiting domain and anoptimized Fc domain to prolong half-life. In this prespecified interim analysis of a phase 1first-in-human trial, 61 patients with advanced solid tumors received intravenous IMA401(0.0066 mg-2.5 mg) with or without pembrolizumab. The primary endpoint wasdetermination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose(RP2D) of IMA401 monotherapy and in combination with pembrolizumab. Secondaryobjectives included safety and tolerability, antitumor activity and pharmacokinetics. TheMTD was not reached as defined by the clinical trial protocol, and the RP2D was 1-2 mgIMA401 biweekly. Treatment-related adverse events (TRAEs) were well manageable; the mostcommon any-grade TRAEs were cytokine release syndrome (38%, grades 1-2 only), transientlymphopenia (33%) and reversible neutropenia (31%). Five patients experienced dose-limitingtoxicity (DLT) events primarily related to neutropenia. No further DLTs occurred in the RP2Drange with dexamethasone premedication. One possibly-related death (pneumonia in apatient with rapidly progressing lung metastases) was reported outside RP2D at 2.5 mgIMA401. In the overall efficacy-evaluable population across all dose levels (n = 56), includinglow starting doses (from 0.0066 mg), the confirmed objective response rate (ORR) was 14%(8/56). In patients receiving IMA401 at the RP2D, an ORR of 20% 8/41) was observed across 15different indications (post hoc analysis). In the largest subgroup of patients treated at RP2D,namely head and neck cancer, the ORR was 29% (4/14) with a median duration of response of8.8 months. These findings show that the bispecific TCER platform has a manageable safetyprofile with mostly transient adverse events and promising antitumor activity at the RP2D ofIMA401 with or without pembrolizumab. ClinicalTrials.gov identifier: NCT05359445
