MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: 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 its high-affinity TCR-based domain, incorporating a low-affinity T-cell-recruiting domain and an optimized Fc domain to prolong half-life. In this prespecified interim analysis of a phase 1 first-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 was determination of the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of IMA401 monotherapy and in combination with pembrolizumab. Secondary objectives included safety and tolerability, antitumor activity and pharmacokinetics. The MTD was not reached as defined by the clinical trial protocol, and the RP2D was 1-2 mg IMA401 biweekly. Treatment-related adverse events (TRAEs) were well manageable; the most common any-grade TRAEs were cytokine release syndrome (38%, grades 1-2 only), transient lymphopenia (33%) and reversible neutropenia (31%). Five patients experienced dose-limiting toxicity (DLT) events primarily related to neutropenia. No further DLTs occurred in the RP2D range with dexamethasone premedication. One possibly-related death (pneumonia in a patient with rapidly progressing lung metastases) was reported outside RP2D at 2.5 mg IMA401. In the overall efficacy-evaluable population across all dose levels (n = 56), including low 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 15 different 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 of 8.8 months. These findings show that the bispecific TCER platform has a manageable safety profile with mostly transient adverse events and promising antitumor activity at the RP2D of IMA401 with or without pembrolizumab. ClinicalTrials.gov identifier: NCT05359445 .
Source: Nature Medicine
Authors: Martin Wermke, Sebastian Ochsenreither, Dirk Jaeger, Heiko Becker, Annalen Bleckmann, Farastuk Bozorgmehr, Manik Chatterjee, Stefanie Groepper, Mathias Haenel, Judith S. Hecker, Max-Felix Häring, Daniel Heudobler, Norbert Hilf, Martin Hofmann, Meike Hutt, Andrea Mayer-Mokler, Sarah Missel, Manuel Ruh, Heiko Schuster, Olga Veremchuk, Moritz Kleemiss, Stefan Knop, Simon Laban, Martin Sebastian, Silvia Spoerl, Cedrik Michael Britten, Carsten Reinhardt
Institutions: Nationales Centrum für Tumorerkrankungen Dresden, Technische Universität Dresden, Charité - Universitätsmedizin Berlin, National Center for Tumor Diseases, University of Freiburg, University Medical Center Freiburg, University of Münster, University Hospital Münster, University Hospital Heidelberg, Comprehensive Cancer Center Mainfranken, Universitätsklinikum Würzburg, Marien Hospital Düsseldorf, Klinikum Chemnitz, TUM Klinikum, Technical University of Munich, Universitätsklinikum Tübingen, University Hospital Regensburg, Immatics Biotechnologies (Germany), University Hospital Bonn, Nuremberg Hospital, Universität Ulm, University Hospital Ulm, Goethe University Frankfurt, University Hospital Frankfurt, Frankfurt Cancer Institute, Universitätsklinikum Erlangen
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, Regeneron Pharmaceuticals, Jazz Pharmaceuticals, Novocure, Les Laboratories Pierre Fabre, BeiGene, Astellas Pharma, Servier, Swedish Orphan Biovitrum, PharmaMar, Ipsen, Genentech, Daiichi Sankyo Europe
OpenAlex ID: W7162937651