MAGE-A4/MAGE-A8-targeted TCR-based bispecific T cell engager in recurrent and/or refractory solid tumors: a phase 1 trial
(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C
In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.
Contributed by Alex Najibi
(1) Wermke M (2) Ochsenreither S (3) Jaeger D (4) Becker H (5) Bleckmann A (6) Bozorgmehr F (7) Chatterjee M (8) Groepper S (9) Haenel M (10) Hecker JS (11) Häring MF (12) Heudobler D (13) Hilf N (14) Hofmann M (15) Hutt M (16) Mayer-Mokler A (17) Missel S (18) Ruh M (19) Schuster H (20) Veremchuk O (21) Kleemiss M (22) Knop S (23) Laban S (24) Sebastian M (25) Spoerl S (26) Britten CM (27) Reinhardt C
In a phase 1 trial, 61 patients with advanced solid tumors were treated with a TCE comprising (1) a high-affinity TCR binder for a shared MAGE-A4/MAGE-A8 CTA peptide presented on HLA-A*02:01, (2) a humanized, low(er)-affinity anti-TCRαβ/CD3 antibody for T cell binding and activation, and (3) a silenced Fc domain to extend half-life. 12 patients also received pembrolizumab. Median serum half-life was ~15d, an MTD was not reached, and a RP2D was determined. TRAEs were manageable (often CRS, lymphopenia, or neutropenia) and the ORR was 14% in evaluable patients. Pembrolizumab did not significantly affect safety or response rates.
Contributed by Alex Najibi
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 .
Author Info:
(1) NCT/UCC Early Clinical Trial Unit and Department of Medicine I, Dresden University of Technology, Dresden, Germany. (2) Charit Universittsmedizin Berlin, Berlin, Germany. (3)
National Center for Tumor Diseases, Heidelberg, Germany. (4) Department of Hematology, Oncology, and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. (5) Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany. (6) National Center for Tumor Diseases, Heidelberg, Germany. Thoraxklinik Heidelberg gGmbH, University Hospital Heidelberg, Heidelberg, Germany. (7) University Hospital Wrzburg, Comprehensive Cancer Center Mainfranken, Wrzburg, Germany. (8) Marien Hospital Dsseldorf, Dsseldorf, Germany. (9) Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany. (10) Department of Medicine III, Technical University of Munich (TUM), Klinikum rechts der Isar, School of Medicine and Health, Munich, Germany. TranslaTUM, Center for Translational Cancer Research, Technical University of Munich (TUM), Munich, Germany. (11) University Hospital of Tbingen, Tbingen, Germany. (12) University Hospital Regensburg, Regensburg, Germany. (13) Immatics Biotechnologies GmbH, Tbingen, Germany. (14) Immatics Biotechnologies GmbH, Tbingen, Germany. (15) Immatics Biotechnologies GmbH, Tbingen, Germany. (16) Immatics Biotechnologies GmbH, Tbingen, Germany. (17) Immatics Biotechnologies GmbH, Tbingen, Germany. (18) Immatics Biotechnologies GmbH, Tbingen, Germany. (19) Immatics Biotechnologies GmbH, Tbingen, Germany. (20) Immatics Biotechnologies GmbH, Tbingen, Germany. (21) University Hospital Bonn, Bonn, Germany. (22) Nuremberg General Hospital, Nuremberg, Germany. (23) Department of Otorhinolaryngology and Head & Neck Surgery, Ulm University Medical Center, Ulm, Germany. (24) University Hospital, Goethe University Frankfurt, Frankfurt Cancer Institute, Frankfurt, Germany. (25) University Hospital Erlangen, Erlangen, Germany. (26) Immatics Biotechnologies GmbH, Tbingen, Germany. (27) Immatics Biotechnologies GmbH, Tbingen, Germany. Carsten.Reinhardt@immatics.com.
