A phase 1, first-in-human study of safimaltib, a MALT1 inhibitor, in B-lymphocytic malignancies
Mark Hertzberg, Chan Y. Cheah, Stephen Opat, Matko Kalac, Pau Abrisqueta, Vincent Ribrag, Emmanuel Bachy, Loïc Ysebaert, Lugui Qiu, Erel Joffe, Shuhua Yi, Pier Luigi Zinzani, Alessandra Tedeschi, Noriko Nishimura, Charlotte R. Lemech, Jacqueline Bussolari, Changchun Deng, Alemu Takele Assefa, Sandy Van Hemelryck, Jan Snoeys, Brendan P. Hodkinson, Nele Fourneau, Yu Cao, Srimathi Srinivasan, Yue Guo, Virginie Soete, Isabel Soriano Paradinas, Lorena Fontan, Ulrike Philippar, John F. Gerecitano, Franck MorschhauserAbstract
Following preclinical findings, we evaluated safimaltib (MALT1 protease inhibitor; JNJ-67856633) in relapsed/refractory B-cell non-Hodgkin lymphomas or chronic lymphocytic leukemia in a multi-center, phase-1, dose-escalation/dose-expansion study (NCT03900598). Primary endpoints were recommended phase-2 dose (RP2D) and safety. Among 226 patients, 56.2% had diffuse large B-cell lymphoma (DLBCL); 47.3% received ≥4 prior therapy lines. RP2D was once-daily, 300-mg, oral safimaltib±loading dose. Most common adverse events (AEs) were hyperbilirubinemia (48.2%; off-target related), anemia (36.7%), neutropenia (31.4%), and thrombocytopenia (27.4%). Dose reduction mitigated safimaltib-related AEs. Objective response rate was 28.8% (95% CI: 23.0%–35.1%), including 9 (3.9%) complete responses. All patients with non-germinal–center B-cell–like DLBCL and ≥1 B-cell–receptor pathway activating mutation (n=5) responded to safimaltib. Safimaltib exhibited on-target activity in translational studies, affecting NF-κB-regulated cytokines. Proof-of-principle activity in this first MALT1-targeting study in hematologic malignanices suggest MALT1 may be a feasible target in humans and supports further investigation despite observed off-target effects.