A phase 1, first-in-human study of safimaltib, a MALT1 inhibitor, in B-lymphocytic malignancies.

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.