Safimaltib (JNJ-67856633) MALT1 inhibitor posts 28.8% pooled ORR across heavily pretreated B-cell lymphomas and CLL, with frequent hyperbilirubinemia

Safimaltib is an oral, once-daily MALT1 (paracaspase) protease inhibitor designed to dampen B-cell receptor/NF-κB signaling and was evaluated in a multi-center Phase 1 dose-escalation/expansion study in relapsed/refractory B-cell non-Hodgkin lymphomas or CLL (NCT03900598; n=226; 56.2% DLBCL; 47.3% had ≥4 prior lines). RP2D was 300mg QD (±loading dose); ORR pooled across the enrolled B-cell lymphoma and CLL histologies was 28.8% (95% CI 23.0%-35.1%) with 3.9% CR (9/226), rather than a DLBCL-specific response estimate. This pooled rate is numerically below response rates typically seen with active later-line DLBCL immunotherapies like CD20xCD3 bispecific epcoritamab (~63% ORR; ~39% CR in pivotal LBCL cohort) and regimens like polatuzumab vedotin + bendamustine/rituximab (~45% ORR; ~40% CR in transplant-ineligible R/R DLBCL), albeit those benchmarks are in more defined DLBCL-only populations and often later-line DLBCL-focused trials. Safety was notable for hyperbilirubinemia (48.2%; described as off-target related) plus cytopenias (anemia 36.7%, neutropenia 31.4%, thrombocytopenia 27.4%); dose reductions reportedly mitigated safimaltib-related AEs, and translational data supported on-target pathway modulation (NF-κB–regulated cytokines); in an ultra-small biomarker slice, all non-GCB DLBCL with ≥1 BCR-pathway activating mutation responded (n=5).