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

Abstract 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.

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Journal
Blood Cancer Discovery
Published
2026-09-30
DOI
https://doi.org/10.1158/2643-3230.bcd-26-0179
Primary Topic
NF-κB Signaling Pathways
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article
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article

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

Erel Joffe, Alessandra Tedeschi, Loïc Ysebaert, Ulrike Philippar et al.
Blood Cancer Discovery
NF-κB Signaling Pathways
article

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

Erel Joffe, Alessandra Tedeschi, Loïc Ysebaert, Ulrike Philippar, Lugui Qiu, Sandy Van Hemelryck, Charlotte Lemech, Shuhua Yi, Vincent Ribrag, Srimathi S. Srinivasan, Jan Snoeys, Alemu Takele Assefa, Lisa Argnani, Franck Morschhauser, Emmanuel Bachy, Matko Kalac, Jacqueline Bussolari, Noriko Nishimura, Chan Yoon Cheah, Mark Hertzberg, John F. Gerecitano, Virginie Soete, Lorena Fontán, Stephen Opat, Nele Fourneau, Yue Guo, Changchun Deng, Pau Abrisqueta, Brendan Paul Hodkinson, Isabel Soriano Paradinas, Yu Cao
article en

Abstract

Abstract 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.

Blood Cancer Discovery
Johnson & Johnson (United States) (US), Memorial Sloan Kettering Cancer Center (US), Janssen (Belgium) (BE), Tel Aviv University (IL), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), University of California, Irvine (US), Université de Lille (FR), Peking Union Medical College Hospital (CN), Institut Gustave Roussy (FR), Sir Charles Gairdner Hospital (AU), UNSW Sydney (AU), Johnson & Johnson (Switzerland) (CH), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Johnson Engineering (United States) (US), GNA University (IN), Institut universitaire du cancer de Toulouse Oncopole (FR), Hospices Civils de Lyon (FR), Prince of Wales Hospital (AU), Hôpital Lyon Sud (FR), Monash Health (AU), Vall d'Hebron Hospital Universitari (ES), Azienda Socio Sanitaria Territoriale Lariana (IT), Irvine University (US), Janssen (United States) (US), Johnson & Johnson (Brazil) (BR), University of Bologna (IT)
Good health and well-being
Openalex Percentile: Top 16%
NF-κB Signaling Pathways
DOIOpen Access PDFOpenAlex
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