Safety and Efficacy of Rocbrutinib in Patients with Relapsed/Refractory Marginal Zone Lymphoma

Background: Marginal zone lymphoma (MZL) comprises approximately 8% to 12% of non-Hodgkin lymphomas (NHL), characterized by malignant cells that consistently rely on B-cell receptor signaling. Covalent Bruton's tyrosine kinase inhibitors (cBTKis) have shown activity in relapsed or refractory (R/R) MZL, achieving an overall response rate (ORR) of 40-60%. Rocbrutinib, a new-generation BTKi, is highly selective with excellent bioavailability and a unique dual binding mechanism: covalent binding, otherwise non-covalent with C481 mutation. Here, we present the efficacy and safety outcomes of rocbrutinib in patients with R/R MZL enrolled in an ongoing phase 1 study (NCT04993690) in B-cell malignancies.

Methods: Patients with R/R MZL who received ≥1 line of prior therapies, including an anti-CD20 antibody-containing regimen, were enrolled. Adverse events (AEs) were graded per CTCAE v5.0 and disease responses were assessed per Lugano 2014 response criteria.

Results: Between 30 July 2021 and 31 May 2024, 30 R/R MZL patients were enrolled and received treatment of rocbrutinib at 100mg (n=3), 150mg (n=21) and 200mg (n=6) QD respectively, till disease progression or unacceptable toxicities. The median age was 65 (range, 32 to 79) years. 22 were with extra-nodal MZL (73.3%), and 5 nodal MZL (16.7%). Most patients (90%) were with advanced-stage disease; 46.7% had intermediate to high-risk disease per International Prognostic Index (IPI). All 30 patients received at least one prior line of CD20-based treatment per study eligibility. The median line of prior therapies was 1 (range, 1-4), and 26.7% of patients had refractory disease at study entry.

The most common treatment emergent adverse events (TEAEs) (occurring in ≥20% patients) were platelet count decreased or thrombocytopenia (30.0%), white blood cell count decreased (26.7%), serum creatinine increased (23.3%), petechiae (23.3%), infectious pneumonia (23.3%), neutrophil count decreased or neutropenia (20.0%) and hyperuricemia (20.0%), most of which were Grade 1. 13 (43.3%) patients experienced ≥grade 3 TEAE. Serious AEs occurred in 9 (30.0%) patients. Dose interruptions and dose reductions due to AEs were observed in 8 patients (26.7%) and 1 patient (3.3%), respectively; however, no AE led to drug discontinuation. One fatal case of hypotension was assessed by the investigator as unlikely related to the study treatment.

Of 29 efficacy evaluable patients with median follow-up of 10.9 months (range: 2.0-32.0), 21 (72.4%) achieved response including 3 (10.3%) complete response (CR). The ORR for the extra-nodal (n=21), nodal (n=5), and unknown (n=3) subtypes was 76.2%, 80.0%, and 33.3%, respectively. For the 13 patients who had received ≥2 lines of prior therapies, the ORR was 53.8% with a CR rate of 15.4%. Among the 7 patients who had refractory disease, the ORR was 71.4%. Of 2 patients who had progressed on prior cBTKi, 1 (50.0%) responded to rocbrutinib. As of data cutoff, the median duration of response (DOR) and median progression-free survival (PFS) have not reached.

Conclusion: Rocbrutinib is well tolerated and has shown promising anti-tumor activity in terms of response rate in patients with R/R MZL. Longer follow-up is needed to assess the long-term benefit.

Chen:Newave Pharmaceutical Inc.: Current Employment, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Newave Pharmaceutical Inc.