Trium study: Exploring MRD-guided triplet therapy with sonrotoclax, zanubrutinib, and CD20mab in Untreated Mantle Cell Lymphoma: A prospective, multicenter, Phase II Study

Abstract Background Targeted therapy-based induction regimens provide novel treatment options for newly diagnosed mantle cell lymphoma (MCL). Recent studies have demonstrated the promising efficacy of triple-drug combinations comprising BCL-2 inhibitors, BTK inhibitors, and CD20 monoclonal antibodies (e.g., IVO, IVR, AVO, ZVO). Sonrotoclax (BGB-11417), a next-generation BCL-2 inhibitor, exhibits higher selectivity and pharmacological potency than venetoclax, with a shorter half-life and no drug accumulation. Zanubrutinib, a next-generation BTK inhibitor, has shown favorable safety and efficacy profiles in treatment-naïve (TN) MCL patients. Objective To evaluate the efficacy and safety of sonrotoclax-containing, chemotherapy-free triplet induction therapy in TN MCL. Methods This open-label, single-arm, multicenter trial (NCT06463691) enrolled treatment-naïve MCL patients. Patients received zanubrutinib (160 mg BID) plus zuberitamab, a novel CD20mab with enhanced antibody-dependent cellulal cytotoxicity, for 2 cycles as lead-in treatment. Sonrotoclax was added at Cycle 3 Day 1 with dose escalation to target 320 mg daily. Triplet therapy continued through Cycle 12. After induction, patients achieving complete remission (CR) with undetectable minimal residual disease (MRD) without high-risk features would receive 1 year of sonrotoclax plus zanubrutinib, followed by 1 year of zanubrutinib monotherapy. Patients assessed as partial response (PR), or MRD-positive, or with high-risk, and who in the judgment of the investigator, are frail or intolerant of transplantation or intensive chemotherapy, would receive the same maintenance therapy as CR patients. Others would receive R-DHAP consolidation (4 cycles), with transplant eligibility assessed per investigator, followed by zanubrutinib maintenance. High-risk features were defined as blastoid histology, Ki-67 ≥30%, TP53 aberration, and simplified MIPI score >6. Patients who meet any one of the features are considered high risk. The primary endpoint was the CR rate after triplet induction. Secondary endpoints included ORR, PFS, OS, MRD negative rate, and safety. And at the end of Cycle 6, patients received an evaluation by CT to assess the efficacy of the triplet regimen. Results At the data cutoff (June 27, 2025), 30 patients were enrolled (median age 62 years [range 42-88]; 80% male). 86.7% (26/30) of patients had stage III/IV disease, and 76.7% (23/30) had extranodal involvement. Twenty patients were high-risk: 80% (16/20) had high Ki-67, 60% (12/20) had elevated as high MIPI scores, and among the TP53 evaluable patients, 5% (1/20) had TP53 aberrations. At baseline, among the 24 patients who underwent MRD assessment, with both bone marrow and peripheral blood samples testing positive. Twenty-eight patients initiated treatment: 4 in the lead-in phase, and 24 received sonrotoclax (13 patients have completed dose escalation to 320mg). At Cycle 6, among 10 evaluable patients (by CT), 8 patients showed CR, 1 patient achieved PR, and 1 patient experienced disease progression after lead-in treatment. Among these, MRD results were available for 3 patients, all achieving undetectable MRD(uMRD) status. With a median duration of treatment of 4.3 months (range, 1.5-11), treatment-related serious adverse events occurred in 2 patients (1 thrombocytopenia and 1 upper-gastrointestinal haemorrhage). No clinical or laboratory tumor lysis syndrome, atrial fibrillation/flutter, or additional sonrotoclax-related safety signals were observed. Conclusions The preliminary results indicate sonrotoclax combined with zanubrutinb and zuberitamab showed promising efficacy, with manageable toxicity and tolerability. The study is ongoing, and further results and details will be updated.