MCL-135 BRUIN MCL-321, a Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Investigator Choice of BTK Inhibitor in Patients With Previously Treated, BTK Inhibitor Naïve Mantle Cell Lymphoma (Trial in Progress)

Context: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of relapsed mantle cell lymphoma (MCL), but many patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type and C481-mutated BTK with equal low nM potency. Objective: Determine whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naïve MCL. Design: BRUIN MCL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy (ibrutinib, acalabrutinib, or zanubrutinib) in patients with previously treated, BTKi-naïve MCL. Approximately 500 patients will be randomized 1:1. Randomization will be stratified by sMIPI risk (low/intermediate vs high), comparator BTKi (ibrutinib vs acalabrutinib/zanubrutinib), and number of prior lines of therapy (1 vs ≥ 2). Setting: Global; community hospitals, academic medical centers. Patients: Eligible patients are adults aged ≥18 years with a confirmed diagnosis of MCL who received ≥ 1 prior line of systemic therapy for MCL that did not include a prior BTKi. Patients must have measurable disease per Lugano criteria and must have progressed on or relapsed following the most recent line of therapy prior to study enrollment. Key exclusion criteria include a history of current or prior CNS involvement, significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of randomization, and allogeneic stem cell transplant (SCT), autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. Interventions: Pirtobrutinib monotherapy versus investigator's choice of covalent BTKi monotherapy. Main Outcome Measures: The primary endpoint is progression-free survival (PFS) per Lugano criteria assessed by an independent review committee, with the goal of demonstrating the superiority of pirtobrutinib over the investigator's choice of covalent BTKi. Secondary endpoints include overall response rate, duration of response, investigator-assessed PFS per Lugano criteria, overall survival, event-free survival, time to treatment failure, time to next treatment, PFS2 (time from randomization to disease progression on next line of treatment or death from any cause), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04662255). Results: Trial in Progress. Conclusions: Trial in Progress.