Mosunetuzumab plus polatuzumab vedotin in relapsed/refractory MCL after BTK inhibitor therapy: a phase 2 study

Patients with relapsed/refractory mantle cell lymphoma (MCL), especially those progressing after Bruton tyrosine kinase (BTK) inhibitor and/or chimeric antigen receptor (CAR) T-cell therapy and those with high-risk features, have poor outcomes. The bispecific antibody, mosunetuzumab, combined with the antibody-drug-conjugate (ADC), polatuzumab vedotin (Mosun-Pola), targets CD20 and CD79b via independent cell-killing mechanisms. In this multicenter phase 2 study, patients with MCL who had received ≥2 prior lines of therapy, including a BTK inhibitor, were enrolled. Patients received outpatient fixed-duration mosunetuzumab subcutaneously (17 cycles), with Cycle 1 step-up dosing to mitigate cytokine release syndrome, and polatuzumab vedotin (1.8 mg/kg intravenously) for 6 cycles. The primary endpoint was centrally assessed best objective response rate. Forty-two patients with a median of 3 prior therapies were enrolled; 26% had prior CAR T-cell therapy. A number of patients had MCL with high-risk features (Ki-67 ≥50%, 67%; blastoid/pleomorphic morphology, 38%; TP53 aberration, 48%). Objective response occurred in 88.1% of evaluable patients (95% CI, 74.4-96.0) and complete response in 78.6% (95% CI, 63.2-89.7). With a median follow-up of 15.9 months, median progression-free survival was 18.6 months (95% CI, 13.9-not estimable). Consistent efficacy was observed in high-risk subgroups. Cytokine release syndrome occurred in 42.9% of patients and was limited to Grade 1-2 events. Mosun-Pola achieved high complete remission rates while maintaining a manageable safety profile in patients with relapsed/refractory MCL exhibiting high-risk features. This is the first bispecific-ADC combination therapy study in MCL. (Funded by F. Hoffmann-La Roche Ltd; ClinicalTrials.gov, NCT03671018).