TOPLINE

In a small open-label phase 2 trial of patients with heavily pretreated relapsed/refractory mantle cell lymphoma (MCL), fixed-duration mosunetuzumab plus polatuzumab vedotin was associated with high rates of objective responses (88%) and complete responses (nearly 80%). However, serious and grade ≥ 3 adverse events were common.

METHODOLOGY

• Patients with relapsed/refractory MCL who progress after Bruton tyrosine kinase (BTK) inhibitor and CAR T-cell therapy, as well as those with high-risk disease features, have poor outcomes. Studies suggest that mosunetuzumab monotherapy can yield promising response rates, and polatuzumab vedotin has shown limited but encouraging activity in MCL.
• To examine whether the combination could improve outcomes in this high-risk setting, researchers conducted a multicenter, phase 2 study of 42 patients (median age, 68.0 years; 73.8% men) with relapsed/refractory MCL who had received at least two previous lines of therapy, including a BTK inhibitor. 
• Patients received subcutaneous mosunetuzumab for a total of 17 cycles. Polatuzumab vedotin (1.8 mg/kg intravenous infusion) was given before each mosunetuzumab dose on day 1 of cycles 1-6. 
• The primary efficacy endpoint was independent review committee-assessed best objective response rate based on PET-CT and/or CT scan. Secondary efficacy endpoints included best complete response rate, duration of response, progression-free survival, and overall survival. The median follow-up duration was 15.9 months. 
• Participants had a median of three previous therapies, with 26% having received previous CAR T-cell therapy. More than 70% had at least three high-risk features; individual features included TP53 aberration (47.6%), a Ki-67 proliferation index of ≥ 50% (66.7%), and blastoid/pleomorphic morphology (38.1%).

TAKEAWAY

• Overall, centrally assessed objective response rate was 88.1%, exceeding the prespecified historical control rate of 30%, and the complete response rate was 78.6%. The median durations of both objective response and complete response were not reached. 
• Median progression-free survival was 18.6 months, with a 12-month progression-free survival rate of 74.8%; median overall survival was 20.7 months, with a 12-month rate of 83.1%. 
• In exploratory subgroup analyses, objective response rates were high across patients with TP53-aberrant disease (100%), high Ki-67 (92.9%), blastoid/pleomorphic variants (93.8%), and prior CAR T-cell therapy (90.9%).
• Grade 3/4 adverse events occurred in 69.0% of patients, with 59.5% experiencing treatment-related events; serious adverse events occurred in 61.9%. The most common adverse events were fatigue (59.5%), injection site reactions (57.1%), diarrhea and neutropenia (45.2% each), and nausea (40.5%). Cytokine release syndrome occurred in 42.9% of patients, though all were limited to grade 1 (28.6%) or grade 2 (14.3%) events occurring during cycle 1.

IN PRACTICE

“If these early findings from a relatively small cohort (n = 42) with limited follow-up (15 months) are confirmed, the combination of mosunetuzumab plus polatuzumab could represent an urgently needed therapeutic strategy for patients with few attractive US Food and Drug Administration-approved options,” remarked Peter Martin, New York University Langone, in an accompanying editorial.

SOURCE

The study was led by Lihua E. Budde of City of Hope National Medical Center in Duarte, California, and Manali Kamdar of the University of Colorado Cancer Center in Aurora, Colorado. It was published online in Blood.

LIMITATIONS

The study was limited by its small sample size, single-arm phase 2 design, and lack of a randomized comparator; efficacy was instead assessed against a prespecified historical control rate. The relatively short median follow-up of 15.9 months also limits assessment of the durability of responses and long-term survival. Exploratory subgroup findings should be interpreted cautiously given the small numbers of patients in each subgroup. In addition, some biological risk features may have been underestimated at baseline because they can emerge or evolve over the course of the disease.

DISCLOSURES

This study was supported by F. Hoffmann-La Roche Ltd. Budde reported receiving consulting/advisory roles with multiple organizations, including F. Hoffmann-La Roche Ltd./Genentech Inc., as well as travel support, patents and intellectual property, and research funding. Kamdar reported receiving consulting/advisory roles with AbbVie, AstraZeneca, BeOne Medicines, Celgene/Bristol Myers Squibb, and Genentech Inc.; speakers bureau participation with Seagen; research funding from Novartis; and expert testimony fees from Terumo. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.