Mosunetuzumab Plus Polatuzumab Achieves Nearly 80% Complete Response Rate in Mantle Cell Lymphoma After BTK Inhibitors

A fixed-duration combination of mosunetuzumab (Lunsumio; Genentech) and polatuzumab vedotin (Polivy; Genentech) produced high response and complete remission rates in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) previously treated with a Bruton tyrosine kinase (BTK) inhibitor, according to phase 2 findings published in Blood.¹

Among 42 heavily pretreated patients, the independently assessed overall response rate (ORR) was 88.1% (95% CI, 74.4%-96.0%), including a complete response (CR) rate of 78.6% (95% CI, 63.2%-89.7%).¹ Responses were observed despite a high prevalence of adverse disease characteristics and previous exposure to advanced therapies, supporting further investigation of the bispecific antibody–antibody-drug conjugate (ADC) combination in a population with limited treatment options.¹

Study Evaluates Combination Following BTK Inhibitor Therapy

The multicenter, open-label phase 1b/2 study (NCT03671018) included adults with R/R MCL who had received at least 2 previous lines of therapy, including an anti-CD20 treatment, a BTK inhibitor, and either an anthracycline or bendamustine.¹^,² Patients had received a median of 3 previous lines of therapy, and 26% had previously undergone chimeric antigen receptor (CAR) T-cell therapy.¹

High-risk disease characteristics were common. Among evaluable patients, 67% had a Ki-67 proliferation index of at least 50%, 38% had blastoid or pleomorphic morphology, and 48% had a TP53 aberration.¹ These features are associated with particularly challenging disease biology and can complicate treatment after progression on BTK inhibitor therapy.¹^,³

Patients received subcutaneous mosunetuzumab in 21-day cycles for a fixed duration of up to 17 cycles, using step-up dosing during cycle 1 to mitigate the risk of cytokine release syndrome (CRS). Polatuzumab vedotin was administered intravenously at 1.8 mg/kg for 6 cycles. Treatment did not require mandatory hospitalization.¹^,²

Mosunetuzumab is a CD20-directed CD3 T-cell engaging bispecific antibody, whereas polatuzumab vedotin targets CD79b and delivers the cytotoxic agent monomethyl auristatin E to malignant B cells.¹ The combination therefore attacks lymphoma cells through distinct mechanisms.

Responses Extend Across High-Risk Subgroups

At a median follow-up of 15.9 months, median progression-free survival (PFS) was 18.6 months (95% CI, 13.9 months-not estimable), and median overall survival was 20.7 months (95% CI, 17.0 months-not estimable).¹ Median duration of response and duration of CR had not been reached.

The median time to first response was 2.7 months.¹ Investigators also reported activity among patients with high-risk characteristics, including those with TP53-aberrant disease and patients who had previously received CAR T-cell therapy.¹

An accompanying commentary in Blood highlighted the magnitude of the findings in the context of this difficult-to-treat population, noting that approximately three-quarters of patients remained free from disease progression at 12 months.³

Safety Profile Could Support Outpatient Administration

Grade 3 or 4 adverse events occurred in 69.0% of patients, with neutropenia occurring most frequently at 40.5%. Grade 3 or 4 anemia and pneumonia each occurred in 9.5% of patients.¹

CRS occurred in 42.9% of patients but was limited to grade 1 or 2 events; no grade 3 or greater CRS was reported.¹ Infections remained an important safety consideration, including serious and fatal infections. Mosunetuzumab carries warnings for CRS, neurologic toxicity including immune effector cell-associated neurotoxicity syndrome, serious infections, and cytopenias.⁴ Polatuzumab vedotin is additionally associated with myelosuppression, peripheral neuropathy, infections, and other toxicities.⁵

Neither agent is currently FDA approved for the treatment of MCL in this combination. Mosunetuzumab is approved for adults with R/R follicular lymphoma following at least 2 lines of systemic therapy, whereas FDA-approved polatuzumab vedotin indications are in large B-cell lymphoma settings.⁴^,⁵

The relatively low severity of CRS, subcutaneous administration of mosunetuzumab, fixed treatment duration, and absence of mandatory hospitalization may make the regimen particularly relevant to outpatient and community-based oncology practice if its efficacy and safety are confirmed in larger studies.¹^,³ Further research will also be needed to determine the optimal sequencing of the combination relative to CAR T-cell therapy and other emerging treatments for R/R MCL.

References

1. Budde LE, Kamdar M, Assouline SE, et al. Mosunetuzumab plus polatuzumab vedotin for relapsed/refractory MCL after BTK inhibitor therapy: a phase 2 study. Blood. 2026;148(6):682-692. doi:10.1182/blood.2025032422

2. ClinicalTrials.gov. A study to evaluate the safety and efficacy of mosunetuzumab (BTCT4465A) in combination with polatuzumab vedotin in B-cell non-Hodgkin lymphoma. NCT03671018. Accessed August 12, 2026. https://clinicaltrials.gov/study/NCT03671018

3. Peter Martin; How soon is now for new treatments for mantle cell lymphoma?. Blood 2026; 148 (6): 641–642. doi: https://doi.org/10.1182/blood.2026034444

4. US Food and Drug Administration. Lunsumio/Lunsumio Velo (mosunetuzumab-axgb) prescribing information. Genentech, Inc. Revised 2026. https://www.gene.com/medical-professionals/medicines/lunsumio

5. US Food and Drug Administration. Polivy (polatuzumab vedotin-piiq) prescribing information. Genentech, Inc. Revised March 2026. https://www.gene.com/download/pdf/polivy_prescribing.pdf