News|Articles|April 23, 2026

First Bispecific-ADC Combo Shows Strong Results in R/R Mantle Cell Lymphoma

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Key Takeaways

Subcutaneous mosunetuzumab with step-up dosing plus six cycles of polatuzumab vedotin enabled fully outpatient delivery without mandatory hospitalization, aligning with access and cost-reduction goals.
Efficacy substantially exceeded historical expectations in post-BTKi MCL, achieving 88.1% ORR and 78.6% CR by independent review, with responses consistent across subgroups.
High-risk biology did not abrogate benefit; TP53-aberrant disease achieved 100% ORR and 90% CR, suggesting activity in traditionally treatment-refractory molecular subsets.
Post–CAR T outcomes were strong (90.9% ORR; 81.8% CR), including responses in prior CAR T nonresponders, supporting utility as a salvage option after cellular therapy.
Safety was characterized by low-grade, early-resolving CRS (no grade ≥3) and rare, reversible ICANS, but infections were frequent and all grade 5 events were infection-related.

Mosunetuzumab, a bispecific, plus polatuzumab vedotin, an antibody-drug conjugate, deliver high response rates in relapsed MCL, potentially enabling outpatient community oncology treatment and wider patient access.

A phase 2 study published this week in Blood reports promising outcomes for a novel combination of a bispecific antibody and an antibody drug conjugate (ADC) in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), a difficult-to-treat B-cell cancer that accounts for roughly 6% of all non-Hodgkin lymphomas (NHLs).^1,2

“Consequently, there remains an urgent need for novel treatment strategies that improve survival outcomes in these challenging patient subsets,” the authors wrote in the study, published Tuesday.¹

The open-label, multicenter, phase 1b dose-escalation and phase 2 dose-expansion study of mosunetuzumab and polatuzumab vedotin, or PV, in patients with B-cell NHL (NCT03671018) is the first to combine the bispecific and ADC drug classes in MCL. It could represent an important advance for a disease that remains incurable and carries a worsening prognosis with each successive relapse, said the authors, who came from leading academic institutions such as City of Hope and The University of Texas MD Anderson Cancer Center, as well as the Sarah Cannon Research Institute, which conducts early-phase trials in the community setting.City of Hope’s L. Elizabeth Budde, MD, PhD, led the study.

The regimen pairs Genentech’s subcutaneous mosunetuzumab (Lunsumio Velo), a CD20xCD3 T-cell engager, with the company’s PV (Polivy), an anti-CD79b therapy that delivers a potent antimitotic payload, monomethyl auristatin E, directly to lymphoma cells.In December 2025, the FDA approved subcutaneous mosunetuzumab to treat R/R follicular lymphoma.³ Polatuzumab vedotin is approved to treat both frontline and R/R LBCL.

“By targeting distinct pathways, mosunetuzumab in combination with polatuzumab vedotin has the potential to mitigate drug resistance and achieve clinical activity across multiple B-cell malignancies,” the authors wrote.¹

In this study, mosunetuzumab was administered subcutaneously for up to 17 cycles on a 21-day schedule, with a step-up dosing strategy in cycle 1 to reduce the risk of cytokine release syndrome (CRS). PV was given intravenously at 1.8 mg/kg for the first 6 cycles.¹Of note, treatment was delivered entirely in the outpatient setting without mandatory hospitalization, consistent with recent efforts to reduce inpatient administration of novel therapies in blood cancers to reduce costs and increase access.

Patient population. Forty-two patients with relapsed/refractory MCL were enrolled between May 2021 and February 2024. All had received at least 2 prior lines of therapy including a Bruton tyrosine kinase (BTK) inhibitor—a standard backbone of MCL treatment—and 92.9% were refractory to their most recent treatment. The population was heavily pretreated, with a median of 3 prior therapies (range, 2-9). Notably, 26% had previously received chimeric antigen receptor (CAR) T-cell therapy.

Results showed 71.4% of the patients had 3 or more high-risk disease features associated with aggressive disease and poor outcomes. A Ki-67 proliferation index of 50% or greater was seen in 67% of patients, TP53 aberrations were seen in 48% of the patients, and blastoid or pleomorphic morphology was present in 38% of patients.

Efficacy. Response rates were high and consistent across subgroups. The primary end point, which was the objective response rate (ORR) as assessed by an independent review committee, was 88.1% (95% CI, 74.4%-96.0%; P < .0001), which far exceeded the historical control rate of 30% for this setting. The complete response (CR) rate was 78.6% (95% CI, 63.2%-89.7%), with other results showing:

With a median follow-up of 15.9 months, the median progression-free survival (PFS) was 18.6 months, and the 12-month overall survival (OS) rate was 83.1%. Median OS was 20.7 months. However, the authors cautioned that PFS data were immature.
In the 20 patients with TP53-aberrant MCL, a condition resistant to many therapies, the ORR was 100% and the CR rate was 90%, with outcomes mirroring those of the overall population.
Among the 11 patients who had already been treated with CAR T-cell therapy, the combination produced an ORR of 90.9%, with a CR rate of 81.8%. The median PFS in this subgroup was 15.8 months and the 12-month OS rate was 81.8%, with a median OS of 15.8 months.
Even among the 3 patients who had not responded at all to prior CAR T therapy, 2 achieved a CR and 1 achieved a partial response with the bispecific-ADC combination.

Safety. The safety profile was considered manageable. CRS, the most feared toxicity of T-cell engaging therapies, occurred in 42.9% of patients but was limited to low-grade events (grade 1 in 28.6%, grade 2 in 14.3%). All CRS events resolved within cycle 1. Immune effector cell–associated neurotoxicity syndrome (ICANS) was investigator-reported in 1 patient and identified retrospectively in 2 additional patients, all resolving without lasting consequence.

The most common adverse events (AEs) of any grade were fatigue (59.5%), injection site reaction (57.1%), diarrhea and neutropenia (45.2% each), and nausea (40.5%). Grade 3/4 AEs occurred in 69% of patients, with severe neutropenia being the most common serious hematologic toxicity (40.5%). Infections were common, reported in 73.8% of patients, and all 5 fatal AEs (grade 5) were infection related—3 from COVID-19, 1 from pneumonia, and 1 from West Nile virus encephalitis. Treatment discontinuation due to adverse events occurred in 23.8% of patients.¹

The authors concluded that the combination of mosunetuzumab and polatuzumab vedotin offers high remission rates in MCL even in patients with ultra-high-risk disease and prior CAR T-cell therapy failure—a group with very few remaining options. “By also offering meaningful safety and logistical advantages, [the combination] represents an accessible and practical outpatient-based therapy, and is a potentially important therapeutic option for patients with relapsed/refractory MCL.”

Further study, including how best to sequence this regimen among other newer MCL therapies, is warranted, they wrote.

References

Budde LE, Kamdar M, Assouline S, et al. Mosunetuzumab plus polatuzumab vedotin in relapsed/refractory MCL after BTK inhibitor therapy: a phase 2 study. Blood. Published online April 21, 2026. doi:10.1182/blood.2025032422
Koff JL, Chihara D, Phan A, et al. To each its own: linking the biology and epidemiology of NHL subtypes. Curr Hematol Malig Rep. 2015;10(3):244-255. doi:10.1007/s11899-015-0267-0
Joszt L. FDA approves subcutaneous mosunetuzumab for R/R follicular lymphoma. AJMC^®. December 22, 2205. Accessed April 23, 2026. https://www.ajmc.com/view/fda-approves-subcutaneous-mosunetuzumab-for-r-r-follicular-lymphoma