Fixed-Duration Mosunetuzumab/Polatuzumab Active in R/R MCL

Among 42 patients, 88% responded to treatment.

Mosunetuzumab-axgb (Lunsumio) combined with polatuzumab vedotin-piiq (Polivy) achieved durable responses and showed a manageable safety profile in patients with relapsed or refractory mantle cell lymphoma (MCL) previously treated with a BTK inhibitor, according to data from the MCL dose-expansion cohort of a phase 2 trial (NCT03671018) presented at the 2025 SOHO Annual Meeting.¹

Among all treated patients (n = 42), the overall response rate (ORR) was 88%; the complete response (CR) and partial response (PR) rates were 79% and 9%, respectively. The efficacy of this combination was observed across high-risk patient subgroups, including those at least 70 years of age (n = 18; ORR, 83%; CR rate, 78%; PR rate, 5%), those who had received prior CAR T-cell therapy (n = 11; 91%; 82%; 9%), those with a Ki-67 score of at least 50% (n = 28; 93%; 79%; 14%), those with pleomorphic or blastoid MCL (n = 16; 94%; 69%; 25%), and those with TP53 mutations or deletions (n = 13; 100%; 92%; 8%).

“Mosunetuzumab and polatuzumab vedotin, in my opinion, is going to be a good off-the-shelf option for relapsed/refractory MCL before or after CAR T-cell therapy,” lead study author Michael L. Wang, MD, said in the presentation.

Wang is a professor in the Department of Lymphoma/Myeloma and the Department of Stem Cell Transplantation in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

What Was the Rationale for Investigating Mosunetuzumab in Combination With Polatuzumab Vedotin in Patients With MCL?

Mosunetuzumab is a CD20xCD3-directed, T-cell engaging bispecific antibody. Polatuzumab vedotin is a CD79-directed antibody-drug conjugate.

“The two are complementary in their mechanisms of action,” Wang noted. “They were synergistic in preclinical studies.”

Previous findings from the dose-expansion large B-cell lymphoma (LBCL) cohort (n = 98) of the phase 2 study showed that at a median follow-up of 23.9 months (95% CI, 21.3-26.8), mosunetuzumab plus polatuzumab vedotin elicited an ORR of 59.2% (95% CI, 48.8%-69.0%) and a CR rate of 45.9% (95% CI, 35.8%-56.3%).² Furthermore, the median duration of CR was not reached (NR; 95% CI, 20.5 months-not estimable [NE]).

What Was the Design of the MCL Portion of the Phase 2 Study of Mosunetuzumab Plus Polatuzumab Vedotin in Relapsed/Refractory MCL?

This phase 2 study is investigating the efficacy, safety, pharmacokinetics, and pharmacodynamics of mosunetuzumab plus polatuzumab vedotin in patients with B-cell non-Hodgkin lymphoma, including LBCL, follicular lymphoma, and MCL.³

The MCL cohort of this trial enrolled patients with relapsed/refractory MCL with an ECOG performance status of 0 to 2.¹ Patients needed to have received at least 2 prior therapies, including an anti-CD20 antibody, bendamustine or anthracycline therapy, and a BTK inhibitor.

Patients received the investigational combination in a fixed-duration treatment approach that included mosunetuzumab administered subcutaneously at 45 mg in 21-day cycles (5-mg step-up dosing occurred in cycle 1) for a total of 17 cycles; and intravenous polatuzumab vedotin administered at 1.8 mg/kg on day 1 of cycles 1 through 6. Hospitalization was not required. Patients received corticosteroid premedication before each dose in cycle 1.

ORR by independent review committee served as the primary end point. Secondary end points included best ORR by investigator assessment, CR rate, duration of response (DOR), duration of CR, progression-free survival (PFS), overall survival (OS), and safety.

What Were the Baseline Characteristics of Patients Included in the Trial?

Patients had a median age of 68 years (range, 44-82) and had received 3 prior lines of therapy (range, 2-9). Prior therapies included BTK inhibition (100%), CAR T-cell therapy (26%), and autologous stem cell transplant (31%). In total, 93% of patients were refractory to their last prior therapy. TP53 mutations or deletions were present in 39% of patients, 38% of patients had blastoid or pleomorphic disease, and 43% of patients had bone marrow involvement. Ki-67 scores of at least 30% and at least 50% were reported in 76% and 67% of patients, respectively. Additionally, 48% of patients had a simplified International Prognostic Index for MCL score of at least 6. Overall, 71% of patients had at least 3 high-risk features.

“This is a high-risk, heavily treated population,” Wang contextualized.

What Additional Efficacy Data Were Observed With Mosunetuzumab Plus Polatuzumab Vedotin?

The responses observed with this combination were early and durable, Wang noted. At a median follow-up of 15.9 months (95% CI, 13.6-29.0), among all responders (n = 37), the median time to first response was 2.7 months (range, 1-7), the median DOR was NR (95% CI, 11.4 months-NE), and the 12-month response rate was 66.0% (95% CI, 45.0%-86.9%). Among complete responders (n = 33), the median time to first CR was 2.8 months (range, 2-18), the median duration of CR was NR (95% CI, 11.4 months-NE), and the 12-month response rate was 71.9% (95% CI, 49.2%-94.6%).

Among all treated patients, the median PFS was 18.6 months (95% CI, 13.9-NE), and the 12-month PFS rate was 74.8% (95% CI, 60.2%-89.4%). The median OS was 20.7 months (95% CI, 17.0-NE), and the 12-month OS rate was 83.1% (95% CI, 71.7%-94.5%).

What Was the Safety Profile of Mosunetuzumab Plus Polatuzumab Vedotin in Patients With MCL?

All patients experienced adverse effects (AEs), and 93% of patients experienced treatment-related AEs (TRAEs). The rates of grade 3/4 AEs and TRAEs were 69% and 60%, respectively. Serious AEs and TRAEs were reported in 62% and 41% of patients, respectively. Grade 5 fatal AEs and TRAEs occurred in 12% and 2% of patients, respectively; these included COVID-19 pneumonia (n = 3), pneumonia (n = 1), and West Nile virus encephalitis (n = 1). Treatment discontinuation related to AEs and TRAEs occurred in 24% and 12% of patients, respectively. Patients received a median of 15 mosunetuzumab cycles (range, 1-17) and 6 polatuzumab vedotin cycles (range, 1-6).

AEs and TRAEs that occurred in at least 20% of patients included fatigue, injection site reaction, neutropenia/decreased neutrophil counts, diarrhea, cytokine release syndrome (CRS), nausea, dyspnea, constipation, cough, headache, pyrexia, thrombocytopenia/decreased platelet counts, COVID-19, and myalgia. AEs of interest included injection site reaction (grade 1, 52%; grade 2, 5%), peripheral neuropathy (grade 1, 29%; grade 2, 12%), immune effector cell–associated neurotoxicity syndrome (grade 2, 2%), infections (any grade, 71%; grade 3/4, 14%; grade 5, 12%), tumor flare (grade 1, 5%; grade 2, 7%), neutropenia/decreased neutrophil counts (any grade, 45%; grade 3/4, 41%), and febrile neutropenia (grade 3, 5%).

Notably, B-cell depletion occurred rapidly during treatment, and investigators observed recovery of B-cell counts following treatment.

What Were the Specific CRS Data Associated With Mosunetuzumab Plus Polatuzumab Vedotin?

Any-grade, grade 1, and grade 2 CRS occurred in 43%, 29%, and 14% of patients, respectively; no grade or 3 higher CRS was reported. On cycle 1 day 1, the respective rates of grade 1 and 2 CRS were 31% and 10%. On cycle 1 day 8, these respective rates were 5% and 7%. All CRS events resolved within cycle 1.

The median time to first CRS onset relative to the last dose of therapy was 2 days (range, 1-5), and the median duration of CRS was 3 days (range, 1-9). CRS management strategies included corticosteroids (14%), tocilizumab (14%), low-fluid oxygen (10%), fluids (7%), and treatment in an intensive care unit (2%).

“Mosunetuzumab plus polatuzumab vedotin is a well-tolerated outpatient regimen,” Wang concluded.

References

1. Wang ML, Kamdar M, Assouline S, et al. Fixed-duration outpatient subcutaneous mosunetuzumab + polatuzumab vedotin shows robust efficacy in a phase II study of relapsed/refractory post-BTKi mantle cell lymphoma. Presented at: 2025 SOHO Annual Meeting. September 3-6, 2025; Houston, TX. Abstract MCL-1493.
2. 2.Budde LE, Olszewski AJ, Assouline S, et al. Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial. Nat Med. 2024;30(1):229-239. doi:10.1038/s41591-023-02726-5
3. 3.A study to evaluate the safety and efficacy of mosunetuzumab (BTCT4465A) in combination with polatuzumab vedotin in B-cell non-Hodgkin lymphoma. ClinicalTrials.gov. Updated November 29, 2024. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT03671018