Mosunetuzumab Treatment Combo Yields Responses in High-Risk MCL

Mosunetuzumab-axgb (Lunsumio) plus polatuzumab vedotin-piiq (Polivy; M-Pola) achieved an overall response rate (ORR) of 88%, with a complete response (CR) rate of 79%, in all patients (n = 42) with mantle cell lymphoma included in an open-label, randomized phase 2 trial (NCT03671018). Furthermore, the combination achieved an ORR of 91%, with a CR rate of 82%, in those who received prior CAR T-cell therapy (n = 11); an ORR of 93%, with a CR rate of 79%, in those with a Ki-67 index score of 50% or higher (n = 28); and an ORR of 100%, with a CR rate of 92%, in patients with TP53 mutations/deletions.

The median duration of response and time to first response were not reached (NR; 95% CI, 11.4-not evaluable [NE]) and 2.7 months (95% CI, 1.0-7.0). Additionally, the median progression-free survival (PFS) and overall survival (OS) were 18.6 months (95% CI, 13.9- NE) and 20.7 months (95% CI, 17.0-NE), respectively.

Regarding safety, treatment-related adverse effects (TRAEs) occurred in 93% of patients, with grade 3 or 4 TRAEs occurring in 60%.

These results were most recently presented at the Society of Hematologic Oncology 2025 Annual Meeting by Michael Wang, MD, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center. During the conference, he spoke with CancerNetwork® about the results and what they mean for the mantle cell lymphoma treatment landscape.

CancerNetwork: Why was this phase 2 study evaluating M-Pola in relapsed/refractory MCL necessary?

Wang: We had 44 patients in this clinical trial, and many patients had high-risk factors. [For example], 71% of patients had 3 or more risk factors. Their [expected] survival is less than a year. But in this very heavily [pretreated] and sick population, we used this combination. Why did we use this combination? Because [with] the combination, mosunetuzumab attacks the CD20 antigen on the surface of a tumor cell, while [polatuzumab vedotin] targets the CD79b antigen on the surface of the cells. We are attacking 2 targets with 2 potent agents. Each agent has generated data in mantle cell lymphoma and large B-cell lymphoma. The combination is complementary to each other, and in preclinical work, it was synergistic.

How was the dosing for this trial determined?

Mosunetuzumab is a bispecific antibody targeting CD20, with a CD3 [component] to recruit T cells. There are at least 2 other monoclonal antibodies. Epcoritamab-bysp [Epkinly] is subcutaneous, and glofitamab-gxbm [Columvi] is [intravenous]. Mosunetuzumab is the first ever bispecific antibody developed in lymphoma and approved for lymphoma. Mosunetuzumab is made for [subcutaneous dosing], which is very good for outpatient dosage. Polatuzumab vedotin is an [intravenous infusion] drug, but it is only given for 6 cycles, on the first day of each cycle. After that, because the infusions are short, it can be given in outpatient settings.

What were the characteristics of the patients enrolled on the trial?

There were 44 patients with a median age of 68 years, their median [number of] prior therapies was 3, [and they received] all the way up to 9 cycles—some of the patients received 9 cycles. About 26% received prior CAR T cells, and 93% of people were refractory to the last therapy. This is a very bad risk factor.

Then, patients with TP53 mutations and deletions were 39% of [the population]. TP53 mutations make the tumor very resistant to therapy, and if you do respond with a TP53 mutation, the response duration is short. Next, pleomorphic and blastoid mantle cell lymphoma, which represents a worse morphological prognostic factor, was [seen] in 38% of the patients. [Overall], 71% of patients had 3 or more risk factors. This is very significant. This population typically, to the best of my knowledge, lives for around 6 months and certainly less than a year.

What were the primary findings with this treatment combination?

The primary objective was the ORR. The ORR in this population was 88%, [which is] probably a record in this population. The CR rate in this very hard-to-treat lymphoma [population] was 79%. This is tremendous, and this is a breakthrough in this very sick population. Not only was the ORR high at 88% [and] the CR rate was high at 79%, but across all the bad risk factors, the response rate was the same. That included older [patients], [patients with the] blastoid and pleomorphic subtype, and [those with] a Ki-67 [index score] over 50%. Most importantly, in patients with the TP53 mutation and deletion, the response rate was 100%. This is a very potent regimen.

Was there anything unexpected in the safety profile of this combination?

The safety [profile] was very light. Mosunetuzumab is a bispecific antibody; it can cause cytokine release syndrome [CRS] or immune-effector cell-associated neurotoxicity syndrome [ICANS]. The CRS [occurred in] 43% of patients as grade 1 or 2, and there were no grade 3, 4, or 5 CRS toxicities. All the CRS [events] were resolved within the first cycle. The neurotoxicity, which is also indicative of the bispecific antibody therapy, was also very rare, with only one [patient] with a grade 1 or 2 [event]; there were no grade 3 neurotoxicities.

There were 5 patients who died from infection after the combination was given, including 3 [cases of COVID-19] and pneumonia; this trial was done during the [COVID-19] pandemic. One [patient died of] pneumonia, and another died from West Nile virus, which is very rare. In this population that had received a median of 3 prior therapies plus our therapy, this was a cause of profound immune compromise, therefore giving rise to the infection rate.

What are the clinical implications of these newfound data?

When we have patients who have big tumors, whose tumors are TP53 mutated, [have a] Ki-67 [index score] over 50%, have blastoid or pleomorphic [subtype], [or have] all these horrible risk factors, and where chemotherapy, radiation therapy, or other therapies don’t seem to work—especially for those who received prior CAR T-cell therapies and relapsed after—their life expectancy is around 6 months. For that, this combination can rescue people with a median PFS of 18 months. [There’s a life expectancy] of less than 6 months, but median PFS was 18 months, and median OS was 21 months. This is tremendous. This will bridge to other therapies that are upcoming in clinical trials or other standard therapies. This is a lifesaving combination therapy.

What other therapies have shown promise in mantle cell lymphoma?

In the relapsed setting, prior to CAR T, we are planning to use this regimen in the front line. We could also probably combine this regimen with other therapies to make it even more effective. Those are the ideas that are being entertained at this point.

References

Wang ML, Kamdar M, Assouline S, et al. Fixed-duration outpatient subcutaneous mosunetuzumab + polatuzumab vedotin shows robust efficacy in a phase 2 study of relapsed/refractory (R/R) post-BTK inhibitor mantle cell lymphoma (MCL). Presented at the Society of Hematologic Oncology 2025 Annual Meeting; September 2-6, 2025. Houston, TX. Abstract MCL-1493.