What Makes M-Pola Superior to R-GemOx in Transplant-Ineligible LBCL?

Results from the SUNMO trial showed that mosunetuzumab plus polatuzumab vedotin achieved a complete response rate of 51.4% in this LBCL population.

At the Society of Hematological Oncology 2025 Annual Meeting, newly presented results from the phase 3 SUNMO trial (NCT05171647) demonstrated that combination therapy with mosunetuzumab-axgb (Lunsumio) plus polatuzumab vedotin-piiq (Polivy; M-Pola) showed a 59% reduction in the risk of progression or death compared with rituximab (Rituxan) with gemcitabine and oxaliplatin (R-GemOx).¹ The 12-month progression-free survival (PFS) rate was 48.5% (95% CI, 39.6%-57.4%) with M-Pola and 17.8% (95% CI, 5.4%-30.3%) with R-GemOx.

The complete response (CR) rate was 51.4% with M-Pola vs 24.3% with R-GemOx, respectively, with overall response rates (ORRs) of 70.3% and 40.0%; at 1 year, approximately 75% of patients with a CR who received M-Pola were still in remission. The 12-month overall survival (OS) was 61.4% (95% CI, 53.0%-69.8%) with M-Pola compared with 53.4% (95% CI, 40.9%-65.8%) with R-GemOx.

Regarding safety, any treatment-related adverse event (TRAE) occurred in 93.3% of the M-Pola group and 89.1% of the R-GemOx group, grade 3 to 4 TRAEs occurred in 52.6% vs 51.6%, and AEs leading to study drug discontinuation occurred in 2.2% and 4.7%.

CancerNetwork® spoke with Adam J. Olszewski, MD, an associate professor of medicine at The Warren Alpert Medical School of Brown University, and the presenting study author of the SUNMO data, at the conference.

CancerNetwork®: Why was M-Pola compared with R-GemOx in ASCT-ineligible relapsed/refractory large B-cell lymphoma?

Olszewski: There is still a high unmet need for patients who have relapsed/refractory large B-cell lymphoma and who are unable to access or undergo potentially curative treatments. Historically, this involves chemotherapy and autologous stem cell transplantation, and now, more commonly in the US, [it is] CAR T-cell therapy. Studies show that a substantial proportion of patients are unable to access this treatment, or, for different reasons, are ineligible to get it. We had previously shown in a phase 2 trial that the combination of mosunetuzumab with polatuzumab vedotin provided high response rates, which appeared to be durable, and that led to the global effort to provide this therapy as an experimental arm for a global phase 3 trial comparing it with R-GemOx, which is a commonly prescribed chemotherapy regimen for these patients. This trial was conducted in multiple countries across many continents, and this treatment was delivered safely [in outpatient settings] for the 208 patients enrolled in this trial. With positive results, we think that this will create an additional option for these patients beyond R-GemOx chemotherapy, which, admittedly, is suboptimal, as we have known for many years.

How was this trial designed?

Patients had to have at least 1 line of prior therapy, and about 40% of patients had only 1 line of prior therapy. About 60% of patients on this trial were refractory to their primary therapy. These were patients who were relapsing soon after completing their [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] or [other] first-line treatment. This trial, [unlike] some other recently reported trials, enrolled high-grade B-cell lymphomas, apart from diffuse large B-cell lymphoma, as well as transformed lymphomas and grade IIIb follicular lymphoma. Patients were randomly assigned in a 2:1 ratio between the experimental regimen, which involves subcutaneous mosunetuzumab for 8 cycles and intravenous polatuzumab vedotin using standard familiar doses of 4 to 6 cycles. The comparator arm was the R-GemOx delivered by design every 14 days, although in some patients it was delayed up to every 21 days. The study enrolled a total of 208 patients. This was a fixed-duration therapy, so all patients in the experimental arm completed therapy after 8 cycles of mosunetuzumab.

How did M-Pola perform in this population?

The trial had, interestingly, a dual primary end point for both ORR and PFS. Both were accounted for statistically, and the trial was terminated early because early analysis of the ORR demonstrated statistically significant improvement. Ultimately, the trial enrollment was terminated by the data safety monitoring boards. Both ORR and the PFS were improved with M-Pola compared with R-GemOx. Most importantly, the PFS was extended from 3.8 months for R-GemOx, which, as we know, is very suboptimal, to 11.5 months [for M-Pola]. It’s tripled or more compared with the control arm. The ORR was 70% with 51% of patients attaining complete response, which is also significantly better than the 40% response rates observed with R-GemOx. Both from the point of view of response rates, complete response rates, and the PFS, the experimental regimen with M-Pola provided benefit for patients.

The primary analysis of PFS was conducted just this year, and there are not enough events for the appropriate power for the OS analysis. The final OS analysis will have to wait until there is a sufficient number of events, but at first look and without statistical testing, there appears to be an improvement in OS by about 8 points at 1 year. Also, the median OS appears to be longer [for M-Pola] than with the control arm. Right now, the HR is 0.8, but the statistical test will have to wait until more events are seen. We remain optimistic that there will be some OS improvement as well, although we have to understand that these patients, compared with some other trials, had access to CAR T-cells and bispecific therapy, so demonstrating OS benefits may not be as easy as in the past.

How was the safety profile of the agent?

This is a unique regimen that does not involve any traditional cytotoxic chemotherapy. Even though the overall rate of AEs was similar between the 2 arms, there were very different adverse effects. Patients [who received] M-Pola did not experience the typical adverse effects of chemotherapy, with a lot of cytopenias, nausea, tiredness, and there were more local injection site reactions from mosunetuzumab, but they are all very low grade and easily manageable. Most importantly, the rate of cytokine release syndrome [CRS] was quite low with this regimen. It’s the lowest among all studied T-cell-engaging therapies, with only 26% of patients having any CRS, and almost all these events being grade 1. As we describe it, 96% of patients receiving this regimen did not have any significant CRS beyond fever that can be easily managed, and the rate of use of these high-intensity resources like tocilizumab [Actemra] or corticosteroids in patients was only 4%.

In general, this regimen has toxicities; the rate of infections was higher than in the R-GemOx arm, partly because of [COVID-19] infections, which obviously are continuing to occur, but the rate of serious infections was similar between the arms. The rate of grade 3/4 infections was similar. The rate of fatal adverse events was very low in both arms. This is a regimen that can be delivered [in an outpatient setting] from my perspective and my patients’ perspective, in a very tolerable manner. [There are] certainly fewer annoying daily adverse effects, including neuropathy, which was expected to occur with blood; there was significantly less in the M-Pola arm than with R-GemOx. This regimen is quite tolerable for older outpatients who, by definition, are not eligible to get curative, more intense therapy.

We’re very excited that this regimen has such low toxicity that it appears to be easily deliverable in community settings. We think this may contrast with some other therapies, including CAR T-cells or bispecific agents that have higher rates of CRS, where many community practices have some reservations about providing these services. This treatment can be managed in outpatient settings, without any elective hospitalizations, minimal use of high-intensity resources, and this is partly because of the use of [polatuzumab vedotin], which significantly lowers the CRS rates when combined with bispecific agents, and mostly doesn’t have a lower rate of CRS than other bispecifics. From the point of view of both patients, especially those who have to travel or who are not willing to take treatments that could potentially cause the risk of CRS or immune-effector cell-associated neurotoxicity syndrome [ICANS]. Since ICANS was not observed in this trial at all, this is an option that provides them more confidence that they will be able to go through the first few cycles without hospitalization or major toxicities.

What are the next steps for research?

As a community, we will find ourselves with a lot of different second-line options for patients with relapsed/refractory diffuse large B-cell lymphoma beyond CAR T cells. We will have to ultimately understand which patients are most appropriate for which treatment in what setting. This may differ for academic settings and centers that can easily deliver CAR T-cell therapy vs centers that have challenges with accessing this or patients.

The next research steps are currently under question. We would love to have a comparative study between bispecific antibodies and CAR T cell therapy, but it’s going to be very difficult to execute. We’ll have to see over the next couple of years where each of these agents will find their way into their first-line treatments and will fall off as a second-line option. We will have to see what the exposure of patients on first-line polatuzumab vedotin is since M-Pola was delivered to patients who were not primary refractory to polatuzumab vedotin. If patients had a progression within 12 months of completing [Pola-R-CHOP], they would not be eligible for this regimen. Where this will stand in a couple of years, we’ll have to see. But altogether, many practitioners have a feeling that delivery of bispecifics in the outpatient setting in the community will be easier than deploying CAR T cells, especially on a global scale.

References

Westin J, Zhang H, Kim W, et al. Mosunetuzumab plus polatuzumab vedotin is superior R-GemOx in transplant-ineligible patients with R/R LBCL: primary results of the phase III SUNMO trial. Presented at the Society of Hematological Oncology 2025 Annual Meeting; September 2-6, 2025; Houston, TX. Abstract ABCL-1492.