Is There Space for Single-Agent Mosunetuzumab in Frontline MZL Care?

In all patients with marginal zone lymphoma (MZL), single-agent mosunetuzumab-axgb (Lunsumio) administered subcutaneously demonstrated an overall response rate of 78%, with a complete response rate in 64% and partial responses in 14%. The median progression-free survival (PFS) was not reached (NR; 95% CI, not evaluable (NE)-NE), with 6-month and 12-month event-free rates of 90.5% (95% CI, 73.4%-96.8%) and 83.6% (95% CI, 64.8%-92.8%), respectively.¹

Any grade adverse effects (AEs) occurred in 100% of patients, with grade 3/4 AEs occurring in 63.9%; the most common grade 3/4 AEs were neutropenia/neutrophil count decreased (27.8%) and anemia (11.1%). AEs led to mosunetuzumab discontinuation in 16.7% of patients.

Cytokine release syndrome (CRS) occurred in 36.1% of patients, with 22.2% being grade 1 and 13.9% being grade 2; the median CRS duration was 2.5 days (range, 1-7), and all patients had their CRS resolved. No events of immune-effector cell-associated neurotoxicity syndrome (ICANS) were reported.

These results from the phase 2 MorningSun trial (NCT02500407), which was a basket trial that evaluated mosunetuzumab in patients with relapsed/refractory B-cell non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, were most recently presented at the Society of Hematologic Oncology 2025 Annual Meeting by Tara M. Graff, DO, MS, director of Clinical Research at Mission Cancer and Blood in Des Moines, Iowa.

In the wake of her presentation, she spoke with CancerNetwork® about the implications of this trial’s findings for efficacy and tolerability.

CancerNetwork: What was the rationale for evaluating mosunetuzumab in MZL?

Graff: The rationale backing up the MorningSun trial is that, currently, mosunetuzumab is a CD3/CD20 bispecific antibody approved in relapsed/refractory follicular lymphoma in the third line setting, and it’s approved in an [intravenouns (IV)] formulation—there was a trial done that looked at studying mosunetuzumab in a [subcutaneous] formulation compared with IV to make sure that it was not inferior, and it proved not to be.² Then, with that, the MorningSun trial was born.

The MorningSun trial is basket trial looking at mosunetuzumab subcutaneous formulation across a number of different disease subtypes, [including] follicular lymphoma, both low tumor burden and high tumor burden, you have MZL and all subtypes of MZL and you have diffuse large B cell lymphoma for the elderly unfit population—those are all frontline treatments, so none of those patients have seen any therapy before.

You also have patients with relapsed/refractory mantle cell lymphoma…, transformed lymphoma, and then Richter’s transformation. Specifically, there’s an unmet need for our patients with frontline MZL. Typically, we use a combination of chemoimmunotherapy, but we want to improve on that in the same way we are improving on other types of lymphoma.

How was this trial designed regarding patient characteristics and dosing?

The whole goal of the trial was to develop a therapy that could be done on an outpatient basis, which means it’s easier to do in a community setting. It was a unique trial in that, typically, we think of clinical trials as being done in academic institutions. Fifty-five sites were in this trial, but two-thirds of them were community oncology practices. That’s where the patients live; the patients are in the community. This trial not only had a subcutaneous drug formulation for easy dosing [which is] more convenient for patients and [requires] less chair time. Patients could stay in their own beds and in their own towns. They didn’t have to travel to academic centers. They could be with their primary oncologist in those specific sites that were doing the trial. That was the whole goal.

What were the most significant efficacy takeaways from the MorningSun trial?

The most significant takeaway was that the median PFS was not reached. Currently, there are about 18 months of follow-up, and that is encouraging when you’re thinking about an indolent disease.

I can speak specifically. I’ve had a few patients, but I have 1 patient specifically on this trial, who finished therapy as of September 2023. She just had her 2-year follow-up scan and last clinical trial visit, and she’s still in a complete remission. She was one of those patients with splenic MZL. The…patients with nodal, extra nodal, splenic, and even an unclassified or unknown subtype of MZL were allowed in the trial. Again, patients could have advanced disease, stage III or stage IV for Ann Arbor staging, bulky disease, and higher risk characteristics. With that median PFS, and with that—what we have right now—18 months of follow-up, specifically for the trial the way it’s been reported so far, we’ll see updates coming. It’s proving to be not only an efficacious therapy but also a tolerable therapy.

What did mosunetuzumab’s safety profile look like in this trial?

The most common AEs were injection site reactions, because it’s a shot, and unfortunately, with any of the [subcutaneous] formulations that we’re using nowadays, that’s always a risk. One thing that is important to point out [is that, while] yes, [there was] diarrhea and fatigue, [there was also] neutropenia. We need to be aware of the fact that there are infection risks with using bispecific antibodies, and there were some…higher-grade neutropenic events with mosunetuzumab. [It’s] just something to be aware of. All patients did fine. They weren’t fatal, but, you have to be aware of those. The elephant in the room was CRS. We know with bispecific antibodies, we have to be aware of CRS, and ICANS or neurotoxicity. Fortunately, there were no ICANS events, and most of the CRS events were all grade 1/2; no grade 3/4 events were seen. It is a very safe profile.

What are the immediate clinical implications of these findings?

There’s a chemotherapy-free option for these patients…. Nobody wants chemotherapy, and I’m not saying that chemotherapy is bad, but it’s just that we’ve advanced. We’ve advanced in diffuse large B cell lymphoma and follicular lymphoma, and we’re making advancements all the time to be chemotherapy-free or use the least amount of chemotherapy as possible. MZL, in terms of the indolent lymphomas, gets forgotten about sometimes. This is offering those patients a tolerable and…efficacious [therapy], and it’s a finite amount of therapy; it’s 17 cycles, and then it’s done. They’re not on treatment consistently or constantly; it’s not “treat to progression”. It is 17 cycles, and then you’re done. They can stay home. They don’t have to go to the hospital. They don’t have to travel to another center. This was able to be done as an outpatient in community sites.

What will happen when it gets approved? Not every community site is going to be doing bispecific [antibodies]. We’re trying to get more availability of bispecific [antibodies] in the community, but, hopefully, this therapy will make its way into as many sites as safely possible, so we’ll see how it turns out.

How does frontline mosunetuzumab monotherapy compare with other therapies in MZL?

Currently, for [frontline] MZL, there aren’t a ton of options. It’s chemoimmunotherapy, so bendamustine and [rituximab (Rituxan)], or, what you’ll see a lot throughout the country, is just single-agent [rituximab] use. Physicians will put their patients on [rituximab], give them 4 doses over the course of a month, maybe put them on maintenance, then stop it, and they’ll be in remission for 2 or 3 years, maybe even longer, [but then] they’ll come out of remission, and [their physician’s] put them back on [rituximab], but by itself. It’s almost like a band-aid.

People even asked me today, after I presented, “Well, why should we use mosunetuzumab, which has a little bit of increased toxicity, when we can just use [rituximab]?” Yes, [rituximab] has done a fine job, but it’s also a band-aid. You’re slapping a band-aid on. People are staying in remission, coming back out, [and you’re] putting the band-aid back on. For some patients, that’s enough, but if you have a younger patient with MZL, I’m willing to risk a little extra toxicity to give them a longer-term remission.

Now, we need longer-term data. Right now, all we have is 18 months of follow-up. If we see, say, at 5 years, that 65% of patients are still in a complete remission, then you have your frontline choice, clearly, given single-agent mosunetuzumab is going to be better than giving single-agent [rituximab], but that’s not the trial. We’re not comparing single-agent mosunetuzumab with single-agent [rituximab] in the front line. It was a basket trial. Everybody got the drug. Right now, all we’re going on is what we’re seeing from the data. Conventionally, as of today, the options are single-agent [rituximab], bendamustine and [rituximab], and some combination of chemoimmunotherapy. There are trials looking at different BTK inhibitors in MZL, but, right now, we don’t have the novel therapy treatment landscape that we do in follicular [lymphoma], diffuse large B cell lymphoma, and even [chronic lymphocytic leukemia] and other forms of lymphoma.

What do you believe is the best pathway forward for MZL care?

Specifically, in MZL, combination [therapies]. Eventually, once we know that single-agent mosunetuzumab maintains its efficacy over time—that’s always the big thing, you can have overall response rates, and initial PFS and interim analysis that look good, but you need to maintain that over time. If it does continue to do that, then [we question] “Okay, does it need a partner?”

When you add a partner, you increase the risk for more [AEs]. Not just the CRS and neurotoxicity—again, neurotoxicity is not happening in the [patients with] MZL but that’s just fleeting, and that’s just the first cycle—but the long term infections, and things like that. If single-agent [rituximab] was good enough for all these years, for MZL, I don’t know if you have to put something with it. Is it going to be mosunetuzumab with a [Bruton’s tyrosine kinase] inhibitor? I don’t know. They’re looking at zanubrutinib [Brukinsa] in MZL. Will you have mosunetuzumab and zanubrutinib? Do you need that? Is that more of a second-line therapy? Do you need an extra drug [in the] frontline? We don’t know. MZL is not something like [diffuse large B-cell lymphoma] and follicular [lymphoma], that we’re talking about constantly. It sits over here like the stepbrother. They’re all good questions. From the talks we’ve seen today, [there are] a number of combination bispecific [antibody] trials, but I just don’t know how much we’re going to do that, or how quickly we’re going to do that, in MZL.

References

1. Burke JM, Tun AM, Villasboas J, et al. MorningSun: open-label phase II trial of the efficacy and safety of subcutaneous mosunetuzumab as frontline treatment in symptomatic patients with marginal zone lymphoma. Presented at the Society of Hematologic Oncology 2025 Annual Meeting; September 2-6, 2025; Houston, TX. Abstract IBCL – 1494.
2. FDA grants accelerated approval to mosunetuzumab-axgb for relapsed or refractory follicular lymphoma. FDA. December 22, 2022. Accessed September 17, 2025. https://tinyurl.com/4munzr95