SUNMO, Bispecifics, and a New Standard for Relapsed/Refractory Large B-Cell Lymphoma

For patients with relapsed or refractory large B-cell lymphoma who are not candidates for CAR-T or stem cell transplant, treatment options have long meant cycles of salvage chemotherapy with limited durability and significant toxicity. The SUNMO trial (NCT05171647) is challenging that paradigm.

In a Pharmacy Times interview, Elizabeth Budde, MD, executive medical director of the Enterprise Immune Effector Cell Program and associate professor in hematology at City of Hope, discusses the phase 3 data behind the mosunetuzumab (Lunsumio; Genentech, Inc) plus polatuzumab vedotin (Polivy; Genentech) combination, what grade 1 CRS actually looks like at the bedside, and why she believes a subset of patients treated with bispecific-based regimens may ultimately be cured.

Pharmacy Times: Large B-cell lymphoma is one of the most aggressive cancers a patient can face—and the relapsed/refractory setting is where hope often runs thin. What drew you to this specific moment in the disease, and what have you seen in patients who've exhausted standard options that has driven the work behind SUNMO?

Elizabeth Budde, MD: So large B-cell lymphoma is, as we know, the most common aggressive B-cell lymphoma. And even when I was a fellow, the prognosis for those patients was pretty poor, especially for those who lacked options—for example, autologous stem cell transplant, which now excludes a majority of patients who have no access to transplant or aren't in good enough condition to go to transplant. So, it has always been an unmet need. What drove me is I've always had a passion for immunotherapy and a strong belief in the power of the immune system. It's gratifying to see how much immunotherapy has really become a game changer.

Pharmacy Times: The field has been transformed by CAR T—but CAR T is not available to everyone, and not every patient can wait. When you were designing SUNMO, what was the gap you were trying to fill, and how did the combination of mosunetuzumab and polatuzumab vedotin feel like the right answer to that problem?

Budde: This speaks to how we manage patients with relapsed/refractory large B-cell lymphoma and how we get most patients into very durable remission. CAR T has really revolutionized how we manage those patients in the refractory setting. But as you point out, not every patient has access, and not every patient is able to go to CAR T because of logistical concerns. CAR T cell therapy has been shown to induce durable remission, but for those patients who are not candidates for curative-intent therapy—such as CAR T or autologous stem cell transplant—those patients will typically be managed in what we call a palliative setting, meaning they might go into remission, but it might not be durable, and they might receive a less intense and less effective treatment. So the goal has really been to use novel, targeted, immune-based regimens to see whether we can offer highly effective treatment to that patient population—so we're not just managing those patients in a palliative setting.

Pharmacy Times: Can you speak to the data from SUNMO? What were some of the most meaningful outcomes you observed, and what implications do they have for patients?

Budde: The SUNMO study is a global phase 3 study, so it's not cherry-picking patients—many sites from around the globe joined the study. What the study aims to do is address those patients who are transplant-ineligible, meaning they lack a curative option. It randomized patients 2-to-1 to the treatment arm, which is the investigational combination: the first time we combined a bispecific T-cell engager, mosunetuzumab, together with an antibody-drug conjugate, polatuzumab. So, you're attacking the lymphoma from 2 different angles, trying to kill off as many lymphoma cells as possible, with the hope that this translates into very durable remission and provides patients real hope and real benefit.

And this wasn't just putting 2 drugs together for the first time—it's really built on our experience understanding how each agent works. We tested this in a phase 2 single-arm study, then in a randomized phase 2, and saw very consistent signals. In the meantime, we also transitioned mosunetuzumab from requiring long hours of intravenous administration to subcutaneous injection, cutting administration down to less than 20 minutes, with very similar efficacy as a single agent. That's what prompted us to develop this regimen in the outpatient setting—really going against the traditional thinking that a regimen needs to be very intense to have a good response. This regimen is not intense, but it's very effective.

What we found in this global phase 3 study is that it met the primary end point of progression-free survival—roughly triple what was seen in the control arm, R-GemOx. There are some questions about whether R-GemOx is the right control arm, but back in 2021, in this patient setting—transplant-ineligible with at least one prior line of therapy—second-line CAR T had not yet been approved; that came in 2022. So, R-GemOx is, in my mind, a reasonable control arm, especially thinking from a global perspective—our goal is to get an effective regimen to as many people as possible, regardless of where they are.

The overall response rate end point was also met. The complete response rate was double what we saw in the control arm. And in this article, we report an updated, longer follow-up with more events to see whether we continue to see this benefit—and the answer is yes. For those patients who achieved a complete remission after treatment with mosunetuzumab plus polatuzumab, more than 60%—two thirds—continue to stay in remission after 2 years. With longer follow-up, we have also not seen any concerning safety signals. This combination has stood up to the test of time, and it remains the immune-based therapy with the lowest cytokine release syndrome rates — in terms of both overall incidence and severity—among all bispecific combinations and monotherapy, including CAR T. Ninety-three percent of patients don't need tocilizumab or corticosteroids to manage their cytokine release syndrome (CRS). Most cases are grade one and can be managed with Tylenol or NSAIDs and supportive measures.

Pharmacy Times: CRS is a term that can sound alarming to clinicians who haven't managed it before—but in practice, grade 1 is really just a fever. How important is provider education around that distinction, and what does it mean for the regimen's potential in the community setting?

Budde: When people hear "cytokine release syndrome" without much experience with it, it might sound alarming. But a grade 1 is literally just a fever—similar to what you'd have with a viral infection—and mostly manageable with hydration and an antipyretic like acetaminophen.

Another important feature built into this regimen is minimizing corticosteroid use. Many patients diagnosed with diffuse large B-cell lymphoma in the refractory setting are in their 60s, and we really want to minimize unnecessary complications from medications. Corticosteroids as premedication were only required during cycle one, on the day of injection—very minimal use. We also looked at different age groups using 65% as the cutoff, and we see very comparable efficacy and comparable complication rates in both younger and older patients. Being older is not a barrier to receiving this regimen.

Pharmacy Times: Chemotherapy has anchored salvage treatment in large B-cell lymphoma for decades. If a chemo-free regimen like Mosun-Pola establishes itself as a new standard, what does that mean for how we think about treating this disease—and for patients who have long associated relapse with another round of harsh chemotherapy?

Budde: The main clinical implication of this phase three study is that it's now a validated result—it really demonstrates that you don't need very intense chemotherapy to get patients into a durable remission. This regimen truly sets a new standard for patients who would otherwise have only chemotherapy as an option. It delivers highly effective therapy with a very safe and manageable side effect profile, and it brings realistic hope to those patients. I'm also hoping that colleagues in community settings will begin to adopt this regimen. We're putting a lot of effort into building up confidence around how to administer it so that patients can receive it close to home.

Pharmacy Times: There's also a patient psychology dimension here—for many people, the word 'chemotherapy' alone carries a weight that can make them hesitant to engage with treatment. Does moving away from that framing change the conversation at the bedside?

Budde: I think it also cuts down on potential complications. Technically, this regimen is "chemo-light" rather than completely chemo-free, because the CD79b antibody-drug conjugate polatuzumab carries MMAE as a payload, which is considered chemotherapy—but it's very targeted. It delivers the warhead specifically into the target cells, unlike most conventional chemotherapy, which is non-specific. So you could call this conventional-chemotherapy-free, or chemo-light.

Pharmacy Times: You've built your career at the intersection of cellular therapy, bispecifics, and lymphoma biology—you've watched this field move faster in the last five years than perhaps any other area of hematologic oncology. Where does the R/R LBCL story end—is cure a word you're willing to use for more patients than we could have imagined even a decade ago?

Budde: It's really gratifying to see how much the field has changed even just from 10 years ago. When I was a fellow in 2006 or 2007, patients in the relapsed/refractory setting who weren't transplant candidates basically had a very short life expectancy—chemo, then another chemo, with no good options. Now we have so many different ways to offer targeted, immune-based treatment, with the goal of delivering highly effective therapy with a very reasonable side effect profile and, ideally, durable remission for patients who cannot move on to autologous stem cell transplant.

For bispecific-based regimens, I feel like we're in an early era—similar to when CAR-T was first approved, when we didn't know whether those patients were cured. Many patients who achieved remission with CAR-T went on to allogeneic stem cell transplant for long-term cure. But now we know CAR-T can actually cure about 50% of patients. With bispecifics, I believe that with longer follow-up—say, 5 years—a subset of patients will be cured. I myself have patients who were put on the mosunetuzumab regimen way back in the phase 1 and phase 2 testing around 2018, and quite a few are still in remission. In a year or 2, that will be 10 years. Are they cured? I hope so. I hope we can say that.