Fixed-Duration Bispecific Antibodies Are Effective, Safe, and Convenient for Follicular Lymphoma

Vivek Patel, MD

The favorable long-term efficacy and safety outcomes observed with fixed-duration bispecific antibodies in patients with previously treated follicular lymphoma support the expanded use of this class of agents in community oncology settings, as well as in patients who may not be eligible to receive CAR T-cell therapy, according to Vivek Patel, MD.

In an interview with OncLive®, Patel highlighted the tolerability of bispecific antibodies like mosunetuzumab-axgb (Lunsumio) and epcoritamab-bysp (Epkinly), subtle differences in efficacy between these agents for patients with follicular lymphoma, and considerations for choosing between bispecific antibodies and CAR T-cell therapies.

Patel, an assistant professor at Vanderbilt University Medical Center in Nashville, Tennessee, discussed considerations for the evolving first-line follicular lymphoma treatment paradigm in another article.

OncLive: What are the notable differences between the currently available bispecific antibodies for follicular lymphoma?

Patel: This is an important question to [consider] when we think about bispecific antibody therapies. Are there any real differences between the products? In follicular lymphoma, 2 bispecific antibodies have shown efficacy and are approved in the third-line or later setting. One is mosunetuzumab, and the other one is epcoritamab.

When we consider the differences between these bispecific antibodies, the structures of the antibodies are different. We say that [these agents] have the same mechanism, where they’re bringing a T cell close to a B cell, engaging the 2, and telling the T cell to kill the B cell. For B-cell malignancies, that works well.

However, the motifs of the way these bispecific antibodies are designed are slightly different. We don’t have enough good preclinical evidence to know what the differences between these products are. We know they’re designed slightly differently. We also know that in large B-cell lymphoma [LBCL], mosunetuzumab wasn’t quite as effective as epcoritamab. When it comes to those patients, we’re not even thinking about [using] mosunetuzumab. However, for follicular lymphoma, for whatever reason, maybe just the biology of the lymphoma itself, mosunetuzumab is almost in a sweet spot where it has good efficacy and minimal adverse effects [AEs].

Regarding toxicities and tolerability, [mosunetuzumab and epcoritamab are] similar. Both [are associated with] low rates of high-grade cytokine release syndrome [CRS], rare occurrences of immune effector cell–associated neurotoxicity syndrome [ICANS], and very rare occurrences of higher-grade ICANS. Although they’re both overall well tolerated, regarding efficacy: Is there a difference? We don’t have enough information to answer that.

What patient characteristics and disease factors do you consider when selecting between bispecific antibodies and CAR T-cell therapy for patients with follicular lymphoma?

This question is still unanswered currently. Which patients should we send for CAR T-cell therapy, and in which patients can we consider [a treatment] like a bispecific antibody? One aspect that’s important [to consider is] patient fitness. CAR T-cell therapy is different from autologous stem cell transplant, where patients receive super high doses of chemotherapy. Patients [eligible for CAR T-cell therapy] can be a bit more frail than the standard transplant-eligible patient. However, CAR T-cell therapy is no walk in the park on its own.

We have 3 different CAR T-cell products in follicular lymphoma: axicabtagene ciloleucel [axi-cel; Yescarta], liso cabtagene maraleucel [Breyanzi], and tisa genlecleucel [Kymriah]. Patient [in whom] I might consider a CAR T-cell product, [are those] with rapidly progressive, bulky disease [who, on] a PET scan, have avid adenopathy and where I’m clinically concerned they have had an underlying transformation event. Maybe [the patient had] a biopsy and I didn’t see their follicular lymphoma transform to LBCL. That’s a patient [in whom] there’s no doubt in my mind I would want to get them to CAR T-cell therapy, if they are a candidate.

If that same patient, for whatever reason, was frail and maybe couldn’t tolerate CAR T-cell therapy, then an off-the-shelf bispecific antibody therapy is reasonable for that case, though I would [still] prefer a CAR T-cell therapy. [Additionally], CAR T-cell therapy can be given right now only at specialized centers and often requires patient relocation. Some patients don’t want to do that.

In another scenario—a patient who has relapsed or refractory follicular lymphoma and maybe does not have rapidly progressive disease—there’s less of a concern of underlying transformation, and they have the fitness for either CAR T-cell therapy or bispecific antibody therapy. However, we know now from 3 years of follow-up for the pivotal [phase 1/2 GO29781] study [NCT02500407] for mosunetuzumab that the long-term results mirror what we are seeing from the pivotal [phase 2 ZUMA-5] study [NCT03105336] with axi-cel in patients with follicular lymphoma. Mosunetuzumab is a fixed-duration therapy. For patients who achieve a complete response, it has the same long-term progression-free survival benefit [as axi-cel] and is less toxic.

We also know that we can successfully retreat patients with fixed-duration bispecific antibodies like mosunetuzumab, [although this has been shown in] small numbers. There’s an argument to be made that CAR T-cell therapy is curative, but I don’t think we have the data to say that yet. Right now, [for most patients] coming into my clinic [in whom] I’m less concerned about underlying large cell transformation, I prefer to use a bispecific antibody because [it is] a fixed-duration option, and we have good long-term follow-up [data] that tell me these patients are [likely] going to [have good outcomes].

Lastly, we have data—some of which were presented at the 2024 ASH Annual Meeting from the Spanish group —that patients who receive a CD20-directed bispecific antibody followed by a CD19-directed CAR T-cell therapy tend to have good efficacy with CAR T-cell therapy. Therefore, there is still good efficacy with a bispecific antibody before a CAR T-cell therapy [when the agents] have different targets. [When I use a bispecific antibody before CAR T-cell therapy], I still have CAR T-cell therapy in my back pocket, but I can potentially prevent patients from experiencing a lot of the toxicities and non-relapse mortality [(NRM) associated] with CAR T-cell therapy.

What is your main message regarding the use of bispecific antibodies in patients with follicular lymphoma?

A main takeaway from the current and emerging treatments for follicular lymphoma is the efficacy—and more importantly, the safety—of bispecific antibody therapies. With bispecific antibody combination treatments and monotherapy treatments, there are [low] rates of high-grade CRS and [low] rates of ICANS in general. We now have protocols to optimize the step-up dosing for these patients, and the times to onset of [AEs] like CRS are predictable. For mosunetuzumab, after the first dose, there’s a group of patients who will have CRS. Once they receive their first full dose of therapy, we’re also seeing that they may have a high risk of CRS, and we can predict that well.

Importantly, CRS can be treated in the outpatient setting. Patients can be given [medications] like Tylenol, [and they can] recheck their temperature. They can be given steroids that they can take at home. This is important because we’re rarely needing to reach for [treatments] like Tocilizumab for these patients. High-grade CRS [occurs at] rates of single-digit percentages; maybe 1 in 100 patients will develop [CRS] that requires a Tocilizumab-based treatment. [Bispecific antibodies] are safe therapies to give, and they are not associated with the same NRM as we’ve seen with CAR T-cell therapy.

Bispecific antibodies are [also] effective. They’re poised to be given in the community-based setting. Community-based oncologists have the hardest job in the world. [For example], they’re giving cisplatin chemotherapy with radiation for head and neck cancer. That is far more toxic than a bispecific antibody treatment. The treatment of fever and CRS [with bispecific antibodies] is manageable, and we have well-designed protocols in place. There’s no reason why these [agents] shouldn’t be given in the community. We need to expand access to care for patients, and off-the-shelf bispecific antibodies allow us to do that.