Bispecific Antibodies Improve TTNT and Reshape R/R Follicular Lymphoma Management

Vivek Patel, MD

Bispecific antibody–based combinations are emerging as promising second-line therapies for patients with follicular lymphoma, and ongoing trials with these agents are expected to further redefine this treatment paradigm, according to Vivek Patel, MD.

In an interview with OncLive®, Patel talked through the growing body of evidence supporting the use of mosunetuzumab-axgb (Lunsumio) or epcoritamab-bysp (Epkinly) plus lenalidomide (Revlimid) and rituximab (Rituxan) in patients with relapsed/refractory follicular lymphoma, the clinical benefits and limitations of the efficacy associated with tafasitamab-cxix (Monjuvi) plus lenalidomide and rituximab, and the importance of considering time to next treatment (TTNT) over traditional survival end points when evaluating novel regimens for this disease in clinical trials.

Patel, an assistant professor at Vanderbilt University Medical Center in Nashville, Tennessee, dove into detail regarding the decision between bispecific antibodies and CAR T-cell therapy for patients with follicular lymphoma in another article.

What might the role of tafasitamab in the second-line follicular lymphoma treatment paradigm look like compared with the continued development of bispecific antibodies in this disease?

[The development of] frontline bispecific antibodies is going to delay [treatment developments in] the second-line [setting]. Part of that is because patients do so well in the frontline setting, and it is going to take a long time for those data to mature. The second-line setting is where we [may] see a regulatory approval when the phase 3 CELESTIMO trial [NCT04712097] reads out regarding mosunetuzumab plus lenalidomide [in patients with relapsed/refractory follicular lymphoma]. It's hard for me to believe that [regimen] is not going to beat lenalidomide plus rituximab; that's going to give us an option for a bispecific antibody in the second-line setting.

At the 2024 ASH Annual Meeting, we saw late-breaking results from the phase 3 inMIND trial [NCT04680052], which investigated tafasitamab plus lenalidomide and rituximab vs lenalidomide plus rituximab [alone; this trial showed] a progression-free survival [PFS] benefit [with the tafasitamab regimen]. Many of those patients were refractory to rituximab therapy. The big question is: What was rituximab doing in that scenario? Was it doing anything compared with lenalidomide?

[Tafasitamab plus lenalidomide was FDA-approved [in July 2020] for adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL)].1 In the academic setting, we say we can give bispecific antibodies, and it's no big deal. In the community settings, when we think about the second-line setting in follicular lymphoma, [some hematologists] might be used to giving tafasitamab to patients who have had DLBCL. [Tafasitamab plus lenalidomide and rituximab] is a regimen that many hematologists are comfortable with. Is this going to be more effective than a bispecific antibody for patients with follicular lymphoma? It's unlikely, because single-agent tafasitamab has little long-term, durable activity, whereas a single-agent bispecific [antibody has more durable activity]. It's hard for me to believe that [tafasitamab plus lenalidomide and rituximab is] going to be better than a bispecific antibody therapy [for patients with follicular lymphoma.

[Additionally, regarding] time toxicity, tafasitamab [treatment requires] frequent dosing. In the second-line setting, there may be a short period of an uptick in [the use of] tafasitamab plus lenalidomide and rituximab until we get more experience with bispecific antibodies in the community. [Bispecific antibodies] are well-tolerated treatments. There's a stigma attached to the cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome that [are associated with] CAR T-cell therapies that doesn't apply to lymphoma bispecific antibodies, particularly in the follicular lymphoma setting.

What other notable follicular lymphoma management approaches have emerged in the second-line setting?

Combination approaches with bispecific antibodies are appealing. Right now, we have the ongoing CELESTIMO trial, which is a randomized study comparing mosunetuzumab with lenalidomide compared with lenalidomide plus rituximab. That’ll give us interesting data to see which of those approaches might be more effective. We're all excited about those results to come out, and we're all thinking that at this point, a bispecific antibody combination is likely to [elicit] a better PFS [compared with standard regimens].

Additionally, in follicular lymphoma, one of the more important end points is TTNT. The critical question is: How can we get patients off therapy for the longest period and maximize that TTNT? These [bispecific antibody] combinations are going to be interesting.

We have data right now [from the] phase 1b/2 [EPCORE NHL-2] study [NCT04663347] of epcoritamab plus lenalidomide and rituximab [in patients with relapsed/refractory follicular lymphoma for] a fixed duration of 2 years [and] the lenalidomide [being administered] for 12 months total. The outcomes [with that combination] are outstanding; the complete response rate in relapsed/refractory follicular lymphoma [was] 87%.2 [With] the TTNT of [approximately] 2 years, [that means that more than] 80% of patients still didn't need treatment. Those are promising data and much improved from what we had from the phase 3 AUGMENT trial [NCT01938001], which just [evaluated] lenalidomide plus rituximab [in patients with relapsed/refractory indolent lymphoma].

When you add a third drug to 2 drugs, for most cases, you're going to see a PFS benefit. The big question we're asking ourselves is: How can we improve quality of life? TTNT in the long term, over a 5-year horizon, is going to be important because [improving] survival in follicular lymphoma is difficult when the median [overall survival] is [approximately] 15 to 20 years. What matters most is TNTT. We don't have all the data for that, but the bispecific antibodies are promising because of the depth of response that patients achieve when they receive those treatments. Early data right now are suggesting that TTNT is going to be prolonged [with these approaches].

What are some of the most important factors you consider when selecting later-line treatments for patients with follicular lymphoma?

In the third line and beyond for follicular lymphoma, one [aspect] that's important to me is what [treatments] the patient has received in the first- and second-line settings, as well as what their relapse looks like. This is the most challenging [facet of managing] follicular lymphoma. It's a heterogenous disease, and it relapses quite heterogeneously.

Some patients will have indolent relapses that can be observed. Maybe they have a relapse in a certain location that is close to an important structure like the ureter, and you might treat them with local radiation or potentially rituximab monotherapy, assuming they weren't refractory to that in their prior lines. If I have a third-line patient who has had a decade since their last treatment, now they have a relapse, and they have had an indolent course overall, then that's a patient in whom I can consider lower-intensity options. That's a patient whom I wouldn't want to send to a treatment like CAR T-cell therapy.

If I had a patient who was refractory to their previous line of therapy, and they didn't respond that well, that's a patient I'm a little more worried about and [in whom I’m considering] bispecific antibody therapies or CAR T-cell therapy. In the future, if a patient has received a bispecific antibody in a prior line and if they've had a good long-term benefit from that, retreatment with a bispecific antibody is reasonable. Alternatively, you can consider a treatment like CAR T-cell therapy.

Then we have patients who have an indolent relapse. [If they have already received] rituximab, you could try a therapy like obinutuzumab [Gazyva] as a single agent. If they've [received] some of those single-agent treatments, you still have [the option of] lenalidomide-based treatments. If they've seen those treatments, and you're not going to reach for a bispecific antibody or CAR T-cell therapy, we do have treatments like EZH2 inhibitors; one is tazemetostat [Tazverik], which is incredibly well tolerated. Regarding efficacy, we're not thinking that [tazemetostat is] going to be a long-term fix for these patients. However, if I have a patient who wants an oral therapy that [is associated with] minimal adverse effects, wants to maximize their time at home, is maybe a little spooked by the idea of bispecific antibody or has received one before, and has an overall lower volume of disease and a slower pace of disease, then an agent like tazemetostat is also a reasonable option.

The third-line and beyond setting is complicated. It's not one-size-fits-all. We need to look at what the patient has received before and how long they responded to their last therapy. when [I evaluate their] scans, am I concerned that [these diseases could now be] underlying large cell transformation or an aggressive relapse of follicular lymphoma? In that case, I'm reaching for cellular therapies. Or [considering whether] it is a more indolent relapse where I can consider single-agent, local therapies, or even an agent like the EZH2 inhibitor tazemetostat.

References

1. FDA approves Monjuvi (tafasitamab-cxix) in combination with lenalidomide for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. MorphoSys AG and Incyte. July 31, 2020. Accessed June 5, 2025. https://investor.incyte.com/news-releases/news-release-details/fda-approves-monjuvir-tafasitamab-cxix-combination-lenalidomide
2. Falchi L, Balari AS, Leppä S, et al. Fixed-duration epcoritamab + R2 drives deep and durable responses in patients with relapsed or refractory follicular lymphoma: 2-year follow-up from arm 2 of the Epcore NHL-2 trial. Blood. 2024;144(suppl_1):342. doi:10.1182/blood-2024-200262