Bispecific antibodies are demonstrating significant promise in reshaping the treatment landscape for follicular lymphoma, offering improved efficacy with a favorable safety profile that positions them as ideal candidates for community-based care. Recent clinical data reveal that these agents achieve superior response rates while maintaining low toxicity compared to traditional therapies and CAR T-cell treatments.
Superior Efficacy in Relapsed/Refractory Disease
The phase 1b/2 EPCORE NHL-2 study has produced particularly compelling results for epcoritamab plus lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma. Among 111 patients treated with this combination, the complete response rate reached 87%, representing a substantial improvement over historical outcomes.
"The outcomes [with that combination] are outstanding," noted Dr. Vivek Patel, assistant professor at Vanderbilt University Medical Center. The study employed a fixed duration approach, with epcoritamab administered for 2 years and lenalidomide for 12 months total.
The time to next treatment (TTNT) data from this study are equally impressive, with approximately 2 years median TTNT and more than 80% of patients remaining treatment-free at that timepoint. These results represent a marked improvement from the phase 3 AUGMENT trial, which evaluated lenalidomide plus rituximab alone in patients with relapsed/refractory indolent lymphoma.
Favorable Safety Profile Enables Community Use
A critical advantage of bispecific antibodies in follicular lymphoma is their superior safety profile compared to CAR T-cell therapies. Data from multiple trials demonstrate consistently low rates of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
In the phase 2 Mithic-FL1 trial, 78 patients with follicular lymphoma receiving frontline mosunetuzumab experienced any-grade CRS at a rate of 54%, with events being predominantly grade 1 (51%). Notably, there were no instances of grade 3 or higher CRS and no reports of ICANS-like toxicities.
The EPCORE NHL-2 study showed similar safety results, with CRS occurring mostly as grade 1 to 2 events (50%), only 1% of patients experiencing grade 3 and 4 CRS, and no grade 5 events. There was only one instance of ICANS, which was low grade and quickly resolved.
"There were very low rates of high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome," Patel emphasized. "Most instances of CRS can be treated in the outpatient setting."
Emerging Second-Line Treatment Paradigm
The ongoing phase 3 CELESTIMO trial is evaluating mosunetuzumab plus lenalidomide compared with lenalidomide plus rituximab in the second-line setting. This randomized study is expected to provide regulatory approval for bispecific antibody combinations in 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," Patel stated.
The development contrasts with recent results from the phase 3 inMIND trial, which showed a progression-free survival benefit for tafasitamab plus lenalidomide and rituximab versus lenalidomide plus rituximab alone. However, experts question the long-term durability of tafasitamab-based regimens compared to bispecific antibodies.
Focus on Time to Next Treatment
In follicular lymphoma management, TTNT has emerged as a more meaningful endpoint than traditional survival measures, given the disease's median overall survival of approximately 15 to 20 years. The depth of response achieved with bispecific antibodies appears to translate into prolonged treatment-free intervals.
"How can we get patients off therapy for the longest period and maximize that TTNT? These [bispecific antibody] combinations are going to be interesting," Patel explained. "The bispecific antibodies are promising because of the depth of response that patients achieve when they receive those treatments."
Expanding Access to Effective Treatment
The safety profile of bispecific antibodies positions them as ideal treatments for community-based oncology practices, potentially expanding access to highly effective therapies. Unlike CAR T-cell therapies, which require specialized centers and carry higher risks of severe toxicities, bispecific antibodies can be administered safely in outpatient settings.
"Bispecific antibodies are safe, effective, and ideal for use in the community-based setting," Patel noted. "These agents will enable investigators to further expand access to care for patients with follicular lymphoma."
The predictable timing of CRS onset and established protocols for step-up dosing further support the feasibility of community-based administration. This accessibility advantage, combined with superior efficacy data, positions bispecific antibodies to become the preferred treatment approach for many patients with follicular lymphoma across different lines of therapy.
