The Advent of Bispecific Antibodies for Large B-cell Lymphomas

While the treatment landscape for relapsed or refractory large B-cell lymphomas (LBCL) has transformed with the introduction of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and their advancement into earlier lines of treatment, a significant proportion of patients are still unable to receive CAR-T, and many will experience disease relapse post-treatment.^{1, 2}  Outcomes in this population remain poor, with few standard-of-care options providing durable survival benefits.^{3, 4}  Given this ongoing unmet need in patients with LBCL, the outcomes observed for CD20-directed T-cell-engaging bispecific antibodies (BsAbs) in pivotal trials published this year make a compelling case that BsAbs can potentially fill this void.

Epcoritamab, a CD20xCD3 BsAb with a 1:1 molecular configuration given subcutaneously, was granted accelerated approval in May 2023 for patients with relapsed or refractory LBCL who have received at least two prior lines of therapy, based on the results of the phase I/II multicenter, single-arm EPCORE NHL-1 trial.⁶  A total of 157 patients received the recommended phase II dose (RP2D) of epcoritamab in 28-day cycles until disease progression or unacceptable toxicity. The objective response rate (ORR) was 63%, and the complete response (CR) rate was 39%, with a median duration of response (DOR) of 12 months. Among treated patients, 39% had previously received CAR-T therapy, with a subgroup analysis demonstrating a consistent treatment effect when compared with that observed among CAR-T-naïve patients.

Glofitamab, a CD20xCD3 BsAb with a 2:1 molecular configuration given intravenously, was granted accelerated approval in June 2023 for patients with relapsed or refractory LBCL who had received at least two prior lines of therapy, based on the results of the phase II multicenter, single-arm NP30179 trial.⁵  In this trial, 155 patients received the RP2D of glofitamab with obinutuzumab pre-treatment in 21-day cycles, for a total of 12 cycles. The ORR was 52%, and the CR rate was 39%, with a median DOR of 18.4 months. Notably, a majority of CRs were sustained at the time of the last follow up, in the setting of a fixed-duration therapy. Among treated patients, 33% had previously received CAR-T therapy, with a prespecified subgroup analysis demonstrating a consistent treatment effect when compared with that observed among CAR-T-naïve patients.

In both studies, the most common adverse events (AEs) were consistent with those observed in previously reported studies of BsAbs, including cytokine release syndrome (CRS) and cytopenias. Notably, the majority of CRS cases were grade 1 or 2 based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria.⁷  Neutropenia was the most common hematologic toxicity with both agents, occurring in 22 to 38% of patients; febrile neutropenia was rare (3%). Neurotoxicity (immune effector cell-associated neurotoxicity syndrome [ICANS]) was an infrequent event, occurring in only 6 to 8% of patients, with nearly all cases being mild (grade 1 or 2 according to ASTCT criteria) and self-limiting. Overall, 5% of patients in each study experienced fatal, treatment-emergent AEs. Premedication with corticosteroids (and in the case of glofitamab, with obinutuzumab) successfully mitigated the incidence of infusion-related or injection-site reactions and severe CRS, with grade 3 or higher infections occurring in a similar proportion (15%) of patients over the course of follow up.

Ultimately, both studies leave several questions unanswered: (1) How generalizable are the data for these agents to real-world clinical practice, including outpatient treatment and community oncology practices? (2) How should these agents be incorporated into the current treatment landscape for LBCL, including sequencing with CAR-T therapy? (3) What is the curative potential of BsAbs based on longer-term follow up?

Despite these uncertainties, the data indicate that epcoritamab and glofitamab are effective new additions to our therapeutic arsenal against relapsed or refractory LBCL, including cases of relapse after CAR-T therapies. Their recent approvals could lead to a significant paradigm shift in the treatment of LBCL, where challenges in the broader adoption of cellular therapy due to logistical and financial burdens from unique toxicities, costs, manufacturing issues, and product variability have proven difficult to overcome. Given the promising efficacy observed with BsAbs, it will be critical to address the potential barriers to access and generalizability that have been a challenge with CAR-T therapies to ensure these agents fulfill their promise in improving outcomes in lymphoma.