Bispecific Antibody Shows Deep Remission in Patients with Relapsed/Refractory Follicular Lymphoma

A highly refractory population of patients with follicular lymphoma achieved longstanding responses and few significant adverse events from odronextamab monotherapy, according to findings of the ELM-2 study. The study outcomes were published in Clinical Lymphoma, Myeloma & Leukemia.

Of the 128 patients in the study, 80% achieved an objective response rate (ORR), with 73% achieving a complete response (CR). The progression-free survival (PFS) was 20.7 months. “For patients who achieved a complete response, it appears that they’re able to sustain that response for a long period of time,” says study coauthor and Vice-Chair of Quality and staff physician in the Department of Hematology and Medical Oncology at Cleveland Clinic Cancer Institute Deepa Jagadeesh, MD.

Background

Follicular lymphoma is typically indolent but patients with disease progression within two years of initial treatment as well as those who are refractory to rituximab tend to have poor outcomes. Many patients with relapsed/refractory disease also struggle with lymphadenopathy, fevers, fatigue and weight loss. With each subsequent therapy, patients tend to have shorter periods of remission, so more effective therapies are needed.

Study design

This phase 2 multicenter study investigated the safety and efficacy of the CD20 x CD3 bispecific antibody odronextamab, primarily among patients with advanced-stage disease or intermediate- to high-risk characteristics. Half of the patients in the study had relapsed within two years of initial treatment. Roughly 74% were refractory to an anti-CD20 antibody and approximately 40% were refractory to an alkylator as well as an anti-CD20 antibody.

For the study, odronextamab was administered intravenously in 21-day cycles in step-up dosing:

• 0.7/4/20 mg on days 1/2, 8/9, and 15/16*
• 80 mg weekly on cycles 2-4
• 160 mg every two weeks for cycles 5 and beyond
• Patients who achieved a durable complete response for more than nine months were moved to a regimen of 160 mg every 4 weeks.

*The initial regimen started with 1/20 mg but was modified to 0.74//20mg to lower the risk of cytokine release syndrome (CRS).

The median duration of treatment was 31 weeks. The primary endpoint was overall response rate by an independent review committee, with secondary endpoints being duration of response, progression-free (PFS), overall survival (OS), as well as safety and tolerability.

Study results

Odronextamab demonstrated high rates of durable response with an overall manageable safety profile. At a median follow-up of 20.1 months, the ORR was 80%, with a CR rate of 73%. The median duration of CR was 25.1 months, median PFS was 20.7 months and median OS was more than four years.

Patients also reported improved quality of life and functional status, based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Improved physical and emotional functioning continued through 50 weeks.

Adverse events were generally manageable. The most common side effects were cytokine release syndrome (56%), neutropenia (39%) and pyrexia (38%). Most instances of CRS were grade 1, occurring during the first cycle and resolving without incident. Only one patient experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS).

There were high rates of infection, including eight patients who succumbed to COVID-19. Some patients had received up to 13 lines of therapy prior to the study, and roughly one third had undergone an autologous stem cell transplant before. “When giving treatments like CAR T-cell therapy or bispecifics to highly immunosuppressed patients, we are noticing higher infection rates so that’s something to watch for,” says Dr. Jagadeesh.

Discussion points

• Data at the 12-week follow-up point showed patients with undetectable ctDNA had slightly longer PFS. However, researchers would like to understand if this trend will continue over a longer follow-up period.
• Odronextamab is approved for use in Europe and is under FDA review. “There are already two other bispecifics approved to treat follicular lymphoma, so the question is how do physicians pick one over the other,” says Dr. Jagadeesh. “Less toxicity, higher efficacy and less financial toxicity are factors they would influence this decision. For this therapy, the CRS rate was very low with step-up dosing. However, the study did require hospitalization for cycle one, and that may be a barrier for some patients. It would be encouraging if we had data in the future showing the medication could be administered on an outpatient basis.”
• Researchers would like to better understand if odronextamab could be given as a time-limited treatment rather than continuously to reduce the financial impact as well as the risk of infection.