Data from the Phase II ELM-2 trial was presented at the American Society of Hematology (ASH) 2024 Annual Meeting, held on December 7–10. The trial evaluated Regeneron's Ordspono (odronextamab) for relapsed/refractory (r/r) marginal zone lymphoma (MZL) in extranodal, nodal, and splenic locations in patients who had undergone second-line or later systemic therapy. The limited treatment options in the third-line setting for MZL highlight a significant opportunity for novel therapeutic modalities, such as bispecific antibodies, to fill this gap.
Ordspono is a CD20xCD3 bispecific monoclonal antibody that facilitates T cell engagement for the targeted killing of CD20-expressing tumor B cells. The Phase II ELM-2 study implemented a step-up dosing strategy to mitigate cytokine release syndrome (CRS), followed by maintenance dosing every two weeks or every four weeks for patients who achieved a complete response (CR) lasting over nine months. While 88.1% of patients completed one cycle, patient adherence beyond the fourth cycle was relatively low (64.3%), highlighting a potential challenge in long-term administration. The trial reported promising efficacy with an objective response rate (ORR) and CR rate of 77.1% each (95% CI 59.9–89.6). The 12-month duration of response (DOR) was 80.2 (95% CI 49.6–93.3), indicating a durable response. However, the overall median DOR, median duration of complete response (DOCR), median progression-free survival (PFS), and median overall survival (OS) were not reached, with a median of 11 months.
The safety profile was generally manageable. Common treatment-emergent adverse events (TEAEs) included CRS (54.8%), infusion-related reaction (35.7%), pyrexia (35.7%), and neutropenia (31%). Grade 3 or higher TEAEs occurred in 83.3% of patients, the most common of which was neutropenia (23.8%). Notably, CRS was reported in 56.5% of patients who received the step-up regimen. All CRS events were limited to grade 1–2 severity, reflecting the effectiveness of step-up dosing and prophylactic steroid use. Additionally, no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) events were observed, further supporting the safety profile.
Overall, Ordspono demonstrates promising clinical efficacy and a manageable safety profile in r/r MZL, but challenges persist. The FDA rejected Regeneron's biologics license application for Ordspono, as the confirmatory trials were not underway, and the agency required Regeneron to establish a clear timeline before resubmission. This regulatory setback could delay broader US market adoption, affecting its competitiveness. However, Ordspono received European Commission approval earlier this year based on the same Phase II ELM-2 trial for treating adult patients with r/r FL or r/r diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. This approval indicates regulatory confidence and may make future expansion into MZL, an indolent lymphoma similar to FL, possible.
Ordspono faces pressures from other bispecific T-cell engager therapies (BiTEs), like AbbVie and Genmab's Epkinly (epcoritamab), Roche's Columvi (glofitamab), and Roche's Lunsumio (mosunetuzumab). In terms of route of administration, Ordspono’s intravenous administration is less convenient than Epkinly’s subcutaneous administration. While Columvi and Lunsumio are also intravenously administered, their dosing schedules are more defined and less frequent than that of Ordspono, which occurs over two days. Additionally, increasing the limited sample size within the study poses another challenge given the rarity of MZL. GlobalData's analyst consensus forecast projects Ordspono's total global sales to reach $569 million by 2030, contingent on confirmatory trials that provide robust comparisons to standard-of-care treatments or competing BiTEs. Regeneron’s OLYMPIA odronextamab development program is expected to establish Ordspono’s niche in several B-cell non-Hodgkin lymphoma subtypes and earlier lines of therapy with multiple ongoing studies, such as the Phase III OLYMPIA-5 trial evaluating odronextamab-lenalidomide versus lenalidomide-rituximab (R2) including a cohort of patients with r/r MZL. If these challenges are addressed, Ordspono could represent a significant advancement in the treatment landscape across other B-cell malignancies and potentially expand its impact to the underserved third-line MZL setting.
