Efficacy and Safety of Odronextamab in Relapsed/Refractory Marginal Zone Lymphoma (R/R MZL): Data from the R/R MZL Cohort in the ELM-2 Study

Introduction

Odronextamab, an investigational, off-the-shelf, CD20×CD3 bispecific antibody, has shown compelling efficacy and generally manageable safety in heavily pretreated patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) (Taszner M, et al. EHA 2024). The objective response rate (ORR) was 80%, the complete response (CR) rate was 73%, and 86% of pts had Grade (Gr) ≥3 treatment-emergent adverse events (TEAEs; most common Gr ≥3 TEAEs were neutropenia [32%], anemia [12%], and neutrophil count decreased [12%]). MZL is a rare, heterogeneous, indolent type of B-cell non-Hodgkin lymphoma (B-NHL) that is often managed with chemo-immunotherapy in the front line; however, limited treatment options exist for pts at relapse. Bruton's tyrosine kinase inhibitors are approved for MZL after 1 prior line of therapy, but CR rates are modest (3-26% [Noy A et al. Blood 2017; Opat S et al. Clin Cancer Res 2021]). Currently, no treatment options are approved at third line or later for MZL, representing an unmet medical need. ELM-2 (NCT03888105), an ongoing, global, open-label, Phase 2 study of odronextamab in R/R B-NHL, included a dedicated cohort for R/R MZL pts. Here, we report the first preliminary results from the R/R MZL cohort of ELM-2.

Methods

Pts aged ≥18 years with ECOG PS 0-1, adequate organ function, and MZL (extranodal, splenic, or nodal subtypes) that relapsed or was refractory after ≥2 prior lines of systemic therapy were eligible for enrollment. Intravenous odronextamab was given with steroid prophylaxis during step-up dosing in Cycle (C) 1 (each cycle=21 days) to help mitigate the risk of cytokine release syndrome (CRS). Pts received odronextamab 80 mg on Days 1, 8, and 15 of C2-4, then maintenance dosing of 160 mg Q2W post-C4 until disease progression or unacceptable toxicity. Pts with a CR for ≥9 months switched to Q4W dosing. Infection prophylaxis, including IVIG supplementation, PJP prophylaxis, and antivirals, was recommended for all pts. Primary endpoint was ORR by independent central review according to Lugano classification. Secondary endpoints included ORR by local investigator, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Results

At data cutoff (May 2, 2024), 34 pts with R/R MZL (extranodal n=19, nodal n=12, splenic n=2, and unknown n=1) were enrolled. Twenty-nine pts were evaluable for efficacy. Median follow-up was 11.7 (95% CI 5.1-40.1) months. Median age was 64.5 years (range 34-82), and 16 pts (47.1%) were male. Pts had received a median of 2 (range 1-8) prior lines of therapy, with 58.8% refractory to their last therapy, 52.9% refractory to an anti-CD20 antibody, and 38.2% double refractory. Median odronextamab exposure was 27.2 weeks (range 2.0-197.4); 94.1% of pts completed C1 and 64.7% completed ≥4 treatment cycles.

The ORR in efficacy-evaluable pts was 79.3% (95% CI 60.3-92.0), with a CR rate of 79.3% (95% CI 60.3-92.0) by local investigator assessment. Median DOR was not reached (NR) (95% CI 11.8 months-not evaluable [NE]) and median duration of CR was NR (95% CI 11.8 months-NE). 36-month DOR was 72.4% (95% CI 41.8-88.7). Median PFS was NR (95% CI 14.5-NE), and the 36-month PFS rate was 69.4% (95% CI 40.5-86.3).

The most common TEAEs (any grade) were CRS (52.9%), neutropenia (44.1%), and pyrexia (35.3%). Gr ≥3 TEAEs occurred in 85.3% of pts, the most common being neutropenia (35.3%), alanine aminotransferase increased (20.6%) and aspartate aminotransferase increased (20.6%). CRS occurred in 53.3% (8/15) of pts who received the optimized 0.7/4/20 mg step-up regimen, with all CRS events being Gr 1-2 (Gr 1, 33.3% [n=5]; Gr 2, 20.0% [n=3]). No ICANS events were reported. Gr ≥3 infections occurred in 23.5% of pts, with no Gr 5 infections. Five pts (14.7%) discontinued treatment due to TEAEs. No new safety signals were observed.

Conclusions

Odronextamab showed promising clinical efficacy with a generally manageable safety profile in heavily pretreated pts with R/R MZL. Responses were durable, with 72.4% maintaining response at 3 years. CRS events were all Gr ≤2 with the 0.7/4/20 mg step-up regimen, and the overall safety profile in R/R MZL was consistent with that observed in other indolent lymphomas. Odronextamab may be an important potential treatment option in the future management of R/R MZL, and these results support the continued investigation of odronextamab in Phase 3 trials. Updated data will be presented.

Kim:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy; AstraZeneca/MedImmune: Consultancy, Honoraria; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IMBDx Inc: Honoraria; Samsung Bioepis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, HK inno.N, F. Hoffmann-La Roche Ltd/Genentech, Yuhan: Consultancy. Taszner:Roche: Consultancy; Takeda: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau. Chong:Amgen, AstraZeneca, Bayer, Dizal Pharma, HUTCHMED, Incyte, Innate Pharma, Merck, Pfizer, Pharmacyclics, Roche: Research Funding; Bristol Myers Squibb, Regeneron Pharmaceuticals, Inc.: Consultancy, Research Funding; Takeda: Consultancy. Cai:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Uppala:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Allan:Genentech: Consultancy, Research Funding; BeiGene: Consultancy, Speakers Bureau; Epizyme: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau.

Odronextamab, an investigational CD20xCD3 bispecific antibody, for the treatment of patients with relapsed or refractory Marginal Zone Lymphoma (MZL)