Efficacy and Safety of Odronextamab in Rare Subtypes of Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL): Data from a Dedicated Cohort of Other B-NHLs in the ELM-2 Study

Introduction

Other aggressive B-NHL encompasses multiple rare subtypes (e.g., primary mediastinal B-cell lymphoma [PMBL], high-grade B-cell lymphoma [HGBL], and follicular lymphoma [FL] Grade 3b) that demonstrate rapid disease progression and poor prognosis, especially in the relapsed/refractory (R/R) setting. Importantly, these subtypes are often excluded from enrollment in studies of R/R diffuse large B-cell lymphoma (DLBCL); therefore, clinical trial experience with novel agents is limited. Odronextamab, an investigational, off-the-shelf, CD20×CD3 bispecific antibody, has shown compelling efficacy and generally manageable safety in various B-NHL subtypes in the ELM-1 study (Bannerji R et al. Lancet Haematol 2022). ELM-2 (NCT03888105) is an ongoing, global, open-label, Phase 2 study evaluating the efficacy and safety of odronextamab in patients with R/R B-NHL. Here, we report the first preliminary results from the other aggressive B‑NHL cohort of the ELM-2 study.

Methods

Patients aged ≥18 years with ECOG PS 0–1, adequate organ function, and aggressive B-NHL subtypes (excluding DLBCL and mantle cell lymphoma) that relapsed or were refractory after ≥2 prior lines of systemic therapy were eligible for enrollment. Odronextamab was given intravenously with steroid prophylaxis and step-up dosing in Cycle (C) 1 (each cycle=21 days) that was optimized to help mitigate the risk of cytokine release syndrome (CRS). Patients received odronextamab 160 mg on Days 1, 8, and 15 of C2–4, then maintenance dosing of 320 mg Q2W post-C4 until disease progression or unacceptable toxicity. Patients with a complete response (CR) for ≥9 months switched to Q4W dosing. Infection prophylaxis, including IVIG supplementation, PJP prophylaxis, and antivirals, was recommended for all patients. The primary endpoint was objective response rate (ORR) by independent central review according to Lugano classification. Secondary endpoints included ORR by local investigator, duration of response (DOR), progression-free survival, overall survival, and safety.

Results

At data cutoff (May 2, 2024), 49 patients with R/R aggressive B-NHL were enrolled, including HGBL, NOS (n=9); PMBL (n=8); FL Grade 3b (n=7); mixed histology B-NHL (n=4); Burkitt lymphoma (n=3); EBV+ DLBCL (n=3); HGBL with MYC and BCL-2 and/or BCL-6 rearrangements (n=3); T-cell/histiocyte-rich large B-cell lymphoma (n=3); and others (n=9). Forty-six patients were evaluable for efficacy. The median follow-up was 12.0 (95% CI 8.2–21.1) months. Overall, the median age was 58 years (range 24–83), and 59.2% of patients were male. Patients had received a median of 3 (range 2–9) prior lines of therapy, with 69.4% refractory to their last therapy, and 61.2% double refractory. Median odronextamab exposure was 19.0 weeks (range 2.0–131.9); 98.0% of patients completed C1 and 65.3% completed ≥4 treatment cycles.

The ORR in efficacy-evaluable patients was 60.9% (95% CI 45.4–74.9), and the CR rate was 43.5% (95% CI 28.9–58.9), by local investigator assessment. The median DOR was not reached (95% CI 4.8 months–not evaluable); 36-month DOR was 54.3% (95% CI 27.5–75.0).

In all patients, the most common treatment-emergent adverse events (TEAEs) of any grade were CRS (53.1%), anemia (42.9%), and pyrexia (30.6%). Grade ≥3 TEAEs occurred in 81.6% of patients, the most common being anemia (20.4%) and neutropenia (22.4%). CRS occurred in 51.4% (18/35) of patients who received the optimized 0.7/4/20 mg step‑up regimen: Grade 1, 40.0% (n=14); Grade 2, 8.6% (n=3); Grade 3, 2.9% (n=1). No cases of ICANS were reported. Grade ≥3 infections occurred in 15 patients (38.8%), with 2 Grade 5 cases; 24.5% of all patients had COVID-19 infection. Five patients (10.2%) discontinued treatment due to TEAEs. No new safety signals were observed.

Conclusions

Odronextamab showed promising efficacy in heavily pretreated patients with rare subtypes of R/R aggressive B-NHL, achieving an ORR of 60.9% and CR rate of 43.5%. Responses were durable, with 54.3% maintaining response at 3 years. The safety profile of odronextamab was generally manageable and consistent with previous reports of bispecific antibodies in lymphoma, with no new safety concerns identified. These findings support the potential role of odronextamab in the treatment paradigm for rare subtypes of R/R aggressive B-NHL. Updated data, including efficacy in each subtype, will be presented.