Dynamics of Complete Responses in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with Odronextamab in the ELM-2 Study

Introduction

Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of B-cell non-Hodgkin lymphoma (B-NHL). Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard of care for the first-line (1L) treatment of patients (pts) with DLBCL; however, up to 50% of pts are refractory to or relapse after 1L chemoimmunotherapy, and outcomes worsen with each subsequent relapse (Ip A et al. Adv Ther 2024). In ELM-2 (NCT03888105), odronextamab (an investigational CD20×CD3 bispecific antibody) demonstrated encouraging efficacy and generally manageable safety in pts with relapsed/refractory (R/R) DLBCL who had received ≥2 prior lines of systemic therapy. Median progression-free survival (PFS) and overall survival (OS) in pts with complete response (CR) were 20.4 months (95% CI 12.7-not evaluable [NE]) and not reached (95% CI 17.2-NE), respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 84.3% of pts (Ayyappan S et al. ASH 2023). For the current analysis, we present details on the efficacy and safety of 3L+ odronextamab treatment in pts with R/R DLBCL who attained CR in ELM-2.

Methods

ELM-2 is an ongoing, open-label, multicenter, Phase 2 trial of odronextamab in pts with R/R B-NHL, including a cohort with DLBCL. Intravenous odronextamab was administered in step-up doses with steroid prophylaxis during Cycle (C) 1, followed by 160 mg on Days 1, 8, and 15 of C2-4. After C4, dosing continued at 320 mg once every 2 weeks (Q2W); pts switched to Q4W dosing if they had a durable CR for ≥9 months. The primary endpoint was objective response rate (ORR) according to Lugano classification, by independent central review. Secondary endpoints included CR rate, PFS, OS, duration of response, and safety.

Results

Primary results in pts with R/R DLBCL evaluable for efficacy and safety (N=127) using the Aug 18, 2023, data cutoff have been reported previously. As of the Oct 20, 2023, data cutoff, median duration of efficacy follow-up was 32.5 months (95% CI 17.4-36.3). The ORR was 52.0% (66/127 pts; 95% CI 42.9-60.9), and the CR rate was 31.5% (40/127; 95% CI 23.5-40.3). Median duration of CR (DOCR) was 17.9 months (95% CI 10.2-NE), and median OS in pts with CR was 38.6 months (95% CI 19.8-NE). Among the 40 pts with CR, median age was 71 years, 1 patient had triple-hit DLBCL, and median duration of treatment exposure was 11.4 months (range 2.6-40.5). Of these pts, 32 had CR at the first response assessment (~Week 12) and 8 reached CR at a later time point, including 2 pts who had stable disease initially.

At the time of the current analysis, 8 pts (20.0%) were still receiving treatment, and 32 (80.0%) had discontinued treatment (27 who still had CR at the last response assessment and 5 who had progressive disease). Among the 27 pts with CR who discontinued, the median duration of treatment exposure was 10.1 months (range 2.6-31.5), compared with 4.1 months (0.2-40.5) in the overall study population. Reasons for treatment discontinuation included TEAEs (n=9), physician decision (n=9), death (n=8), and progressive disease (determined by clinical assessment but not confirmed radiologically; n=1). TEAEs included COVID-19 in 3 pts, which was detected 11.0, 26.7, and 31.1 months after treatment initiation. All 8 deaths resulted from TEAEs, including infections and infestations in 7 pts (COVID-19 in 2 pts).

Fifteen pts (37.5%) were able to switch to Q4W dosing, 14 of whom still had CR at the last response assessment. In pts who switched to Q4W dosing, the median duration of exposure was 19.8 months (range 15.4-40.5), and 9 pts discontinued treatment. Reasons for treatment discontinuation were physician decision (n=4), TEAEs (n=2), death (n=2, attributed to COVID-19), and progressive disease (n=1).

Conclusions

Pts with R/R DLBCL and CR to 3L+ odronextamab treatment in ELM-2 had a median DOCR of 17.9 months that was prolonged beyond the median duration of treatment exposure (11.4 months). Over a third (37.5%) of pts proceeded to monthly odronextamab administration, with a median duration of treatment exposure of 19.8 months. The findings reported here show the sustainability of CR in pts with DLBCL treated with 3L+ odronextamab and demonstrate the generally manageable safety profile of odronextamab despite prolonged drug exposure, thus supporting the potential of odronextamab as a treatment for R/R DLBCL.

Ayyappan:ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Iowa Oncology Society: Speakers Bureau; PeerView: Speakers Bureau; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; TotalCME: Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Speakers Bureau. Prince:Bristol Myers Squibb: Honoraria; GSK: Honoraria; Amgen: Honoraria; Johnson and Johnson: Honoraria; Takeda: Honoraria; Mallinckrodt: Honoraria; AbbVie: Research Funding; Kyowa Kirin: Honoraria. Carpio:Gilead: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Regeneron Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AstraZeneca: Honoraria. Jarque:Pfizer: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BeiGene: Research Funding; Incyte: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; Gilead: Honoraria; Grifols: Honoraria; Novartis: Consultancy; Kyowa Kirin: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Lin:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Antico:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. Otele:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. Walewski:Polish Myeloma Consortium: Research Funding; Polish Lymphoma Research Group (PLRG): Research Funding; NanoVector: Research Funding; MSD: Consultancy, Research Funding; MorphoSys: Research Funding; Karyopharm: Research Funding; Janssen-Cilag: Research Funding; Incyte: Research Funding; GSK: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; Bristol Myers Squibb/Celgene: Research Funding; AstraZeneca/MedImmune: Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Research Funding; Roche: Honoraria; Seagen: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Vanda Pharmaceuticals: Research Funding.

Odronextamab, an investigational CD20xCD3 bispecific antibody, for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma.