Dynamics of Complete Responses in Patients with Relapsed or Refractory Follicular Lymphoma Treated with Odronextamab in the ELM-2 Study

Introduction

Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) experience progressively worse outcomes with each successive line of therapy; complete response (CR) rates are 44% with third-line (3L), 27% with 4L, and 22% with 5L+ therapies (Ghione P et al. Haematologica 2023). CR duration is particularly important considering the rapid disease progression observed with 3L+ therapies in pts with FL, with especially poor outcomes in those with high-risk features (Liu J et al. Front Oncol 2023; Philips T et al. ASH 2023). In ELM-2 (NCT03888105), odronextamab (an investigational CD20×CD3 bispecific antibody) demonstrated deep and durable responses and generally manageable safety in pts with R/R FL who had received ≥2 prior lines of systemic therapy. Median progression-free survival (PFS) and overall survival (OS) in pts with CR were 28 months (95% CI 23.0-not evaluable [NE]) and not reached (95% CI 40.4-NE), respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 86% of pts (Taszner M et al. EHA 2024). For the current analysis, we present details on the efficacy and safety of 3L+ odronextamab treatment in pts with R/R FL who attained CR in ELM-2, including those with high-risk features.

Methods

ELM-2 is an ongoing, open-label, multicenter, Phase 2 trial of odronextamab in pts with R/R B-cell non-Hodgkin lymphoma, including a cohort with FL Grade 1-3a. Intravenous odronextamab was administered in step-up doses with steroid prophylaxis during Cycle (C) 1, followed by 80 mg on Days 1, 8, and 15 of C2-4. After C4, dosing continued at 160 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 (ICR). Secondary endpoints included CR rate, PFS, OS, duration of response, and safety.

Results

Primary results in pts evaluable for efficacy and safety (N=128) using the Oct 20, 2023, data cutoff have been reported. Median duration of efficacy follow-up was 20.1 months (95% CI 17.3-27.8). The ORR was 80.5% (103/128 pts; 95% CI 72.5-86.9), and CR rate was 73.4% (94/128; 95% CI 64.9-80.9). Median duration of CR (DOCR) was 25.1 months (95% CI 20.5-NE), and median time to CR was 2.7 months (range 2.3-7.9). Baseline characteristics of pts with CR (n=94) were similar to those of the overall population, and median duration of treatment exposure was 13.8 months (range 1.8-45.0). In total, 88 pts (93.6%) had CR at the first response assessment (~Week 12) and 6 (6.4%) reached CR later, including 3 pts who had stable disease initially.

Twenty-eight pts (29.8%) were still receiving treatment at data cutoff, and 66 (70.2%) had discontinued treatment. Of those who discontinued, 42 still had CR at the last response assessment. Primary reasons for treatment discontinuation were disease progression (n=17), TEAEs (n=16 [including 6 pts with COVID-19]), physician decision (n=12), withdrawal by subject (n=11), and death (n=8). All 8 deaths resulted from TEAEs, including COVID-19 in 5 pts. Eighty-five pts (90.4%) with CR had high-risk features (POD24, 48.9%; FLIPI score 3-5, 55.3%; refractory to last treatment, 70.2%); median DOCR and median time to CR in these pts were similar to those in all pts (23.7 months [95% CI 18.2-NE] and 2.7 months [range 2.3-7.9], respectively).

At the time of the current analysis, 44 pts with CR by ICR (46.8%) had switched to Q4W dosing, with a median duration of exposure of 17.7 months (range 13.1-45.0). Among these pts, 22 had discontinued treatment at data cutoff due to adverse events (n=7 [including 1 with COVID-19]), physician decision (n=6), death (n=3), withdrawal by subject (n=3), progressive disease (n=2), and an “other” reason (n=1).

Conclusions

Pts with R/R FL and CR to 3L+ odronextamab treatment in ELM-2 had a median DOCR of 25.1 months that was prolonged beyond the median duration of treatment exposure (13.8 months). Almost half (46.8%) of pts proceeded to monthly odronextamab administration, with a median duration of treatment exposure of 17.7 months. These data show the sustainability of CR in pts with FL treated with 3L+ odronextamab, including in those with high-risk features. The safety profile of odronextamab was generally manageable in the overall population, including in pts with CR, despite their prolonged drug exposure. These findings support the potential of odronextamab as a treatment for R/R FL.

Luminari:Kite: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Villasboas Bisneto:Aptose: Research Funding; CRISPR: Research Funding; Enterome: Research Funding; Epizyme: Research Funding; Genentech: Research Funding; Regeneron: Research Funding. Chong:Amgen: Research Funding; AstraZeneca: Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Dizal Pharma: Research Funding; HUTCHMED: Research Funding; Incyte: Research Funding; Innate Pharma: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Research Funding; Roche: Research Funding; Takeda: Consultancy. Tucker:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immunovant Corps: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. 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. Otele:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. Antico:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. Jiménez Ubieto:Genmab: Consultancy; Kite-Gilead: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Sandoz: Speakers Bureau; Lilly: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy; Roche: Consultancy, Speakers Bureau.

Odronextamab, an investigational CD20xCD3 bispecific antibody, for the treatment of patients with relapsed/refractory follicular lymphoma.