Odronextamab in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Grade 1-3a: Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2

Background Odronextamab is a hinge-stabilized, human IgG4-based CD20×CD3 bispecific antibody that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity of malignant B cells. In ELM-1 (Ph1, NCT02290951), pts with FL Grade 1-3a receiving ≥2 prior lines of therapy and treated with odronextamab doses of ≥5 mg, had an ORR of 91% and CR rate of 72%. Responses were durable with a 4-y PFS rate of 54% (Bannerji R, et al. Lancet Haematol. 2022). The RP2D dose in R/R FL pts was determined as 80 mg weekly. Here, we present for the first time, results from a prespecified analysis of the FL Grade 1-3a cohort from the pivotal ELM-2 study (Ph2, NCT03888105), which incorporated an optimized step-up regimen designed to maintain efficacy while minimizing acute toxicity including cytokine release syndrome (CRS).

Methods ELM-2 is a global, multicenter study enrolling pts at 91 sites in 13 countries. Adult pts with FL Grade 1-3a who had relapsed or were refractory to ≥2 prior lines of therapy including an anti-CD20 antibody and alkylator were enrolled. IV odronextamab was administered in 21-day cycles with steroid prophylaxis and weekly step-up dosing during Cycle (C) 1 to mitigate risk of acute toxicity. The initial step-up regimen consisted of 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 80 mg full dose on C1D15 (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate CRS risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16, followed by the 80 mg full dose on C2D1 (0.7/4/20 regimen). 80 mg weekly continued until the end of C4. After C4, maintenance treatment with 160 mg odronextamab occurred every 2 wks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to Lugano 2014 criteria. CRS was assessed using 2019 ASTCT criteria.

Results As of April 20, 2022, 96 pts were evaluable for safety; 85 for efficacy. Median age 59 y (range 22-84), 52% male, 58% FLIPI 3-5, 15.6% had bulky disease, and median prior lines of therapy were 3 (range 2-13). 74% were refractory to their last therapy, 79% refractory to prior anti-CD20 therapy, and 48% had progression of disease within 2 y (POD24). Median duration of study follow-up was 17.3 mos. ORR and CR rate by ICR were 81% (69/85) and 75% (64/85), respectively. ORR and CR rate were consistent across high-risk subgroups, including pts aged ≥65 y, POD24, FLIPI 3-5, and pts refractory to their last line of therapy; ORR and CR rate were also consistent for the subgroup of pts treated with the 0.7/4/20 step-up regimen. Responses were durable with both a median duration of response and a median duration of CR of 18.2 mos. Median PFS was 20.2 mos (95% CI 14.8-not estimable [NE]) and median OS was not reached (95% CI 23.0 mos-NE).

TEAEs occurred in 95 (99%) pts, considered treatment related in 86 (90%). In the overall safety evaluable population, the most common TEAEs (>30% all grades) were CRS (51%), pyrexia (32%), anemia (31%), and infusion-related reaction (31%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥2 CRS was observed; only Grade 1 CRS was reported in 39% of pts. All CRS events resolved and only 1 pt received tocilizumab for CRS management. No ICANS was reported in the 0.7/4/20 regimen compared with 3% in the 1/20 regimen. COVID-19 was reported (n=13,14%), including Grade ≥3 (n=5, 5%). Treatment-related Grade 5 AEs were reported for 2 pts; treatment-related AEs led to discontinuation in 6 pts.

Conclusions Consistent with the ELM-1 Ph1 study, the ELM-2 pivotal Ph2 study of odronextamab demonstrated compelling efficacy in pts with FL Grade 1-3a receiving ≥2 prior lines of therapy, with 75% of pts achieving CR by ICR and an acceptable safety profile. Durability of responses and favorable survival outcomes are clinically important in the context of heavily pretreated, highly R/R FL, where prognosis is typically poor. The 0.7/4/20 step-up regimen compares favorably to other CD20×CD3 bispecifics, with no Grade 2 or higher CRS reported. Odronextamab may represent an important treatment option for R/R FL, providing a more accessible option with favorable benefit/risk compared with existing therapies including CAR T cell therapy. Updated safety and efficacy data will be presented.

Kim:Celgene: Other: Clinical trial research funding to my institution; Boryung: Consultancy, Other: Clinical trial research funding to my institution; Boehringer-Ingelheim: Other: Clinical trial research funding to my institution; BMS: Other: Clinical trial research funding to my institution; Bayer: Consultancy, Other: Clinical trial research funding to my institution; AstraZeneca/MedImmune: Consultancy, Other: Clinical trial research funding to my institution; Takeda: Consultancy, Honoraria, Other: Clinical trial research funding to my institution; Roche/Genentech: Consultancy, Honoraria, Other: Clinical trial research funding to my institution; Novartis: Consultancy, Honoraria, Other: Clinical trial research funding to my institution; Janssen: Consultancy, Honoraria, Other: Clinical trial research funding to my institution; Hanmi: Consultancy, Honoraria, Other: Clinical trial research funding to my institution; AstraZeneca: Honoraria; AstraZeneca-KHIDI: Research Funding; Genmab: Other: Clinical trial research funding to my institution; Merck Serono: Other: Clinical trial research funding to my institution; Merck Sharp & Dohme: Other: Clinical trial research funding to my institution; Regeneron: Consultancy, Other: Clinical trial research funding to my institution; Sanofi: Other: Clinical trial research funding to my institution. Taszner:Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BeiGene: Research Funding. Novelli:Mundipharma: Consultancy; Novartis: Research Funding. Le Gouill:Novartis, Kite/Gilead, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Villasboas:Aptose: Research Funding; CRISPR: Research Funding; Enterome: Research Funding; Epizyme: Research Funding; Kite Pharma: Research Funding; Regeneron: Research Funding. Champion:AbbVie: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Bachy:Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Hospices Civils de Lyon: Current Employment; Amgen, BMS: Research Funding. Guidez:Gilead Kite: Honoraria; Takeda: Honoraria; Incyte: Honoraria; AstraZeneca: Honoraria. Alonso Alonso:AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria. Jagadeesh:ATARA Biotherapeutics: Research Funding; AstraZeneca: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees; LOXO Pharmaceuticals: Research Funding; Debio pharma: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; MEI Pharma: Research Funding; Seagen: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium Pharmaceuticals: Research Funding. Tucker:Immunovant Corps: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cai:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Leite De Oliveira:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Zhu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees.

Odronextamab for the treatment of patients with follicular lymphoma.