Introduction

CD19-directed CAR T-cell therapies are an important option for the management of relapsed/refractory (R/R) DLBCL. Studies suggest that ~50% of pts receiving CAR T-cell therapies will relapse within 6 months, with an estimated overall survival (OS) of only 5 months. Additionally, 25-35% of pts do not receive subsequent treatment, indicating a high unmet need. CD19 loss is a potential mechanism of resistance to CAR T-cell therapies; thus, treatments that target alternate B-cell antigens are an attractive option. Here, we report for the first time the primary analysis of the ELM-1 expansion cohort investigating the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in pts with R/R DLBCL progressing after CAR T-cell therapy (NCT02290951).

Methods

Pts aged ≥18 with DLBCL and disease progression after CAR T-cell therapy received intravenous odronextamab weekly in 21-day (D) cycles during Cycles (C) 1-4, with steroid prophylaxis and step-up dosing in C1 (described previously), followed by 160 mg on D 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg Q2W until disease progression or unacceptable toxicity. Pts with complete response (CR) for ≥9 months transitioned to Q4W dosing. All pts received infection prophylaxis. The primary analysis was conducted when all pts had completed ≥9 months of follow-up. Primary endpoint was objective response rate (ORR), as assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and OS. Exploratory endpoints included immune biomarker assessment.

Results

As of January 22, 2024, 60 pts were treated and evaluable for efficacy and safety, with median follow-up of 16.2 months. Prior CAR T-cell therapies were axi-cel (50%), tisa-cel (12%), liso-cel (10%), and not specified (28%). Median time since prior CAR T-cell therapy was 6.5 months (range 1.2-46.2). Median age was 63 years (range 27-82; aged ≥75 years: 10%), and 65% were male. Pts had received a median of 3 prior lines of therapies (range 2-9); 77% of pts were refractory to their last therapy, 77% were double refractory, and 72% were refractory to prior CAR T-cell therapy. 48% of pts relapsed within 90 D of CAR T-cell therapy, and 67% relapsed within 180 D. Of the 20 pts with available tumor biopsies at baseline, 10 were CD19(-) and only 2 were CD20(-). 92% of pts completed C1 and 52% completed ≥4 C of treatment. The median duration of treatment was 12 weeks (range 0.7-154.1).

The ORR and CR rate by ICR were 48% and 32%, respectively, and were consistent across pts with high-risk features and across prior CAR T products. ORR in pts relapsing in ≤90 D was 21% (6/29) and in pts relapsing in ≤180 D was 33% (13/40). ORR was observed even in pts with low CD20. Median DOR was 14.8 months (95% CI 2.8-not estimable [NE]) and median duration of CR was not reached (NR) (95% CI 3.3-NE); the probability of maintaining CR for 24 months was 68%. Median PFS was 4.8 months (95% CI 2.6-5.4) and median OS was 10.2 months (95% CI 4.6-15.8). Median PFS and OS in complete responders was NR.

T-cell counts increased at Week 14 and demonstrated a functional phenotype (CD69 expression and TEMRA count), which was confirmed by ex vivo stimulation. T-cell expansion was observed regardless of CAR T product or time from CAR T administration.

The most common TEAE was CRS (any grade [G]: 48%; G1: 25%; G2: 23%; G≥3: 0%). G≥3 TEAEs occurred in 77% of pts (most common: neutropenia 17%, anemia 13%, and neutrophil and white blood cell count decrease 10% each). Five pts (8%) permanently discontinued odronextamab due to AEs (COVID-19, pneumonia, encephalopathy, epilepsy, and gait disturbance [n=1 each]). There was one treatment-related death (COVID-19 pneumonia). No cases of ICANS were reported. G≥3 infections occurred in 12 pts (20%); 2 were due to COVID-19. No cases of tumor flare or TLS were reported.

Conclusions

ELM-1 is the only study to prospectively evaluate efficacy and safety of a CD20×CD3 bispecific antibody in pts with R/R DLBCL progressing after CAR T-cell therapy. Odronextamab monotherapy was associated with encouraging efficacy and generally manageable safety in a setting with limited treatment options and historically dismal outcomes. Efficacy was observed even in pts relapsing in ≤90 D, supporting the potential of odronextamab as an accessible, off-the-shelf option in the post-CAR T setting.

Disclosures

Matasar:Epizyme: Honoraria; Kite: Honoraria; IMV Therapeutics: Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Merck: Current equity holder in publicly-traded company; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; AstraZeneca: Honoraria; Allogene: Membership on an entity's Board of Directors or advisory committees; GM Biosciences: Consultancy, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria; Pfizer: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS/Celgene: Honoraria; Immunovaccine Technologies: Research Funding. Topp:Autolus Therapeutics: Consultancy; Universitatsklinikum Wurzburg: Current Employment; Incyte: Consultancy; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; Roche: Honoraria, Other: Travel Support, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding. Allan:Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Epizyme: Consultancy; BeiGene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Ansell:Regeneron Pharmaceuticals, Inc.: Research Funding; ADC Therapeutics: Research Funding; SeaGen: Research Funding; Takeda: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Research Funding. Arnason:BMS: Other: Speaker fees; Regeneron Pharmaceuticals, Inc.: Other: Speaker fees. Michot:Institute Gustave Roussy: Current Employment; Curio Sciences: Consultancy; Regeneron Pharmaceuticals, Inc.: Honoraria; Gilead: Consultancy. O'Brien:Regeneron Pharmaceuticals, Inc.: Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Nurix Therapeautics, Inc.: Research Funding; Mustang Bio: Research Funding; Merck: Consultancy; Loxo Oncology, Inc: Consultancy; Kite: Research Funding; Johnson and Johnson: Consultancy; Janssen Oncology: Consultancy; GlaxoSmithKline: Consultancy; Gilead: Research Funding; Eli Lilly and Company: Consultancy; Caribou Biosciences, Inc.: Research Funding; Bristol Myers Squibb: Consultancy; Beigene, Ltd: Consultancy; Autolus: Consultancy; AstraZeneca: Consultancy, Research Funding; Alliance: Research Funding; Vaniam Group LLC: Consultancy; Abbvie: Consultancy. Avivi Mazza:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Cai:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. Zecchini:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. Zhu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company, Other: Current holder of individual stocks in a privately-held company. Brouwer-Visser:Regeneron Pharmaceuticals, Inc.: Current Employment, Other: Shareholder. 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. Crombie:Merck: Research Funding; Genentech: Consultancy; Genmab/Abbvie: Consultancy; Seagen: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy; ADCT: Consultancy; Bayer: Research Funding; Genentech/Roche: Research Funding; Abbvie: Research Funding.

Off Label Disclosure:

Odronextamab, an investigational CD20xCD3 bispecific antibody, for the treatment of patients with relapsed or refractory DLBCL

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2024
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