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866 Efficacy and Safety of Odronextamab Monotherapy in Patients (Pts) with Diffuse Large B-Cell Lymphoma (DLBCL) Progressing after CAR T-Cell Therapy: Primary Analysis from the ELM-1 Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphomas: Pharmacologic Therapies: Novel Monotherapies or Novel Disease Indications
Hematology Disease Topics & Pathways:
Research, Lymphomas, Bispecific Antibody Therapy, Clinical Research, B Cell lymphoma, Diseases, Treatment Considerations, Biological therapies, Lymphoid Malignancies, Study Population, Human
Monday, December 9, 2024: 3:00 PM

Matthew Matasar, MD, MS1, Max S. Topp2*, John N. Allan, MD3, Stephen M. Ansell, MD, PhD4, Jeffrey A. Barnes, MD, PhD5*, Jon E. Arnason, MD6, Jean-Marie Michot7*, Neta Goldschmidt8*, Susan M. O'Brien9, Uri Abadi, MD10,11*, Irit Avivi Mazza12*, Jingxian Cai13*, Julia Zecchini13, Min Zhu13*, Jurriaan Brouwer-Visser13, Aafia Chaudhry13, Hesham Mohamed13, Srikanth Ambati13 and Jennifer L. Crombie, MD14

1Division of Blood Disorders, Rutgers Cancer Institute and RWJBarnabas Health, New Brunswick, NJ
2Universitätsklinikum Würzburg, Würzburg, Germany
3Weill Cornell Medicine, New York, NY
4Mayo Clinic, Rochester, MN
5Massachusetts General Hospital Cancer Center, Boston, MA
6Beth Israel Deaconess Medical Center, Boston, MA
7Gustave Roussy Cancer Campus, Villejuif, France
8Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
9Chao Family Comprehensive Cancer Center, UC Irvine Medical Center, Orange, CA
10Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
11Meir Medical Center, Kfar Saba, Israel
12Ichilov University Hospital, Tel-Aviv, Israel
13Regeneron Pharmaceuticals, Inc., Tarrytown, NY
14Dana-Farber Cancer Institute, Boston, MA

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: Genentech: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Epizyme: Honoraria; GM Biosciences: Consultancy, Research Funding; Merck: Current equity holder in publicly-traded company; ADC Therapeutics: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria; Kite: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria; Allogene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; IMV Therapeutics: Honoraria; AstraZeneca: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; Bayer: Consultancy, Honoraria, 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.

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

*signifies non-member of ASH