Introduction: AZD0486, a novel IgG4 fully human CD19xCD3 bispecific T-cell engager (TCE), is uniquely designed to bind CD3 with low affinity to reduce cytokine release upon T-cell activation, while preserving effective T-cell cytotoxicity against malignant B cells. AZD0486 was active and well tolerated in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL), including those with R/R diffuse large B-cell lymphoma (DLBCL) (Gaballa, et al. Blood. 2023). Here, we present interim results from the ongoing phase 1, dose-escalation trial of AZD0486 in pts with R/R DLBCL (NCT04594642).

Methods: Pts with R/R CD19+ B-NHL that was R/R to ≥2 prior lines of therapy were eligible. Escalating doses of AZD0486 were administered in either fixed target dose (day [D]1, D15 0.03-2.4 mg), single step-up dose (1SUD) (D1 0.27-1 mg, D15 0.8-10 mg), or double SUD (2SUD) (D1 0.27 mg, D8 1 mg, D15 2.4-15 mg) schedules. AZD0486 was given intravenously every 2 weeks in 28-D cycles (C) for up to 2 years (y). Pts in complete response (CR) after C6 were considered for monthly dosing. RECIL 2017 criteria were used to assess response by central imaging review. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per 2019 ASTCT criteria. Adverse events (AEs) were graded by CTCAE v5.0.

Results: As of March 15, 2024, 51 pts with R/R DLBCL received AZD0486 at target doses of ≤0.8 mg (n=2), 2.4 mg (n=18 [2SUD, n=8]), 7.2 mg (n=19 [2SUD, n=15]), and 15 mg (n=12 [2SUD, n=12]). Median prior lines of therapy (pLOT) was 4 (range, 2-9) with 10 (20%) pts having received >5 pLOT. Additionally, 31 (61%) pts previously received chimeric antigen receptor T-cell therapy (CAR-T), 14 (28%) pts previously received polatuzumab vedotin, 4 (8%) received prior CD20 TCE therapy, and 3 (6%) received other CD19-directed therapies; 20 (39%) pts were refractory to last line of therapy. Among the 40 efficacy-evaluable pts who received AZD0486 at doses ≥2.4 mg, the objective response rate (ORR) and CR rate were 43% and 33%, respectively. At a target dose of 7.2 mg, ORR was 47% (9/19) with a 42% (8/19) CR rate. Of 14 pts who previously progressed on CAR-T and received a target dose of 7.2 mg, the ORR and CR rate were 36% and 29%, respectively. Of 5 CAR-T-naive pts who received a target dose of 7.2 mg, ORR and CR rate were both 80%. With a median time on study of 7.5 months (range, 2.1-24.7) for pts who received a target dose of 7.2 mg, there was an estimated 12-mo duration of response rate of 75% and 12-mo overall survival rate of 77%. Grade 3/4 AEs observed in ≥10% of pts with DLBCL who received 2SUD were neutropenia (26%) and anemia (17%). No treatment-related deaths or AEs leading to discontinuation occurred. Among pts who received 2SUD (n=35), CRS events occurred in 12 (34%) pts (all grade 1), grade 1-2 ICANS occurred in 4 (11%) pts, and grade 3 ICANS occurred in 2 (5.7%) pts (0/2 at target dose); all CRS and ICANS events were fully reversible and without sequelae, limited to cycle 1, and did not lead to treatment discontinuation. Exposure-response analyses (n=46) demonstrated a relationship between higher Cavg of AZD0486 and higher probability of ORR and CR, and confirmed higher response rate at target dose of 7.2 mg and 15 mg vs doses ≤2.4 mg.

Conclusion: AZD0486 is active in pts with heavily pretreated DLBCL and responses appear to be target dose-dependent at least up to 15 mg. At target doses evaluated, AZD0486 was well tolerated, with 2SUD mitigating CRS and ICANS events. Dose escalation is ongoing.

Disclosures

Gaballa:Gilead: Consultancy; Eli Lilly: Honoraria; AstraZeneca: Consultancy; Genmab: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy; ADC Therapeutics: Consultancy, Honoraria; Ipsen: Consultancy; Genentech: Consultancy; Regeneron: Consultancy. Devata:Eli Lilly: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Merck: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Bristol Myers Squibb: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Novo Nordisk: Current equity holder in publicly-traded company; Bayer: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Johnson & Johnson: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Research Funding; GSK: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Nair:280 Bio Inc.: Membership on an entity's Board of Directors or advisory committees. Yoon:Abbvie, Abclon, Beigene, BMS, GI cell, GI innovation, GC cell, Verismo, Janssen, Lilly, Novartis, Roche, and Pharos Bio: Consultancy; Regeneron: Membership on an entity's Board of Directors or advisory committees; Asan Medical Center, University of Ulsan College of Medicine: Current Employment; Abbvie, Beigene, Boryung, Celltrion, Kyowa Kirin, Janssen, Samyang and Sanofi: Honoraria, Research Funding. Jacobs:Genentech: Consultancy; AbbVie: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding; Galapagos: Consultancy; Lilly: Consultancy, Research Funding; Beigene: Consultancy, Research Funding, Speakers Bureau; Regeneron: Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Adaptive: Speakers Bureau; SecuraBio: Consultancy. Izutsu:Ono Pharma, Symbio, Takeda: Consultancy, Honoraria; Pfizer, Janssen, Gilead, Daiichi Sankyo: Honoraria, Research Funding; Beigene, Yakult, Otsuka: Consultancy, Research Funding; MSD, AstraZeneca, Genmab, Chugai, BMS, Kyowa Kirin, Novartis, AbbVie: Consultancy, Honoraria, Research Funding; Incyte, Bayer, O Oncology, Regeneron: Research Funding; AstraZeneca, Eli Lily, Astellas, Ono Pharmaceuticals, Eisai, Chugai, Janssen, Symbio, Bristol Myers Squibb, Daiichi Sankyo, Otsuka, Abbvie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, MeijiSeika Pharma, Novartis, Nihon Kayaku, Gilead,: Honoraria; MSD, AstraZeneca, Abbvie, Incyte, Bristol Myers Squibb, Novartis, Bayer, Pfizer, Janssen, Yakult, Kyowa Kirin, Daiichi Sankyo, Chugai, Beigene, Genmab, LOXO Oncology, Otsuka, Regeneron, Gilead: Research Funding; AstraZeneca, Zenyaku, Ono Pharmaceuticals, Mitsubishi Tanabe Pharma, Eisai, Chugai, Bristol Myers Squibb, Takeda, Otsuka, Abbvie, Zenyaku, Kyowa Kirin, MSD, Carna Biosciences, Novartis, Yakult, Nihon Shinyaku, Abe Pharma, Eisai,Beigene: Consultancy. Maruyama:Ono: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Research Funding; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Symbio: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Astellas: Research Funding; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Honoraria, Research Funding; Taiho: Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tam:AstraZeneca: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Lilly: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Sawalha:Beigene: Research Funding; ADC: Consultancy; AbbVie: Research Funding; Genmab: Honoraria, Research Funding. Ramakrishnan:Novartis: Research Funding; BMS: Research Funding; Gracell/AstraZeneca: Research Funding; Janssen: Research Funding; Poseida: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Marker: Research Funding; Cellectis: Honoraria; Juno: Research Funding; Autolus: Research Funding; Sumitomo: Research Funding; Schrodinger: Research Funding; Macrogenics: Research Funding; Fate: Research Funding; Chimeric: Research Funding; Sanofi: Research Funding; Kadmon: Research Funding. Matasar:Epizyme: Honoraria; Merck: Current equity holder in publicly-traded company; Allogene: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals, Inc.: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; IMV Therapeutics: Honoraria; Roche: Consultancy, Honoraria, Research Funding; GM Biosciences: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; BMS/Celgene: Honoraria; AstraZeneca: Honoraria; ADC Therapeutics: Honoraria; Kite: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; Pfizer: Honoraria. Brennan:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Zhu:Novartis Institute for BioMedical Research: Ended employment in the past 24 months; AstraZeneca: Current Employment. Lesley:AstraZeneca: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Oki:AstraZeneca: Current Employment. Sermer:AstraZeneca: Current Employment. Kim:Daiichi Sankyo, HK inno.N, F. Hoffmann-La Roche Ltd/Genentech, Yuhan: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IMBDx Inc: Honoraria; AstraZeneca/MedImmune: Consultancy, Honoraria; Samsung Bioepis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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2024
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