Five-Year Outcomes of Patients (Pts) with Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL) Treated with Brexucabtagene Autoleucel (Brexu-cel) in ZUMA-2 Cohorts 1 and 2

Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved in the US and EU for treatment of adults with R/R MCL (after ≥2 prior therapies in EU) based on a high objective response rate (ORR; 93%; 67% complete response [CR] rate) in pts who received the pivotal dose (2×10⁶ anti-CD19 CAR T cells/kg; Cohort 1; N=60) in ZUMA-2 (NCT02601313; Wang et al, N Engl J Med 2020). After ~4 years (y) of median follow-up, Brexu-cel demonstrated a median overall survival (OS) of 46.4 months (mo) in 68 pts with R/R MCL in Cohort 1 (Goy et al. ASH 2023). Cohort 2 was established to assess a lower dose (0.5 x 10⁶ anti-CD19 CAR T cells/kg); however, the risk/benefit ratio of the Cohort 1 dose was deemed the optimal dose before Cohort 2 reached full enrollment. Here we report primary outcomes of Cohort 2 and 5-y outcomes of Cohorts 1 and 2.

Methods: Pts with R/R MCL and ≤5 prior therapies including a BTKi received optional bridging therapy (protocol-defined), lymphodepleting chemotherapy, and 1 infusion of brexu-cel. The primary endpoint was ORR (CR + partial response [PR]) per Lugano classification (Cheson et al. J Clin Oncol. 2014) by independent radiology review committee (IRRC) assessment. Key secondary endpoints were duration of response (DOR), best objective response (BOR), progression-free survival (PFS), OS, and safety. After ≥24 mo of assessment, pts could transition to long-term follow-up (LTFU), NCT05041309, where they were monitored for late-onset targeted/serious adverse events (AEs) possibly related to brexu-cel, presence of replication-competent retrovirus (RCR), and/or insertional mutagenesis. Descriptive statistics are reported herein.

Results: As of the primary analysis data cutoff date, July 24, 2019, 17 pts enrolled in Cohort 2, 14 (82%) of whom were treated with brexu-cel with median follow-up of 16.0 mo (range, 13.9-18.0). Pt characteristics for Cohort 2 (N=14) were similar to Cohort 1; median (range) age and number or prior therapies was 61.5 y (52-73) and 3 (2-5); 100% US-treated, 79% male, 71% extranodal disease, 50% intermediate or high s-MIPI scores, 50% refractory to last therapy, and 43% had prior autologous stem cell transplantation. ORR was 93% (95% CI, 66.1-99.8) per IRRC; 64% had a CR (95% CI, 35.1-87.2), 29% had a PR (95% CI, 8.4-58.1) and 1 pt was not assessed. All 14 pts had ≥1 AE of any grade (Gr), with Gr ≥3 AEs occurring in 93% of pts; the most common being hypotension (50%), white blood cell count decrease (50%), anemia (43%), and neutrophil count decrease (43%). Rates of Gr ≥3 cytokine release syndrome (CRS) and neurological events were 7% and 43%, respectively.

As of April 1, 2024, median follow-up (range) for Cohort 1 and 2 was 67.8 mo (58.2-88.6; N=68) and 72.3 mo (70.1-74.3; N=14), respectively. In Cohort 1, 24 pts were still alive (35%; 2 withdrew consent and 1 lost to follow up) and 44 pts died (65%). In Cohort 2, 8 pts were still alive (57%; 2 withdrew consent and 1 lost to follow up) and 6 pts died (43%). A total of 27 pts (Cohort 1, n=23; Cohort 2, n=4) enrolled in the LTFU study by data cutoff with a median follow-up time of 70.2 mo (range, 58.2-88.6).

Median (95% CI) investigator-assessed DOR and PFS were 36.5 mo (17.7-48.9; n=60; 17 patients in ongoing response, all CR) and 25.3 mo (12.7-46.6; N=68) in Cohort 1; and 57.5 mo (4.7-not estimable [NE]; n=12; 3 pts in ongoing response, all CR) and 29.5 mo (3.3-NE; N=14) in Cohort 2. Median OS (95% CI) and 60-mo OS rates (95% CI) were 46.5 mo (24.9- 60.2) and 38.5% (26.7-50.1) in Cohort 1; and not reached (9.4-NE) and 53.6% (23.8-76.2) in Cohort 2. One pt had 3 ongoing AEs on LTFU, hypogammaglobulinemia and 2 viral infections that arose prior to LTFU. Two pts died on LTFU, both due to progressive disease; no new secondary malignancies or RCR cases were reported.

Conclusions: Consistent with Cohort 1, brexu-cel demonstrated a high ORR, durable responses, and an expected safety profile in pts with R/R MCL in Cohort 2 despite the lower dose. However, small sample size limits interpretation of these results. With >5 y of median follow-up, pts in Cohort 1 and 2 continued to experience durable responses with high 60-mo OS rates. No new safety signals were detected and no secondary malignancies or RCR cases were reported in LTFU. Additionally, ZUMA-2 results are consistent with real-world outcomes of brexu-cel in the post BTKi R/R MCL setting (89% ORR and 81% CR rate; Wang Y, et al. J Clin Oncol. 2023). These results support the continued use of brexu-cel in R/R MCL.

Wang:NIH: Honoraria; Research to Practice: Honoraria; Scripps: Honoraria; Studio ER Congressi: Honoraria; Amphista Therapeutics Limited: Consultancy; ADC Therapeutics: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Nurix: Honoraria; Physicians Education Resources: Honoraria; Merck: Consultancy, Honoraria; MSC National Research Institute of Oncology: Honoraria; Pepromene Oncology: Consultancy; Miltenyi Biomedicine: Consultancy; Oncternal: Consultancy, Research Funding; Lilly: Consultancy, Research Funding; bE Biopharma: Consultancy; Praxel: Consultancy; South African Clinical Hematology Society: Honoraria; WedMD: Honoraria; Deciphera: Consultancy; Genentech: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Juno Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; MJH Life Sciences: Honoraria; Janssen: Honoraria; Genmab: Honoraria, Research Funding; Dava Oncology: Honoraria; Catamount Medical Education: Honoraria; CAHON: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Munoz:Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; Alexion: Consultancy; Targeted Oncology: Honoraria; Physicians' Education Resource: Honoraria; OncView: Honoraria; Curio: Honoraria; Portola: Research Funding; Merck: Research Funding; Bayer: Consultancy, Research Funding; Eli Lilly: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; MEI: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Epizyme: Consultancy; ADC Therapeutics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Genzyme: Consultancy; Genmab: Consultancy; Verastem: Consultancy, Research Funding; Aurobindo: Consultancy; Fosunkite: Consultancy; Alexion: Consultancy; Kyowa: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Gilead/Kite: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics/Abbvie: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/Bristol Myers Squibb, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis,: Consultancy; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, Beigene.: Research Funding; Targeted Oncology, OncView, Curio, Genzyme, and Physicians' Education Resource.: Honoraria. Locke:Iovance: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Cellular Biomedicine Group: Consultancy; Calibr: Consultancy; Celgene: Consultancy; ecoR1: Consultancy; Cowen: Consultancy; Emerging Therapy Solutions Gerson Lehman Group: Consultancy; Moffit Cancer Center: Patents & Royalties: cellular immunotherapy; Sana: Consultancy; Pfizer: Consultancy; CERo Therapeutics: Research Funding; 2SeventyBio: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Bluebird Bio: Consultancy, Research Funding; ASH: Honoraria, Other: Travel support; Gerson Lehrman Group (GLG): Consultancy; GammaDelta Therapeutics: Consultancy; BioPharma: Honoraria; Communications CARE Education: Honoraria; Clinical Care Options Oncology: Honoraria; Caribou: Consultancy; A2: Consultancy; Umoja: Consultancy; BMS: Consultancy, Research Funding; Aptitude Health: Honoraria; Aptitude Health: Honoraria; Leukemia and Lymphoma Society Scholar in Clinical Research: Research Funding; National Cancer Institute: Research Funding; Gilead Company: Consultancy; Legend Biotech: Consultancy; iMedX: Honoraria; Society for Immunotherapy of Cancer: Honoraria; Wugen: Consultancy; Novartis: Consultancy, Research Funding; Allogene: Consultancy, Research Funding. Jacobson:Caribou Biosciences: Consultancy; Daiichi Sankyo: Consultancy; ImmPACT Bio: Consultancy; Instil Bio: Consultancy; Novartis: Consultancy; Abintus Bio: Consultancy; ADC Therapeutics: Consultancy; Ipsen: Consultancy; Pfizer: Research Funding; Synthekine: Consultancy; Miltenyi: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Bristol Myers Squibb/Celgene: Consultancy; MorphoSys: Consultancy; AbbVie: Consultancy. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Timmerman:Merck Sharp & Dohme: Research Funding; Cargo Therapeutics: Research Funding; Kite, a Gilead Company: Research Funding; Regeneron: Research Funding; Sobi: Consultancy. Flinn:Vincerx Pharma, 2seventybio: Research Funding; Myeloid Therapeutics: Research Funding; Novartis: Research Funding; Nurix: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; Step Pharma: Research Funding; Tessa Therapeutics: Research Funding; TG Therapeutics: Research Funding; MorphoSys: Research Funding; Merck: Research Funding; Millennium Pharmaceuticals: Research Funding; Marker Therapeutics: Research Funding; Loxo: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Incyte: Research Funding; IGM Biosciences: Research Funding; Gilead Sciences: Research Funding; InnoCare Pharma: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Epizyme: Research Funding; CTI: Research Funding; Biopharma: Research Funding; Curis: Research Funding; Constellation Pharmaceuticals: Research Funding; City of Hope Medical Center: Research Funding; Celgene: Research Funding; CALGB: Research Funding; CALIBR: Research Funding; BioPath: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; Agios: Research Funding; Acerta: Research Funding; Roche: Consultancy; Vincerx: Consultancy; Kite, a Gilead Company: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Vincerx Advisory Committee: Membership on an entity's Board of Directors or advisory committees; Tennessee Oncology & OneOncology: Current Employment; Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding. Miklos:Miltenyi: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Juno Therapeutics: Consultancy; Adicet: Research Funding; Fosun Kite Biotechnology: Honoraria; Adaptive Biotechnologies: Research Funding; Janssen: Consultancy, Patents & Royalties; 2SeventyBio: Research Funding; Novartis: Consultancy; Galapagos: Consultancy; Kite, a Gilead Company: Consultancy, Other: Travel Support, Research Funding; Allogene: Research Funding. Pagel:AstraZeneca: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy; MorphoSys/Incyte: Consultancy; Actinium: Consultancy; Eli Lilly and Company: Current Employment. Kersten:AbbVie: Other: Travel support; Adicet Bio: Honoraria; BeiGene: Honoraria; BMS/Celgene: Honoraria; Galapagos: Honoraria; Kite, a Gilead company: Honoraria, Research Funding; Miltenyi Biotec: Honoraria; Novartis: Honoraria; Roche: Honoraria. Forcade:Alexion: Other: Travel support, Speakers Bureau; Maat Pharma: Consultancy; Gilead: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; Sanofi: Other: Travel support, Speakers Bureau; Novartis: Other: Travel support, Speakers Bureau; Astellas: Research Funding; GSK: Speakers Bureau; Sobi: Speakers Bureau; Novartis: Consultancy. Topp:Universitatsklinikum Wurzburg: Current Employment; Roche: Honoraria, Other: Travel Support, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Autolus Therapeutics: Consultancy; Incyte: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; AbbVie: Consultancy. Houot:BMS/Celgene: Honoraria; Gilead Sciences: Consultancy, Honoraria; ADC Therapeutics: Honoraria; Janssen: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria. Beitinjaneh:Autolus: Consultancy, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Atara: Research Funding; CRISPOR: Research Funding; Lyell: Research Funding; Tessa: Research Funding. Zheng:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company, Honoraria, Other: Travel support. Chang:Kite, a Gilead Company: Current Employment; BeyondSpring Pharmaceuticals Inc.: Current holder of stock options in a privately-held company. Shen:Kite, a Gilead Company: Current Employment, Patents & Royalties; Gilead Sciences: Current holder of stock options in a privately-held company; Atara: Patents & Royalties. Zhang:Kite, a Gilead Company: Current Employment. Damico Khalid:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company, Other: Travel Support. Kloos:Kite, a Gilead Company: Current Employment. Reagan:Kite, a Gilead Company: Consultancy, Honoraria; Genentech: Research Funding; Seagen: Research Funding; Caribou Biosciences: Consultancy.