Zuma‐22: a phase 3, randomized controlled study of axicabtagene ciloleucel (axi‐cel) vs standard‐of‐care therapy in patients with relapsed/refractory follicular lymphoma

Introduction: Patients with relapsed/refractory (R/R) follicular lymphoma (FL) experience progressively shorter remissions with each successive line of therapy, and the disease is largely considered incurable (Batlevi et al. Blood Cancer J. 2020). Patients who relapsed <24 months after initiating first-line chemoimmunotherapy (POD24) have inferior overall survival compared with those who did not experience POD24 (Casulo, Barr. Blood. 2019). However, outcomes of R/R FL have improved with the introduction of novel options including chimeric antigen receptor (CAR) T-cell therapy, a highly effective approach with potential to change the treatment paradigm (Jacobson et al. Lancet Oncol. 2021; Freedman, Jacobson. Am J Hematol. 2020). Axi-cel, an autologous anti-CD19 CAR T-cell therapy, is approved for the treatment of R/R FL. In ZUMA-5, a single-arm, Phase 2 study of axi-cel in indolent non-Hodgkin lymphoma, patients with FL (n=127) had a median progression-free survival of 40.2 months and median overall survival not yet reached after median follow-up of 41.7 months, with manageable long-term safety (Neelapu et al. ASH 2022. Abstract 4660). In ZUMA-5, POD24 did not adversely affect progression-free survival or overall survival. ZUMA-22 is a Phase 3, open-label, multicenter, randomized controlled trial that will evaluate the efficacy and safety of axi-cel compared with standard-of-care therapy in patients with R/R FL. Methods: The study will enroll approximately 230 adult patients with FL (Grades 1-3a) who have either had 1 prior line of therapy and experienced POD24 or had ≥2 prior lines of systemic therapy. Patients will be randomized 1:1 to receive axi-cel or standard-of-care therapy. Patients in the standard-of-care therapy arm will receive investigator’s choice of either rituximab + lenalidomide, rituximab + CHOP, or rituximab + bendamustine. Patients in the axi-cel arm will undergo leukapheresis, followed by optional bridging therapy, lymphodepleting chemotherapy (fludarabine/cyclophosphamide), and a single axi-cel infusion (2×106 CAR T cells/kg). The primary endpoint is progression-free survival by blinded central assessment per Lugano classification (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete and overall response rates, duration of response, overall survival, event-free survival, time to next treatment, safety, and quality-of-life assessments. Additional key inclusion criteria are ECOG 0-1, presence of ≥1 measurable lesion, and adequate bone marrow and organ function. Those with HIV or hepatitis B or C and an undetectable viral load are eligible. Key exclusion criteria are a history of large B-cell lymphoma or transformed FL, and FL Grade 3b. The study is currently open and actively accruing patients at several sites globally (NCT05371093). Encore Abstract - previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Kite, a Gilead Company Keywords: cellular therapies, indolent non-Hodgkin lymphoma, ongoing trials Conflicts of interests pertinent to the abstract. I. W. Flinn Consultant or advisory role AbbVie, BeiGene, Century Therapeutics, Genentech, Genmab, Hutchison MediPharma, InnoCare Pharma, Kite Pharma, Myeloid Therapeutics, Novartis, Secura Bio, Servier Pharmaceuticals, TG Therapeutics, Vincerx Pharma, and Xencor Research funding: 2seventy bio, AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Biopath, Bristol Myers Squibb, CALIBR, CALGB, Celgene, City of Hope National Medical Center, Constellation Pharmaceuticals, Curis, CTI Biopharma, Epizyme, Fate Therapeutics, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, InnoCare Pharma, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Kite Pharma, Loxo, Marker Therapeutics, Merck, Millennium Pharmaceuticals, MorphoSys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Step Pharma, Tessa Therapeutics, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, Verastem, and Vincerx Pharma C. A. Jacobson Consultant or advisory role Kite, a Gilead Company, Novartis, BMS/Celgene, Instill Bio, ImmPACT Bio, Lonza, Ipsen, Epizyme Blubird Bio, and Daiichi-Sankyo Honoraria: Kite, Novartis, BMS/Celgene, Instill Bio, ImmPACT Bio, Lonza, Ipsen, Epizyme, BlueBird Bio, and Daiichi-Sankyo Research funding: Kite and Pfizer L. J. Nastoupil Honoraria: ADC Therapeutics, BMS/Celgene, Epizyme, Genentech, Janssen, Kite, a Gilead Company, Novartis, and Takeda Research funding: BMS/Celgene, Caribou, Genentech, IGM, Janssen, Kite, Novartis, and Takeda F. Morschhauser Consultant or advisory role AbbVie, Bristol-Myers Squibb, Epizyme, GenMab, Gilead Sciences, Novartis, and Roche Other remuneration: Speakers' bureau participation for Roche; and expert testimony for Roche and Genentech. A. Davies Consultant or advisory role Abbvie, AstraZeneca, Genmab, Kite, a Gilead Company, and Roche Honoraria: Abbvie, AstraZeneca, Bristol Myers Squibb, Genmab, Incyte, Kite, and Roche Research funding: AstraZeneca, Cellcentric, MSD, and Roche Educational grants: Roche C. Buske Consultant or advisory role Gilead Sciences, Janssen, Roche, Pfizer, BeiGene, Celltrion, AbbVie, Incyte, Regeneron, Morphosys, and Novartis Honoraria: AbbVie, BeiGene, Celltrion, Gilead Sciences, Incyte, Janssen, Morphosys, Novartis, Pfizer, Regeneron, and Roche/Genentech Research funding: Amgen, Bayer, Celltrion, Janssen, MSD, Pfizer, and Roche/Genentech Other remuneration: Speaker’s bureau participation with AbbVie, BeiGene, Celltrion, Gilead Sciences, Janssen, Pfizer, and Roche P. Corradini Consultant or advisory role AbbVie, ADC Theraputics, Amgen, BeiGene, Celgene, Daiichi Sankyo, Eli Lilly, GSK, Incyte, Janssen, Kite, a Gilead Company, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, SOBI, and Takeda Honoraria: AbbVie, ADC Theraputics, Amgen, BeiGene, Celgene, Daiichi Sankyo, Eli Lilly, GSK, Incyte, Janssen, Kite, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, SOBI, and Takeda Educational grants: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, Kite, Novartis, Roche, and Takeda A. Lopez-Guillermo Consultant or advisory role Celgene, Incyte, Kite, a Gilead company, Novartis, Roche, and Takeda Research funding: Celgene, Kite, and Roche Educational grants: Kite Other remuneration: Accomodations and expenses from Kite R. Reshef Consultant or advisory role Atara, Gilead Sciences, Jasper, MidaTech, Regeneron, Synthekine, and TScan Honoraria: Gilead Sciences and Novartis Research funding: Atara Biotherapeutics, Incyte, Pharmacyclics, Shire, Immatics, Takeda, Gilead Sciences, Johnson & Johnson, and Precision Biosciences Educational grants: Gilead Sciences Other remuneration: Expert testimony for Bayer; and Data Safety Monitoring Board or Advisory Board participation at University of Pennsylvania A. Sehgal Educational grants: Juno and Kite, a Gilead Company Other remuneration: Grants and contracts from Juno and Kite C. Lui Employment or leadership position: Kite, a Gilead Company Stock ownership: Kite Educational grants: Kite W. Xue Employment or leadership position: Biogen and Kite, a Gilead Company Stock ownership: Biogen and Kite Educational grants: Kite S. Beygi Employment or leadership position: Kite, a Gilead Company Consultant or advisory role Kite Educational grants: Kite N. Grechko Employment or leadership position: Kite, a Gilead Company and Clovis Oncology Consultant or advisory role Kite and Clovis Oncology Educational grants: Kite and Clovis Oncology Other remuneration: Kite P. Bolsue Employment or leadership position: Kite, a Gilead Company Other remuneration: Kite A. Giovanetti Employment or leadership position: Kite, a Gilead Company Consultant or advisory role Kite C. To Employment or leadership position: Kite, a Gilead Company Stock ownership: Gilead Sciences M. Nahas Employment or leadership position: Kite, a Gilead Company Stock ownership: Kite