KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study
Authors: Wang Michael L. , Munoz Javier , Goy Andre , Locke Frederick L. , Jacobson Caron A. , Hill Brian T. , Timmerman John M. , Holmes Houston , Jaglowski Samantha , Flinn Ian W. , McSweeney Peter A. , Miklos David B. , Pagel John M. , Kersten Marie Jose , Peng Weimin , Zheng Lianqing , Rossi John M. , Jain Rajul K. , Rao Arati V. , Reagan Patrick M 
Published: February 2020

Background: Outcomes with salvage regimens in pts with MCL who progress after Bruton tyrosine kinase inhibitor (BTKi) therapy are poor, with a median overall survival (OS) of 5.8 months (Martin, et al. Blood. 2016) and few pts proceeding to allogeneic stem cell transplant. ZUMA-2 is a Phase 2, registrational, multicenter, global study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL who received 1-5 prior therapies, including a BTKi. Here, we present interim efficacy and safety results from ZUMA-2.
Methods: Eligible adults (aged ≥ 18 years) with R/R MCL had an ECOG score of 0 - 1 and ≤ 5 prior therapies, including chemotherapy, an anti-CD20 antibody, and a BTKi. Pts underwent leukapheresis and conditioning chemotherapy (cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days) followed by a single infusion of KTE-X19 at a target dose of 2 × 106 CAR T cells/kg. Pts could have received bridging therapy with dexamethasone, ibrutinib, or acalabrutinib after leukapheresis and before conditioning chemotherapy at the investigator's discretion. The primary endpoint was objective response rate (ORR [complete response (CR) + partial response]) assessed by an Independent Review Committee according to the Lugano Classification (Cheson, et al. J Clin Oncol. 2014). Interim efficacy endpoints were investigator-assessed using the revised IWG Response Criteria for Malignant Lymphoma (Cheson, et al. J Clin Oncol. 2007). Key secondary endpoints were duration of response (DOR), progression-free survival (PFS), OS, frequency of adverse events (AEs), levels of CAR T cells in blood, and levels of cytokines in serum. Efficacy and safety analyses included all pts who received KTE-X19. A total of 60 pts received KTE-X19; here, we present results in pts who had ≥ 1 year of follow-up. Updated safety and efficacy results in the full 60 pts, including pts who received revised AE management with the aim of decreasing toxicity, will be reported in the presentation.
Results: As of May 30, 2018, 28 pts received KTE-X19 with ≥ 1 year of follow-up (median 13.2 months [range, 11.5 - 18.5]). The median age was 65 years (range, 50 - 75) and 86% of pts were male. Forty-three percent of pts had ECOG score of 1, 21% had blastoid morphology, 82% had stage IV disease, 50% had intermediate/high-risk MIPI, 86% received a median of 4 (range, 1 - 5) prior therapies, and 57% were refractory to last prior therapy. In 20/28 pts with available data, the median Ki-67 index was 38% (range, 5% - 80%). Eight pts received bridging therapy; all had disease present post-bridging.
Investigator-assessed ORR was 86% (95% CI, 67% - 96%) with a CR rate of 57% (95% CI, 37% - 76%). As of May 30, 2018, 75% of responders remained in response and 64% of treated pts had ongoing responses. The 12-month estimates of DOR, PFS and OS were 83% (95% CI, 60% - 93%), 71% (95% CI, 50% - 84%), and 86% (95% CI, 66% - 94%), respectively and the medians were not reached. The most common Grade ≥ 3 AEs (≥ 20% of pts) were anemia (54%), platelet count decreased (39%), neutropenia (36%), neutrophil count decreased (32%), white blood cell count decreased (29%), encephalopathy (25%), and hypertension (21%). Grade 3/4 cytokine release syndrome (CRS) assessed by Lee et al. (Blood. 2014) was reported in 18% of pts, most commonly manifesting as hypotension (14%), hypoxia (14%), and pyrexia (11%). Grade 3/4 neurologic events (NE) were reported in 46% of pts and included encephalopathy (25%), confusional state (14%), and aphasia (11%). No Grade 5 CRS or NE occurred. All CRS events and most NE (15/17 pts) were reversible. Median time to onset and resolution of CRS was 2 days (range, 1 - 7) and 13 days (range, 4 - 60), respectively. Median time to onset of NE was 6 days (range, 1 - 15) and median time to resolution was 20 days (range, 9 - 99). There was 1 Grade 5 AE of organizing pneumonia that was considered related to conditioning chemotherapy. Median CAR T cell levels as measured by peak and area under the curve were 99 cells/µL (range, 0.4 - 2589) and 1542 cells/µL (range, 5.5 - 27239), respectively. Peak CAR T cell expansion was observed between Days 8 and 15 and declined over time.
Conclusions: ZUMA-2 is the first multicenter Phase 2 study of CAR T cell therapy in pts with R/R MCL. With ≥ 1 year of follow-up, KTE-X19 demonstrated significant and durable clinical benefit, including a majority of pts achieving CR, and a manageable safety profile in pts with R/R MCL for whom there are no curative treatment options.

Disclosures
Wang: VelosBio: Research Funding; Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding. Goy:Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Jacobson:Humanigen: Consultancy, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Bayer: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support; Celgene: Consultancy, Other: travel support; Pfizer: Research Funding. Hill:Amgen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Takeda: Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding. Timmerman:Spectrum Pharmaceuticals: Research Funding; Kite, A Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; Merck: Research Funding; ImmunGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: travel support, Research Funding. Holmes:ADC Therapeutics: Research Funding; Kite, A Gilead Company: Consultancy, Speakers Bureau; Genentech: Research Funding; Janssen: Consultancy; Rigel: Consultancy, Speakers Bureau; Bayer: Consultancy; Novartis: Research Funding; Unum: Research Funding; Gilead: Consultancy; Juno: Consultancy; Seattle Genetics: Research Funding, Speakers Bureau. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board; Novartis: Consultancy, Other: advisory board, Research Funding. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. McSweeney:Fred Hutchinson Cancer Research Center: Patents & Royalties; Colorado Blood Cancer Institute Medical Group: Employment; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Miklos:AlloGene: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Kite, A Gilead Company: Consultancy, Research Funding; Celgene-Juno: Consultancy; Novartis: Consultancy; Miltenyi: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Becton Dickinson: Consultancy; Precision Bioscience: Consultancy. Pagel:Gilead Sciences: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy. Kersten:Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Gilead: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards. Peng:Kite, A Gilead Company: Employment. Rossi:Kite, A Gilead Company: Employment. Jain:Vida Ventures: Employment; Kite, A Gilead Company: Employment, Equity Ownership, Other: Travel support; Amgen: Equity Ownership. Rao:Kite, A Gilead Company: Employment. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding.

OffLabel Disclosure:
ZUMA-2 is a clinical trial evaluating KTE-X19, an investigational CAR T cell therapy