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3319 ZUMA-8: A Phase 1 Study of KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, Biological therapies, Lymphoid Leukemias, clinical trials, CLL, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Clinical Research, Diseases, Therapies, Lymphoid Malignancies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Matthew S. Davids, MD1, Saad S. Kenderian, MD2, Ian W. Flinn, MD PhD3, Brian T. Hill, MD, PhD4, Michael Maris, MD5, Paolo Ghia, MD, PhD6, Michael Byrne, DO7, Nancy L. Bartlett, MD8, John M. Pagel, MD, PhD9, Yan Zheng, MS10*, Justyna Kanska, PhD10*, Wangshu Zhang, PhD10*, Behzad Kharabi Masouleh, MD10*, Enrique Granados, MD, SH10* and Javier Pinilla Ibarz, MD11

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
3Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN
4Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
5Sara Cannon Research Institute, Denver, CO
6Universita' Vita-Salute San Raffaele C.F. 97187560152, Milano, MI, Italy
7Department of Medicine, Division of Hematology and Oncology, Vanderbilt University, Nashville, TN
8Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
9Divison of Oncology, University of Washington School of Medicine, Swedish Cancer Institute, Seattle, WA
10Kite, a Gilead Company, Santa Monica, CA
11Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

Background

Despite recent advances in treatments for patients with chronic lymphocytic leukemia (CLL), such as Bruton’s tyrosine kinase (BTK) inhibitors and a Bcl-2 inhibitor, the disease remains generally incurable (Todorovic Z et al. Curr Oncol. 2022). Brexucabtagene autoleucel (brexu-cel; KTE-X19) is a CD19-directed genetically modified autologous T-cell (CAR T-cell) immunotherapy approved for use in patients with relapsed/refractory (R/R) mantle cell lymphoma and in patients with R/R B-cell precursor acute lymphoblastic leukemia; however, no CAR T-cell therapies are currently approved in CLL. The multicohort, multicenter Phase 1 ZUMA-8 (NCT03624036) trial is the first to evaluate the safety and tolerability of KTE-X19 in patients with R/R CLL.

Methods

In ZUMA-8, patients had R/R CLL after treatment with ≥2 prior lines of therapy (including a BTK inhibitor). Leukapheresis was performed within ~5 days after confirmed eligibility. Optional bridging therapy (continuation of preceding targeted therapy, anti-CD20 antibody, and/or high-dose corticosteroids) before conditioning therapy (CC) was allowed. Patients received 3 days of CC (fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day) before KTE-X19 infusion. Patients in Cohorts 1 and 2 were administered 1 × 106 and 2 × 106 anti-CD19 CAR T cells/kg, respectively. Patients in Cohort 3 (patients who had low tumor burden, defined as ≤1% malignant cells in peripheral blood or absolute lymphocyte count [ALC] <5,000 cells/µL [patients with small lymphocytic lymphoma were also allowed]) and Cohort 4 (patients with any degree of tumor burden who were treated with the BTK inhibitor ibrutinib [alone or in combination] as the last line of therapy up to 30 hours prior to leukapheresis) received a target dose of 1 × 106 anti-CD19 CAR T cells/kg. Patients were hospitalized for observation ≥7 days after infusion. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints were incidence of adverse events (AEs), objective response rate per investigator review according to the International Workshop on Chronic Lymphocytic Leukemia 2018 criteria, and CAR T-cell expansion.

Results

A total of 15 patients received KTE-X19 therapy across Cohort 1 (n=6), Cohort 2 (n=3), Cohort 3 (n=3, all with CLL), and Cohort 4 (n=3). At the data cutoff date of May 2, 2022, the median follow-up duration was 30.3 months (range, 15.5–40.4 months; Table). The median age was 63.0 years (range, 52–79 years), 10 patients (67%) were male, 8 patients (53%) had an Eastern Cooperative Oncology Group performance status of 1, 4 patients (27%) had a 17p deletion, and 7 patients (47%) presented with a complex karyotype (defined as ≥3 clonal chromosomal abnormalities). Patients were heavily pretreated; 12 patients (80%) received >3 prior lines of therapy, and 13 of 15 patients received bridging therapy. DLTs were observed in 1 patient in Cohort 3 (Grade 3–4 hypocalcemia, hyponatremia, hypotension, and cytokine release syndrome [CRS] events that met prespecified criteria for DLTs). Grade ≥3 AEs and Grade ≥3 serious AEs were reported in all patients (100%) and 5 patients (33%), respectively. Grade ≥3 treatment-related AEs were reported in 9 patients (60%). In addition to Grade 4 CRS reported in 1 patient (7%), Grade ≥3 neurologic events were reported in 3 patients (20%). Excluding disease progression, there were no Grade 5 AEs. As of the data cutoff date, objective responses were observed in 7 of 15 patients, including 2 patients with complete responses (CR; Figure). Two of 3 patients with low tumor burden (Cohort 3) achieved CR and 1 patient achieved a partial response. Appreciable CAR T-cell expansion occurred in 4 of 15 patients overall and in 3 of 3 patients with a low tumor burden. Peak CAR T-cell expansion (range, 0–679.38 cells/µL; n=14) had an apparent weak inverse correlation with baseline ALC (range, 0.72–122.95 × 109/L; n=15). Additional translational data will be presented.

Conclusions

KTE-X19 therapy did not have any new safety signals in patients with R/R CLL. Peak CAR T-cell expansion and objective responses in heavily pretreated patients with low tumor burden appeared to be improved compared with other cohorts.

Disclosures: Davids: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Ono Pharmaceuticals: Consultancy; Novartis: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Eli Lilly and Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; TG Therapeutics: Consultancy, Research Funding; Research to Practice: Honoraria; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding. Kenderian: Novartis: Consultancy, Patents & Royalties: CART cell therapy , Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Juno/BMS: Consultancy, Research Funding, Speakers Bureau; Humanigen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: CART cell therapy , Research Funding, Speakers Bureau; Lentigen: Research Funding; Tolero: Research Funding; Viracta/Sunesis: Research Funding; LEAH Labs: Current holder of stock options in a privately-held company, Research Funding; Morphosys: Research Funding; Life Engine: Current holder of stock options in a privately-held company; MustangBio: Patents & Royalties; Mettaforge: Patents & Royalties. Flinn: IGM Biosciences: Research Funding; Celgene: Research Funding; Curis: Research Funding; MorphoSys: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Forma Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Unum Therapeutics: Research Funding; Infinity Pharmaceuticals: Research Funding; Incyte: Research Funding; Loxo@Lilly: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Trillium Therapeutics: Research Funding; Secura Bio: Consultancy; Biopath: Research Funding; CALIBR: Research Funding; CTI Biopharma: Research Funding; Epizyme: Research Funding; 2seventy bio: Research Funding; Verastem: Consultancy, Research Funding; Vincerx Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Novartis: Consultancy, Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Triphase Research & Development Corp: Research Funding; Tessa Therapeutics: Research Funding; TCR2 Therapeutics: Research Funding; Millenium Pharmaceuticals: Research Funding; Fate Therapeutics: Research Funding; InnoCare Pharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Gilead Sciences: Research Funding; Genmab: Consultancy; Century Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; CALGB: Research Funding; Bristol Myers Squibb: Research Funding; Xencor: Consultancy; Myeloid Therapeutics: Research Funding; Rhizen Pharmaceuticals: Research Funding; Portola Pharmaceuticals: Research Funding; ArQule: Research Funding; Agios: Research Funding; Forty Seven: Research Funding; Hutchison MediPharma: Consultancy; City of Hope National Medical Center: Research Funding; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Research Funding; Roche: Consultancy, Research Funding; Takeda: Consultancy; Servier Pharmaceuticals: Consultancy; Kite Pharma: Consultancy, Research Funding. Hill: Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Ghia: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; MSD: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Lilly/Loxo: Consultancy, Honoraria. Byrne: Celularity, Concert: Consultancy, Other: DSMC; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Taiho: Research Funding; Karyopharm: Research Funding. Bartlett: Autolus, Bristol-Meyers Squibb, Celgene, Forty Seven, Janssen, Kite Pharma, Merck, Millennium, Pharmacyclics: Research Funding; Washington University School of Medicine: Current Employment; ADC Therapeutics, Roche/Genentech, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pagel: AsraZeneca: Consultancy; Kite/Gilead: Consultancy; Morphosys/Incyte: Consultancy; Epizyme: Consultancy; Actinium: Consultancy. Zheng: Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. Kanska: Kite, a Gilead company: Current Employment. Zhang: Kite, a Gilead company: Current Employment. Masouleh: Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company, Other: Travel support; Lava: Current equity holder in publicly-traded company. Granados: Kite, a Gilead company: Current Employment. Pinilla Ibarz: AbbVie: Consultancy; SecuraBio: Research Funding; Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Janssen Pharmaceuticals: Consultancy.

*signifies non-member of ASH