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LBA-6 Kte-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1

Late-Breaking Abstracts
Program: General Sessions
Session: Late-Breaking Abstracts Session
Tuesday, December 6, 2016, 7:30 AM-9:00 AM
Hall AB (San Diego Convention Center)

Sattva S. Neelapu, MD1, Frederick L. Locke, MD2, Nancy L. Bartlett, MD3, Lazaros Lekakis, MD4*, David Miklos, MD, PhD5, Caron A. Jacobson, MD6, Ira Braunschweig, MD7, Olalekan Oluwole, MBBS, MPH8*, Tanya Siddiqi, MD9, Yi Lin, MD, PhD10*, John Timmerman, MD11, Patrick J. Stiff12, Jonathan Friedberg, MD13, Ian Flinn14, Andre Goy, MD15, Mitchell Smith16, Abhinav Deol, M.D.17, Umar Farooq, MD18, Peter McSweeney, MD19, Javier Munoz, MD20, Irit Avivi, MD21*, Januario E. Castro, MD22, Jason R. Westin, MD MS1, Julio C. Chavez, MD23, Armin Ghobadi, MD24, Krishna V. Komanduri, MD4*, Ronald Levy, MD5, Eric D. Jacobsen6, Patrick Reagan, MD13, Adrian Bot, MD, PhD25*, John M. Rossi, MS25*, Lynn Navale, MS25*, Yizhou Jiang, PhD25*, Jeff S. Aycock, BA25*, Meg Elias, RN, BSN25*, Jeff Wiezorek, MD, MS25* and William Y. Go, MD, PhD25

1The University of Texas MD Anderson Cancer Center, Houston, TX
2H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
3Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO
4University of Miami, Miami, FL
5Stanford University, Stanford, CA
6Dana-Farber Cancer Institute, Boston, MA
7Montefiore Medical Center, Bronx, NY
8Vanderbilt University Medical Center, Nashville, TN
9City of Hope National Medical Center, Duarte, CA
10Mayo Clinic, Rochester, MN
11University of California at Los Angeles, Los Angeles, CA
12Loyola University Medical Center, Maywood, IL
13University of Rochester School of Medicine, Rochester, NY
14Sarah Cannon Research Institute, Nashville, TN
15Hackensack University Medical Center, John Theurer Cancer Center, Hackensack, NJ
16Cleveland Clinic, Cleveland, OH
17Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI
18University of Iowa Carver College of Medicine, Iowa City, IA
19Colorado Blood Cancer Institute, Denver, CO
20Banner MD Anderson Cancer Center, Gilbert, AZ
21Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
22University of California San Diego, San Diego, CA
23H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
24Washington University, St. Louis, MO
25Kite Pharma, Santa Monica, CA

Background: Patients (pts) with refractory aggressive non-Hodgkin lymphoma (NHL) have poor outcomes with currently available therapies, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival (OS) of 6.6 months (mo) as demonstrated in the 635 pt SCHOLAR-1 meta-analysis (Crump, ASCO 2016; abstract 7516). ZUMA-1 is the first multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells in refractory, aggressive NHL (NCT02348216). The phase 1 portion of ZUMA-1 showed ongoing CRs at 12+ mos in 43% of pts (Locke, ESMO 2016; abstract 1048O). The pivotal phase 2 portion of ZUMA-1 comprises 2 cohorts based on tumor type: DLBCL (cohort 1) and primary mediastinal B-cell lymphoma or transformed follicular lymphoma (cohort 2). Here, we present results of a prespecified interim analysis from cohort 1.

Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after a low-dose conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days. The primary endpoint is objective response rate (ORR) per 2007 IWG criteria. Key secondary endpoints include duration of response, frequency of adverse events (AEs), and levels of CAR T cells and serum cytokines. Key inclusion criteria include age ≥18 years, ECOG performance status (PS) 0-1, and refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 mos after autologous stem cell transplant (ASCT). Pts must have received a prior anti-CD20 antibody and an anthracycline-containing regimen. A prespecified interim analysis was to be conducted to determine early efficacy with a nominal alpha level of 0.017 in 50 treated pts in cohort 1 with a minimum follow-up of 3 mos.

Results: In total, 111 pts from 22 institutions were enrolled and leukapheresed, and 101 pts received KTE-C19. As of August 24, 2016, 51 pts in cohort 1 were eligible for analysis. Median age was 58 years (range, 25-76), 73% were male, 71% had ECOG PS 1, 78% were refractory to ≥2 lines of therapy, 20% relapsed ≤12 mos of ASCT, and 61% were treated with ≥3 lines of prior therapy. KTE-C19 was successfully manufactured in 99% of pts enrolled. Average turnaround time from apheresis to receipt of KTE-C19 at the clinical site was 17.4 days.

With an ORR of 76%, the study met the primary endpoint (P<0.0001; exact binomial test comparing observed ORR to a historical control assumption of 20%), with 47% CRs and 29% PRs. 92% of responses occurred within the 1st mo, and 39% of pts had ongoing responses (CR in 33%) at 3 mos. Responses were seen across key covariates, including refractory subgroup (refractory to chemotherapy=76%, relapse post ASCT=80%). Kaplan-Meier estimates of progression-free survival at 1 and 3 mos were 92% and 56%, respectively. The most common grade ≥3 treatment-emergent AEs were neutropenia (67%), anemia (39%), thrombocytopenia (29%), febrile neutropenia (27%), and encephalopathy (24%). Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 20% and 29% of pts, respectively. There was 1 grade 5 KTE-C19–related event of hemophagocytic lymphohistiocytosis.

CAR T cells expanded within 14 days of KTE-C19 infusion, and peak expansion was associated with ongoing response at mo 3 (P=0.008). Pts who developed grade ≥3 neurological events had increased serum levels of IL-15 (P=0.0002), IL-6 (P=0.003); IL-10 (P=0.009) and IP-10 (P=0.0003). Cytokines/chemokines returned to baseline levels in most pts by day 28.

Data from 93 pts with at least 1 mo of follow-up at the data cutoff will be presented.

Conclusions: ZUMA-1 is the first reported multicenter trial of CAR T cell therapy in pts with refractory aggressive NHL. KTE-C19 induced a nearly 6-fold higher CR rate compared to historical outcomes in SCHOLAR-1. Efficacy strongly associated with peak CAR T levels. Central manufacturing, logistics, and AE management were successfully implemented across 22 sites, most with no prior CAR T therapy experience. Results from cohort 2 of ZUMA-1 are also presented (Abstract #998). KTE-C19 demonstrated significant clinical benefit in pts with no curative treatment options.

Supported in part by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program®. Drs Neelapu and Locke contributed equally to this study.

Disclosures: Neelapu: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Locke: Kite: Membership on an entity's Board of Directors or advisory committees. Miklos: Roche: Research Funding; Kite Pharma: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, accomodations and expenses, Research Funding; Novartis: Research Funding; Sanofi Oncology: Other: Travel, accomodations and expenses. Jacobson: Kite: Membership on an entity's Board of Directors or advisory committees. Siddiqi: Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Lin: Mayo Clinic: Employment; Janssen: Research Funding. Timmerman: Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding; Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria. Goy: COTA: Membership on an entity's Board of Directors or advisory committees; Janssen/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution; Acerta: 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, Speakers Bureau; Genentech: Other: Research funding for clinical trials through institution. Smith: Abbvie: Research Funding; Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria. Deol: Jazz Pharmaceuticals: Consultancy. Avivi: Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche. Westin: Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Chavez: Janssen: Speakers Bureau. Levy: Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan: Seattle Genetics: Research Funding. Bot: Kite Pharma: Employment, Equity Ownership. Rossi: Kite Pharma: Employment, Equity Ownership. Navale: Kite Pharma: Employment, Equity Ownership. Jiang: Kite Pharma: Employment, Equity Ownership. Aycock: Kite Pharma: Employment, Equity Ownership. Elias: Kite: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Go: Kite Pharma: Employment, Equity Ownership.

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