Sherman, Marika

Abstract Background: ZUMA-1 is a pivotal, multicenter trial of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, for the treatment of patients with refractory, aggressive NHL. The objective response rate (ORR) was 82% with a 54% rate of complete response and 44% of responses were ongoing at the time of the primary analysis (Locke et al. AACR 2017. #9986). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 13% and 28% of patients, respectively. A safety expansion cohort was added to further characterize mechanisms underlying CRS and NE associated with CAR T cell therapy and to evaluate the impact of prophylactic use of tocilizumab and levetiracetam on the rates of these adverse events (AEs). Methods: Patients (≥ 18 years) must have had an Eastern Cooperative Oncology Group performance status of 0-1 and refractory or relapsed transplant ineligible disease. Patients received low-dose conditioning of 500 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days followed by axi-cel at a target dose of 2 × 106 CAR T cells/kg. Patients also received prophylactic treatment with 750 mg of levetiracetam twice a day on day 0 and 8 mg/kg of tocilizumab on day 2 post axi-cel infusion. To evaluate the mechanisms of NE, paired serum and cerebrospinal fluid (CSF) were obtained for all patients prior to conditioning chemotherapy and after axi-cel infusion (day 5). Results: As of April 26, 2017, 31 patients received axi-cel. Median age was 51 years (range, 21-74), 52% were male, 65% had stage III-IV disease, 74% were refractory to ≥ second-line therapy, and 19% relapsed ≤ 12 months after autologous stem cell transplant. Most patients (97%) experienced at least 1 grade ≥ 3 AE. The most common grade ≥ 3 AEs were neutropenia/neutrophil count decreased (71%), anemia (55%), thrombocytopenia/platelet count decreased (52%), leukopenia/white blood cell count decreased (35%), febrile neutropenia (29%), encephalopathy (23%), and hypotension (23%). One patient (3%) experienced a grade ≥ 3 (grade 4) CRS. Grade 3 and 4 NE occurred in 29% and 6% of patients, respectively. One patient died of cerebral edema; there were no other deaths due to AE. Updated efficacy, safety, subgroups, and paired blood/serum/CSF biomarker associative analyses will be presented. Conclusions : Early use of tocilizumab may reduce the incidence of severe CRS but not NE in patients treated with CAR T cell therapy. These data provide evidence that the underlying pathophysiology of NE may differ from that of CRS. Understanding the mechanisms of NE may help to further improve the benefit:risk profile for CAR T cell therapy. Drs Locke and Neelapu contributed equally to this work. Disclosures Locke: Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Neelapu: Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Poseida: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jacobson: Pharmacyclics, LLC: Consultancy; Kite Pharma: Consultancy. Braunschweig: Kite Pharma: Equity Ownership. Oluwole: Kite Pharma: Consultancy. Siddiqi: Seattle Genetics: Speakers Bureau; Juno: Other: Steering committee for JCAR017; Pharmacyclics, an AbbVie Company: Other: Steering committee for ibrutinib, Speakers Bureau. Timmerman: Celgene: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Research Funding; ImmuneGene: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership. Reagan: Seattle Genetics: Research Funding. Bot: Kite Pharma: Employment, Equity Ownership. Rossi: Kite Pharma: Employment, Equity Ownership. Sherman: 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 Pharma: Employment, Equity Ownership. Wiezorek: Kite Pharma: Employment, Equity Ownership. Go: Kite Pharma: Employment, Equity Ownership. Miklos: Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Roche: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel expenses; Sanofi: Honoraria.

Abstract ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

Background: Relapsed/refractory (R/R) large B cell lymphoma (LBCL) is associated with poor outcomes to standard salvage therapy (Crump M, et al. Blood. 2017). In SCHOLAR-1, a large multicenter, patient-level, retrospective study, patients with R/R diffuse LBCL had a 26% objective response rate (ORR) to the next line of therapy, a 7% complete response (CR) rate, and a median overall survival of 6.3 months (Crump M, et al. Blood 2017). Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for patients with R/R LBCL with ≥ 2 prior systemic therapies. With a median follow-up of 27.1 months in ZUMA-1, the ORR with axi-cel was 83% (58% CR rate) in patients with refractory LBCL (Locke FL, et al. Lancet Oncol. 2019). Activation of the costimulatory receptor 4-1BB (CD137) on CAR T cells may enhance axi-cel antitumor activity by enhancing T cell proliferation, function, and survival. Utomilumab (uto), an investigational monoclonal antibody agonist of the 4-1BB pathway, enhanced T cell function and survival in preclinical studies (Fisher TS, et al. Cancer Immunol Immunother. 2012) and had favorable single-agent safety in patients (Segal NH, et al. Clin Cancer Res. 2018). Possible mechanisms of resistance to axi-cel are thought to be suboptimal CAR T cell expansion an exclusionary tumor microenvironment and CD19 target antigen loss (Neelapu SS, et al. Blood 2017, Rossi JM, et al J Immunother Cancer. 2018). Combination strategies that increase proliferation, expansion, and persistence of CAR T cells or prevent activation-induced cell death of CAR T cells may improve clinical outcomes observed with axi-cel. ZUMA-11 is a Phase 1/2 study investigating the efficacy and safety of axi-cel + uto in patients with refractory LBCL. Methods: The primary objectives of this study are to determine the safety, recommended Phase 2 dosing and timing (Phase 1), and efficacy (Phase 2) of axi-cel + uto in adult patients with refractory LBCL. Patients with progressive or stable disease as the best response to second-line chemotherapy or relapse ≤ 12 months after autologous stem cell transplantation, a prior anti-CD20 antibody and anthracycline-containing regimen, and Eastern Cooperative Oncology Group performance status 0-1 are eligible. Patients with histologically proven primary mediastinal B cell lymphoma, history of Richter's transformation or chronic lymphocytic lymphoma, prior CAR T cell therapy, or central nervous system involvement of lymphoma are ineligible. In Phase 1, ≈24 patients in ≤ 3 cohorts will receive a single dose of axi-cel and escalating doses of uto (10, 30, or 100 mg) using a 3 + 3 design in up to 4 of 6 cohorts. The recommended uto dose will be based on dose-limiting toxicities and other factors. Patients will be leukapheresed and may receive optional, nonchemotherapy bridging therapy per investigator decision. After conditioning chemotherapy, patients will receive a single infusion of axi-cel (target dose, 2 × 106 CAR T cells/kg) on Day 0 followed by uto on Day 1 and every 4 weeks for 6 months or until progressive disease. Patients will be treated one at a time during Phase 1, and patients treated with axi-cel will be staggered by ≥ 2 weeks. Day 21 uto administration will be explored if toxicity is unacceptable with Day 1 administration. The primary endpoints are incidence of dose-limiting toxicities in Phase 1 and CR rate in Phase 2. Secondary endpoints include ORR, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells and cytokines in blood. This study uses a single-arm design to estimate the true CR rate; with a sample size of 27 patients, of which ≤ 3 patients will have been treated in the Phase 1 portion, the maximum half-width of the 95% confidence interval about response will be ≥ 21%. ZUMA-11 is open and accruing patients. Disclosures Reshef: Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Incyte: Consultancy, Research Funding; Shire: Research Funding; BMS: Consultancy; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding. Miklos:Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Precision Bioscience: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Miltenyi: Consultancy, Research Funding; Becton Dickinson: Consultancy; Janssen: Consultancy; AlloGene: Consultancy; Novartis: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Celgene-Juno: Consultancy. Timmerman:Spectrum Pharmaceuticals: Research Funding; Kite, A Gilead Company: Consultancy, Honoraria, Other: travel support, Research Funding; ImmunGene: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: travel support, Research Funding. Jacobson:Novartis: Consultancy, Honoraria, Other: travel support; Bayer: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Celgene: Consultancy, Other: travel support; Pfizer: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Bennani:Kite, A Gilead Company: Consultancy, Research Funding. Rossi:Kite, A Gilead Company: Employment. Sherman:Kite, A Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Palluconi:Kite, A Gilead Company: Employment. Kim:Kite, A Gilead Company: Employment. Jain:Kite/Gilead: Consultancy.

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy. ZUMA-1 is a multicenter registrational trial of axi-cel in patients with refractory, aggressive B-cell non-Hodgkin lymphoma. In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with a 76% objective response rate and 47% complete response. The incidence of Grade 3 and higher (Gr 3+) cytokine release syndrome (CRS) and neurologic events (NE) was 13% and 29%, respectively, in 93 patients with 1 month follow-up (Neelapu ASH 2016). We present novel immune signatures of Gr 3+ CRS and NE by analyzing the axi-cel-related biomarker profile in association with clinical outcomes. Methods: In this interim analysis of 62 patients, 44 serum analytes pre- and post-axi-cel treatment were measured via ELISA at multiple timepoints during the first month. The number of CAR+ cells in blood was determined by qPCR. Kinetics and association of these markers with CRS and NE were analyzed. The treatment-related profile was defined by analytes with at least double an increase over baseline in at least 50% of patients. These analytes were selected and evaluated for association with Gr 3+ CRS or NE. Immune signatures were determined based on p-values applied to peak or cumulative levels of analytes and adjusted for multiplicity (stepdown method). Results: Out of 44 analytes measured, 12 demonstrated an increase by double over baseline in at least 50% of patients. This axi-cel-related biomarker profile includes immune proliferative/modulating cytokines, pro-inflammatory cytokines, markers of myeloid activation, and chemokines. Markers with the highest median-fold increase were IFNγ (44x), IL-10 (31x), IL-6 (26x), IL-15 (20x), and GRZB (17x). These peaked within 7-14 days and generally returned to baseline within 1 month post-treatment. Within this panel of 12 analytes elevated post-axi-cel treatment, markers associated with Gr 3+ CRS (p<0.05) were IL-10, IL-6, IL-2Rα, IL-8, MCP-1, IFNγ, IL-1Rα, and IP-10. Markers associated with Gr 3+ NE (p<0.05) were IL-6, IL-15, IL-8, and MCP-1. Peak levels of CAR T cells in blood, occurring within 14 days post-infusion, were associated with Gr 3+ NE (p=0.02) but not Gr 3+ CRS (p=0.6). A majority of patients with Gr 3+ NE had only Gr 0-2 CRS (16/22) while nearly 50% of patients with Gr 3+ CRS had Gr 0-2 NE (5/11). Conclusions: Biomarker and clinical evaluation suggests mechanistic differences underlying CRS and NE following axi-cel treatment. While Gr 3+ NE was associated with CAR T cell expansion, Gr 3+ CRS was instead associated with a broader array of serum markers, many linked to systemic myeloid activation. Further understanding of these immune signatures may provide insight into managing AEs associated with anti-CD19 CAR T cell therapy. Citation Format: Frederick L. Locke, John Rossi, Xiaodong Xue, Sattva S. Neelapu, Daniel H. Ryan, Armin Ghobadi, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Patrick M. Reagan, Marika Sherman, Janice Nagatani, Xiao Zhang, Lynn Navale, William Y. Go, Jeff Wiezorek, Adrian Bot. Immune signatures of cytokine release syndrome and neurologic events in a multicenter registrational trial (ZUMA-1) in subjects with refractory diffuse large B cell lymphoma treated with axicabtagene ciloleucel (KTE-C19) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT020. doi:10.1158/1538-7445.AM2017-CT020