Miklos, David B

Abstract Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of patients with relapsed or refractory large B cell lymphoma with ≥ 2 prior systemic therapies. This report focuses on high-risk patient populations as well as long-term durability of response, and B cell recovery. Methods: In ZUMA-1, eligible patients with refractory large B cell lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma) underwent leukapheresis and received low-dose conditioning followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu and Locke et al. NEJM. 2017; NCT02348216). Outcomes in patients with double-expressor B cell lymphoma (MYC [≥ 40%] and BCL-2 [≥ 50%] protein expression by immunohistochemistry [IHC]) or high-grade B cell lymphoma (HGBCL), defined as double- or triple-hit (MYC+ and BCL2+ and/or BCL6+ by fluorescence in situ hybridization) or not otherwise specified (MYC- and > 70% Ki67 by IHC) were examined by independent pathology review. Exploratory analyses, including normal B cell levels in peripheral blood over time and frequency of use of safety interventions of interest, were also performed. A long-term follow-up analysis will be conducted with a data cutoff of August 11, 2018 for all 108 patients, including the HGBCL subgroup. Results: As of August 11, 2017, all 108 patients had at least 1 year of follow-up, with a median follow-up of 15.4 months. The objective response rate (ORR) was 82% with a complete response (CR) rate or 58%. The CR rate was 53% (29/55) in patients with disease refractory to ≥ 2 consecutive prior lines of therapy and 72% (18/25) in patients who had relapsed within 12 months after autologous stem cell transplantation. High-risk genetics were assessed in the 47 evaluable pre-treatment tumor samples: 37 patients (79%) had HGBCL or double-expressor B cell lymphoma and had an ORR of 89% (33/37) including a CR rate of 68% (25/37). Forty-two percent of patients overall had ongoing responses with a median follow-up of 15.4 months including 49% (18/37) of patients with high-risk genetics. To investigate the relationship between B cell recovery and ongoing response, B cell levels were assessed over time. Overall, of the 87 evaluable patients, 47% had no detectable B cells at baseline, and the remainder had levels close to or below the lower level of quantification of the assay. In patients with ongoing responses at 12 months post axi-cel infusion, 19 of the 35 (54%) patients with evaluable samples had detectable B cells at 12 months. This suggests B cell recovery in some patients with ongoing response as only 6 of 40 (15%) patients with evaluable samples had detectable B cells at 3 months after axi-cel infusion. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) were generally reversible and reported for 12% and 31% of patients, respectively. Tocilizumab (45%) and/or steroids (28%) were used for the management of CRS and NE. The use of vasopressors, dialysis, and intubation were minimal, used in only 17%, 3%, and 3% of patients, respectively. Thirty-four percent of patients (37/108) had either no CRS/NE (6%) or only Grade 1 CRS with (12%) or without (16%) Grade 1 NE. For these 37 patients, the median onset of CRS and NE was 2 and 7 days after infusion, respectively. Patients with Grade 0 - 1 CRS/NE had similar efficacy (ORR, 86%; CR, 65%) but lower peak/AUC CAR T cell levels vs the overall population. Updated safety and efficacy results will be presented with a minimum follow-up of 2 years and a median follow-up of 27.1 months. Conclusion: High rates of durable response were observed in patients with HGBCL and double-expressor B cell lymphoma, with approximately half of these patients (18/37) maintaining CR at ≥ 1 year. Efficacy in these high-risk populations was comparable to the overall patient population in ZUMA-1. At 12 months, B-cell recovery was observed in over half the patients with ongoing remission. About one-third of patients had only Grades 0 - 1 CRS/NE yet showed comparable efficacy with the overall patient population. High-grade CRS/NE were largely managed with tocilizumab and steroids with very low use of intensive or invasive interventions. Updated outcomes with a minimum of 2 years of follow-up will be presented. Disclosures Neelapu: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Miklos:Adaptive Biotechnologies: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Kite - Gilead: Consultancy, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Research Funding. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Deol:Novartis: Consultancy; Kite Pharmaceuticals: Consultancy. Reagan:Seattle Genetics: Research Funding. Flinn:Agios: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Calithera: Research Funding; Portola: Research Funding; Kite: Research Funding; Forma: Research Funding; Genentech: Research Funding; Verastem: Research Funding; BeiGene: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Janssen: Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; ArQule: Research Funding; Constellation: Research Funding; Infinity: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Curis: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy, Research Funding; Takeda: Research Funding; Pfizer: Research Funding. McSweeney:Kite, a Gilead Company: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munoz:Alexion: Consultancy; Genentech: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Janssen: Consultancy; Kite: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Herrera:Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding. Xue:Kite, a Gilead Company: Employment. Jiang:Kite, a Gilead Company: Employment. Bot:KITE: Employment. Rossi:KITE: Employment. Kim:Kite, a Gilead Company: Employment. Go:KITE: Employment. Locke:Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor.

Abstract Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T cell therapy approved by the US Food and Drug Administration for patients with relapsed or refractory large B cell lymphoma with ≥2 prior systemic therapies. Results from the primary analysis of ZUMA-1 demonstrated an objective response rate of 82%, with 54% complete responses (Neelapu & Locke et al. N Engl J Med. 2017). Grade ≥3 cytokine release syndrome and neurologic events occurred at 13% and 28%, respectively, and were generally reversible. Building on previous reports of CAR treatment-related tumor microenvironment (TME) changes (Galon et al. ASCO 2017. #3025), here, we examine associations between the pretreatment TME and clinical outcomes. Methods: Patients received axi-cel (target dose, 2.0 × 106 cells/kg) in phases 1 and 2 of ZUMA-1 (NCT02348216). Baseline tumor biopsy samples were analyzed by digital gene expression (NanoStringTM). Prespecified bioinformatics algorithm and cutoffs were applied to immune-mediated tumor regression genes (Immunosign®; Galon et al. Immunity. 2013), which included T cell-specific (effector T cell, Th1) genes, interferon pathway-related genes, chemokines, cytokines, and immune checkpoints. Expression analysis and scoring examined potential associations between TME features and response. A broader, hypothesis-generating analysis was performed using all PanCancer Immune Profiling Panel genes (770 genes) by NanoStringTM. Fisher's exact test and Wilcoxon signed rank test with multiple test correction by false discovery rate (Benjamini-Hochberg) were used. Results: Tumor samples from all immediate pre-treatment biopsy samples that passed quality control (6 nonresponders; 21 responders) were analyzed. Pretreatment TME Immunosign21 scores were elevated in responders vs nonresponders. Responses were seen in 18/20 patients (90%) with high and 3/7 patients (43%) with low Immunosign21 scores. Immune-related genes from the Immunosign21 or Pan Cancer profile that showed higher expression at baseline in responders included CTLA4, CD3γ, CD3ϵ, CD27, and ICOSL. Genes with lower expression in responders at baseline included MHC class II genes and cancer-testis antigens. Additional correlative analyses between TME characteristics and CAR T cell activity will be presented. Conclusions: Increased baseline expression of TME genes related to T cell activity, along with decreased expression of MHC class II and cancer testis antigens (CTAs), may be associated with a response to axi-cel. These findings should be validated in ongoing and subsequent studies. Citation Format: John M. Rossi, Jerome Galon, Sarah Turcan, Corinne Danan, Frederick L. Locke, Sattva S. Neelapu, David B. Miklos, Caron A. Jacobson, Lazaros J. Lekakis, Yi Lin, Armin Ghobadi, William Y. Go, Adrian Bot. Characteristics of the pretreatment tumor microenvironment may influence clinical response in patients with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-cel) in the pivotal ZUMA-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-016.