Neelapu, Sattva S.

Background: Pts with high-risk LBCL have poor outcomes with R-CHOP chemoimmunotherapy (Sathyanarayanan, et al. ASH 2016. #106), and ≈50% of pts will not achieve long-term disease remission (Coiffier, et al. ASH Ed Program. 2016), highlighting unmet need for new therapies. Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, was approved for treatment of adults with R/R LBCL after ≥ 2 lines of systemic therapies based on the pivotal study, ZUMA-1 (Neelapu SS, et al. NEJM. 2017). ZUMA-12 is a Phase 2, multicenter, open-label, single-arm study of axi-cel as part of first-line therapy in pts with high-risk LBCL. Here, we present interim efficacy, safety, and pharmacokinetics (PK) results from ZUMA-12. Methods: Eligible adults (≥ 18 y) met 2 criteria for high-risk LBCL: i) double- or triple-hit lymphoma by fluorescent in situ hybridization per investigator or LBCL with IPI score ≥ 3; and ii) positive interim PET per Lugano Classification (Cheson, et al. J Clin Oncol. 2014; Deauville score [DS] 4 or 5) after 2 cycles of an anti-CD20 monoclonal antibody and anthracycline containing regimen, which served as a dynamic risk assessment. Pts with PMBCL were not eligible. Pts underwent leukapheresis (≥ 2 wks after prior systemic therapy) and optional non-chemotherapy bridging at investigator discretion, followed by conditioning chemotherapy (cyclophosphamide 500 mg/m2/d and fludarabine 30 mg/m2/d for 3 d) and a single axi-cel infusion (target dose, 2 × 106 CAR T cells/kg). The primary endpoint was investigator-assessed complete response (CR) rate per Lugano. Key secondary endpoints included objective response rate (ORR), frequency of adverse events (AEs), and levels of CAR T cells and cytokines in blood and serum. Results: As of July 15, 2020, 31 pts have been enrolled and treated, and as of January 24, 2020, in a planned interim analysis, 15 pts were treated with axi-cel with ≥ 3 mos of follow-up. Median age was 60 y (range, 39 - 86), 67% of pts were male, 73% had ECOG of 1, 40%/60% had DS4/5; 60% had double- or triple-hit status per investigator, and 67% had IPI score ≥ 3. Baseline characteristics were largely comparable to ZUMA-1 Cohort 1 except for lower median tumor burden in ZUMA-12 (ZUMA-1: 3897 mm2 vs ZUMA-12: 1610 mm2). Of 12 response-evaluable pts (pts with centrally confirmed high-risk LBCL who received axi-cel), the investigator-assessed ORR was 92% (95% CI, 62% - 100%) with a CR rate of 75% (95% CI, 43% - 95%); 75% of pts had ongoing responses at data cutoff. Of 15 pts treated (safety analysis set), the investigator-assessed ORR was 93% (95% CI, 68% - 100%) with a CR rate of 80% (95% CI, 52% - 96%); 86% of pts had ongoing responses at data cutoff. Of 15 safety-evaluable pts, 80% experienced Grade ≥ 3 AEs. The most common Grade ≥ 3 AEs (≥ 25% of pts) were white blood cell count decreased (40%), anemia (27%), and encephalopathy (27%). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 20% and 27% of pts, respectively. All CRS and 10/11 NEs of any grade resolved (causally unrelated Grade 1 tremor was ongoing in 1 pt at data cutoff). Median time to onset of CRS was 4 d (range, 1 - 8), with median duration of 5 d (range, 2 - 12). Median time to onset of NEs was 9 d (range, 2 - 44), with median duration of 10 d (range, 1 - 40). Grade ≥ 3 infection was reported in 27% and Grade ≥ 3 neutrophil count decreased was reported in 20%. No Grade 5 AEs occurred. Despite similar assessment schedule and methodology, median peak CAR T cell levels were greater in ZUMA-12 vs ZUMA-1 Cohort 1 (131 cells/µL [range, 10 - 555] vs 32 cells/µL [range, 1 - 1514]). Median CAR T cell expansion (AUC0-28) was also greater in ZUMA-12 (1124 cells/µL × d [range, 147 - 4261]; ZUMA-1: 357 cells/µL × d [range, 5 - 11,507]). Median time to peak levels of CAR T cells in blood was 7 d after infusion. PK were similar in pts with double- or triple-hit lymphoma and IPI score ≥ 3. Updated safety, efficacy, and PK results will be reported, along with product characteristics and levels of key cytokines. Conclusion: ZUMA-12 is the first study evaluating CAR T cell therapy as first-line therapy in high-risk LBCL, which notably was defined by both histology and/or IPI and dynamic risk assessment with PET scan. Axi-cel demonstrated significant clinical benefit, with high ORR and CR rates and a manageable safety profile in pts for whom there is an unmet medical need. The study also provides new insights into the pharmacology of CAR T cell therapy for pts exposed to fewer prior therapies. Disclosures Neelapu: Pfizer: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; N/A: Other; Adicet Bio: Other; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Precision Biosciences: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Legend Biotech: Other; Calibr: Other. Dickinson:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Oluwole:Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Herrera:Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy. Thieblemont:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bayer: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Incyte: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Bristol-Myers Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hospira: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Ujjani:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Verastem Oncology: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Lin:Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Gamida Cells: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Riedell:Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding; Karyopharm Therapeutics: Consultancy; Bayer: Consultancy, Speakers Bureau; Kite/Gilead: Research Funding, Speakers Bureau; MorphoSys: Research Funding. Kekre:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy. Yang:Kite, a Gilead Company: Current Employment. Milletti:Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership . Goyal:Kite, a Gilead Company: Current Employment. Kawashima:Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership . Chavez:Merck: Research Funding; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Bayer: Consultancy; BeiGene: Speakers Bureau; Karyopharm: Consultancy; AbbVie: Consultancy; Verastem: Consultancy; Pfizer: Consultancy.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for pts with R/R LBCL with ≥ 2 prior systemic therapies. With a median follow-up of 27.1 months in ZUMA-1, the objective response rate (ORR) with axi-cel was 83% (58% complete response rate) in pts with refractory LBCL. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL, et al. LancetOncol. 2019). Although CRS can be ameliorated with use of the anti-IL-6 receptor antibody tocilizumab, NEs may be unaffected or worsened by tocilizumab (Gust J, et al. Cancer Discov. 2017; Lee DW, et al. Blood. 2014; Santomasso BD, et al. Cancer Discov. 2018; Locke FL, et al. ASH 2017. #1547). Identification of mitigation strategies for NEs is complicated by a significant association between CAR T cell expansion and both ORR and Grade ≥ 3 NEs, suggesting a correlation between efficacy and adverse events (AEs; Neelapu SS, et al. N EnglJ Med. 2017). ZUMA-1 Cohort 4 suggested that earlier utilization of systemic corticosteroids for broad immune system suppression in pts with mild NEs and low-grade CRS may reduce the incidence of Grade ≥ 2 NEs without significant impact on efficacy (Topp MS, et al. ASH 2019. #243). However, this reactive approach has not fully abrogated NEs; as such, proactive strategies to further improve safety management with CAR T cell therapy without negatively impacting efficacy are needed. Upon tumor challenge, CAR T cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF; Giavridis T, et al. Nat Med. 2018), which acts to promote myeloid activation, expansion, and cytokine production (Spath S, et al. Immunity. 2017). GM-CSF was among the cytokines significantly associated with Grade ≥ 3 NEs in ZUMA-1 (Neelapu SS, et al. N Engl J Med. 2017). Notably, peak GM-CSF levels occurred before those of most other cytokines, and no direct association was observed between GMCSF levels and ORR (Rossi JM, et al. EMA Workshop, 2016). These findings suggest that GM-CSF may initiate inflammatory events that cause NEs and that GM-CSF inhibition has the potential to improve the safety of CAR T cells, without impacting efficacy. GM-CSF depletion with lenzilumab, a humanized monoclonal antibody that neutralizes GM-CSF, prevented CRS and NEs in preclinical models of CAR T cell toxicity (Sterner RM, et al. Blood2019). The Phase 1/2 ZUMA19 study is evaluating sequenced therapy with lenzilumab and axi-cel to prevent axi-cel-related CRS and NEs in pts with R/R LBCL. Methods: Eligible pts are adults (≥ 18 y) with LBCL who relapsed after ≥ 2 systemic lines of therapy or are chemorefractory - defined as i) a best response of progressive disease (PD) or stable disease (SD) to ≥ 4 cycles of first-line systemic therapy (SD duration ≤ 6 months); or ii) a best response of PD or SD after ≥ 2 cycles of the most recent second-or-later line of systemic therapy. Prior therapy must have included an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. Pts will undergo leukapheresis and may receive optional corticosteroid bridging therapy. Pts will then receive lymphodepleting chemotherapy on Days ‒3 to ‒5 followed by Day 0 administration of lenzilumab and, 6 hours later, a single infusion of axi-cel (target dose, 2 × 106 CAR T cells/kg). Phase 1 will initially enroll pts in 2 dose-escalation cohorts; each will receive a single infusion of lenzilumab. Safety data will be reviewed after 3 and 6 (if needed) pts in each cohort have been followed for 28 days. The recommended Phase 2 dose (RP2D) of lenzilumab will be based on the dose-limiting toxicity rate (phase 1 primary endpoint), and, if necessary, translational assessment of GM-CSF axis suppression. Phase 2 will assume a Simon 2-stage design. The primary endpoint for phase 2 is the incidence of Grade ≥ 2 NEs within 28 days of axi-cel administration. Efficacy, safety (including CRS and NEs), and blood levels of CAR T cells and cytokines (including GM-CSF) will be evaluated as secondary endpoints. An interim analysis will be performed when 14 subjects have received the RP2D in Phase 1 or 2 and are followed for ≥ 28 days after axi-cel infusion. If futility criteria are not met, enrollment will continue. Primary analysis will be performed after 30 pts are treated with RP2D of lenzilumab and have ≥ 6 months of follow up. ZUMA-19 is open and actively recruiting pts. Disclosures Kenderian: Mettaforge: Patents & Royalties; Humanigen: Consultancy, Patents & Royalties, Research Funding; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy. Oluwole:Bayer: Consultancy; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy. McCarthy:Genentech: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Reshef:Celgene: Consultancy; Pharmacyclics: Research Funding; Shire: Research Funding; Bluebird: Research Funding; Kiadis: Research Funding; Monsanto: Consultancy; Takeda: Research Funding; Atara: Consultancy, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Immatics: Research Funding; Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria; Magenta: Consultancy. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Ahmed:Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company. Le Gall:Kite, a Gilead Company: Ended employment in the past 24 months; Gilead Sciences: Current equity holder in publicly-traded company. Nahas:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Tang:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Neelapu:Takeda Pharmaceuticals: Patents & Royalties; Cellectis: Research Funding; Calibr: Other; Precision Biosciences: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Acerta: Research Funding; Karus Therapeutics: Research Funding; Poseida: Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding; N/A: Other; Adicet Bio: Other; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees.

Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved for treatment of adult pts with R/R LBCL after ≥ 2 lines of systemic therapy. In the pivotal ZUMA-1 study, axi-cel demonstrated durable responses and a largely manageable safety profile (Locke FL, et al. Lancet Oncol. 2019). ZUMA-9 (NCT03153462), a multicenter, open-label study, provided pts with R/R LBCL with expanded access to axi-cel until commercial availability (Cohort 1 [C1]) and later, if commercially manufactured product did not meet commercial release specification(s) (Cohort 2 [C2]). Safety and efficacy of axi-cel (C1 and C2) and translational analyses (C2) are presented. Methods: Eligible adults had histologically confirmed R/R LBCL, ECOG ≤ 1, and received prior CD20-targeting and an anthracycline-containing regimen. C2 pts must have had commercial OOS product. Pts underwent leukaphersis and conditioning chemotherapy (cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days followed by a single axi-cel infusion (target dose, 2 × 106 CAR T cells/kg). C1 and C2 pts with high disease burden could receive bridging therapy before conditioning at investigator's discretion. Endpoints included frequency of adverse events (AEs), objective response rate (ORR) per standard-of-care imaging assessment, overall survival (OS) for C1 and C2, and blood CAR T cells levels and serum cytokines for C2 only. Outcomes were contextualized with the primary analysis of ZUMA-1 C1+2 (n = 101; ≥ 6 mo of follow-up; Neelapu SS, et al. NEJM. 2017). Results: As of 11/29/2019 (C1) and 3/15/2020 (C2), 25 C1 pts and 36 C2 pts received axi-cel with a median follow-up of 27.1 mo (range, 23.6 - 29.6) and 13.2 mo (range, 0.4 - 25.7), respectively. In C1, median age was 56 y (range, 28 - 76), 60% were male, 80% had DLBCL, 48%/0% had ECOG1/≥2, 44% had IPI ≥3, and 64% had ≥ 3 prior lines of therapy. In C2, median age was 61 y (range, 24 - 81), 75% were male, 78% had DLBCL, 58%/17% had ECOG 1/≥2, 56% had IPI ≥3, and 69% had ≥ 3 prior lines of therapy. In C2, 50% of pts had OOS product with low viability, 28% had high IFN-γ, 14% had low IFN-γ, 14% received a low dose, and 6% had high transduction ratio. The ORR was 76% (64% complete response [CR]) for C1, 53% (36% CR) for C2, and 82% (54% CR) for ZUMA-1 C1+2. Median OS was 23.8 mo (95% CI, 13.5 - NE) for C1 and not reached (95% CI, 3.4 - NE) for C2, respectively. ORR and OS were consistent in C2 OOS subgroups (Table). Grade ≥ 3 AEs were reported in 88% and 89% of C1 and C2 pts, respectively. Grade ≥ 3 CRS (Lee et al, Blood. 2014) was not observed in C1 but was reported in 3% of C2 pts (13% in ZUMA-1 C1+2). Grade ≥ 3 neurologic events (NEs) occurred in 36% and 19% of pts in C1 and C2, respectively, and 28% of pts in ZUMA-1 C1+2. No Grade 5 CRS or NEs occurred in C1 or C2. All CRS and NEs resolved in C1, and most CRS (29/30) and NEs (19/24) resolved in C2 as of the data cutoff. Of 3 Grade 5 AEs in C1, 2 were unrelated to axi-cel (clostridial sepsis [on Day (D) 6] and respiratory failure [on D212]) and 1 was related to conditioning (myelodysplastic syndrome [on D563]). Of 3 Grade 5 AEs in C2, 2 were unrelated to axi-cel (multiple organ dysfunction syndrome [on D6] and cardiac arrest [on D482]) and 1 was related to axi-cel (systemic mycosis [on D30]). Median peak CAR T cell levels and median CAR T cell expansion (area under the curve in the first 28 days) were lower in ZUMA-9 C2 (n = 32/36; 12 cells/µL [range, 0 - 442] and 112 cells/µL × days [range, 0 - 3413]) vs ZUMA-1 C1+2 (n = 96/101; 42 cells/µL [range, 1 - 1514] and 462 cells/µL × days [range, 5 - 14,329]). Serum IFN-γ levels peaked within 8 days after axi-cel infusion (median, 170 pg/mL [range, 8 - 1876]) and were lower vs ZUMA-1 C1+2 (median, 477 pg/mL [range, 8 - 8209]). Axi-cel in ZUMA-9 C2 contained fewer, less differentiated CCR7+ naïve and central memory T cells, and a greater proportion of more differentiated CCR7- effector memory and effector T cells vs ZUMA-1 C1+2. No cases of replication-competent retroviruses were reported in C1 or C2. Conclusion: Axi-cel treatment demonstrated a manageable safety profile and meaningful clinical benefit in this expanded access and OOS product study. While CAR T cell therapy showed clinical benefit in C2 (OOS product), the lower CR rate was corroborated by lower CAR T cell expansion and a more differentiated product vs ZUMA-1 C1+2, warranting further investigation. ZUMA-9 C2 is enrolling pts and evaluation is ongoing. Disclosures Jacobson: Precision Biosciences: Consultancy, Honoraria, Other: travel support; Celgene/BMS: Consultancy, Honoraria, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; AXIS: Speakers Bureau; Nkarta: Consultancy, Honoraria, Other: travel support; Clinical Care Options: Speakers Bureau; Pfizer: Research Funding; Lonza: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Locke:Calibr: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; Allogene: Consultancy. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Miltenyi Biotec: Research Funding; Janssen: Consultancy, Other: Travel support; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Vose:Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm Therapeutics: Consultancy, Honoraria; Allogene: Honoraria; Loxo: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Miltenyi Biotec: Honoraria; Janssen: Honoraria; Epizyme: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Kite, a Gilead Company: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Wugen: Honoraria; Celgene: Honoraria; Roche/Genetech: Consultancy, Honoraria, Other. Lin:Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Vineti: Consultancy; Gamida Cells: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding. Budde:Roche: Consultancy; Merck: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding. Maloney:Celgene: Consultancy, Honoraria, Research Funding; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Gilead Sciences: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jaglowski:Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR: Consultancy; Novartis: Consultancy, Research Funding. Riedell:MorphoSys: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Karyopharm Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Perales:Celgene: Honoraria; MolMed: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: 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; Kite/Gilead: Honoraria, Research Funding; Miltenyi Biotec: Research Funding; Merck: Consultancy, Honoraria; Nektar Therapeutics: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Research Funding. Kim:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Kawashima:Kite, a Gilead Company: Current Employment; Gilead Sciences: Other: stock or other ownership . Yang:Kite, a Gilead Company: Current Employment. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Goyal:Kite, a Gilead Company: Current Employment. Neelapu:Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Unum Therapeutics: Other, Research Funding; Adicet Bio: Other; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Poseida: Research Funding; Calibr: Other; Acerta: Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Karus Therapeutics: Research Funding; Cellectis: Research Funding; N/A: Other.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of patients (pts) with relapsed/refractory large B cell lymphoma (LBCL) with ≥ 2 prior systemic therapies. ZUMA-1 is the multicenter, single-arm, registrational Phase 1/2 study of axi-cel in pts with refractory LBCL. In a 2-year analysis of ZUMA-1 (median follow-up, 27.1 months; N=101), axi-cel demonstrated objective response, complete response (CR), and ongoing response rates of 83%, 58%, and 39%, respectively (Locke et al. Lancet Oncol. 2019). Here, we present additional survival follow up and recovery of normal, polyclonal B cells from ongoing responders in ZUMA-1. Methods: Eligible pts with refractory large B cell lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma) underwent leukapheresis at enrollment and subsequently received low-dose conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu et al. NEJM. 2017; NCT02348216). The primary endpoint was objective response rate (ORR), and the first response assessment was 4 weeks post infusion. Response assessments were performed per protocol up to 24 months or disease progression, whichever occurred first. For pts in ongoing response beyond Month 24, response assessments continued per institutional standard-of-care (SOC). Blood levels of CAR T cells were quantified using polymerase chain reaction and B cells were characterized using flow cytometry in pts with ongoing responses and evaluable samples. Results: A total of 111 pts were enrolled, and axi-cel was administered to 101 pts. As previously reported in the ZUMA-1 2-year analysis, among pts who received axi-cel, the median time from axi-cel infusion to both objective response and CR was 1.0 month (range, 1 - 12 months; Locke et al. Lancet Oncol 2019). When the entire enrolled population (N = 111) was included on an intent-to-treat basis, the median manufacturing time was 17 days (range, 14 - 51; n = 110 as manufacturing was not feasible for 1 pt). Additionally, among the 111 pts, the median time from enrollment/leukapheresis to objective response and CR was 1.7 months (range, 0.7 - 12.9) and 1.9 months (range, 0.7 - 13.3), respectively. Responses have been durable, and with a minimum of 3 years of follow-up (median, 39.1 months), the median overall survival (OS) was 25.8 months, and the 3-year OS rate was 47%. Importantly, no axi-cel-related secondary malignancies have been reported. As previously reported, pts in ongoing response after 2 years had significantly greater peak CAR T cell expansion in blood 7 - 14 days after axi-cel infusion than did those with relapse (P = 0.014) or no response (P = 0.0003; Locke et al. Lancet Oncol 2019). Blood samples from 22 pts in ongoing response (per institutional SOC) at ≥ 3 years were available for analysis of CAR T cells and evaluation of B cell recovery. All evaluable pts had detectable B cells in blood at 3 years post axi-cel. Notably, 91% of pts in ongoing response at 3-year follow-up demonstrated recovery of polyclonal B cells measured by presence of both kappa and lambda light chains on non-malignant CD19+CD20+ B cells. The median kappa-lambda ratio of 1.6 and relative levels of key B cell subsets, including memory and naive B cell immunophenotypes, suggested reconstitution of B cell repertoire, consistent with published data from healthy individuals (Deneys et al. J Immunol Methods 2001; Scott et al. J Clin Pathol 2018). Additionally, 15/22 (68%) had both minimal levels of detectable CAR gene-marked cells and detectable polyclonal B cells in blood. Altogether, these findings support the hypothesis that persistence of functional CAR T cells is not necessary for durable remissions of LBCL. Overall survival and translational findings with ≥ 4 years of follow-up will be presented. Conclusions: Axi-cel produced rapid responses and longterm disease control in pts with refractory LBCL. Most responses occurred by the first assessment, and the brief time elapsed between enrollment and response supports both the speed and success of manufacturing. Furthermore, axi-cel-treated pts with ongoing responses at ≥ 3 years showed evidence of restoration of a normal B cell compartment and clearance of functional CAR T cells, a critical component of the long-term safety of CD19-directed CAR T cell therapies. Disclosures Locke: Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ghobadi:Celegene: Consultancy; Wugen: Consultancy; Atara: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Oluwole:Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy. Lin:Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Hill:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Timmerman:Merck: Research Funding; Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Valor: Research Funding. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Reagan:Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Flinn:Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; BeiGene: Consultancy, Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Calithera Biosciences: Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Gilead Sciences: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Curis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding. Farooq:Kite, a Gilead Company: Honoraria. Goy:COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; Bayer: Research Funding; CALBG: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding. McSweeney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Colorado Blood Cancer Institute: Current Employment; Fred Hutchinson: Patents & Royalties. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siddiqi:Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Rossi:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Bot:Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support . Zheng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Vezan:Merck: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. Bashir:Kite, a Gilead Company: Current Employment; OmniacPharmConsult Ltd: Current Employment, Current equity holder in private company. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Chu:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company. Neelapu:N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Kite, a Gilead Company: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Novartis: Other: personal fees; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees.

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.

3022 Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In ZUMA-1 (NCT02348216), the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019). T cell-related biology (Immunosign 21; Immunoscore) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel (Rossi et al. AACR 2018. #LB-016; Rossi et al. AACR 2019. #CT153). This expanded analysis characterized the pretreatment TME immune contexture and examined associations between immune cell subsets and response. Methods: In ZUMA-1, pts received axi-cel at a target dose of 2.0 × 106 CAR T cells/kg. Archival pretreatment tumor biopsy samples were analyzed by multiplex immunohistochemistry (Brightplex). Two panels were developed and applied to assess T cell (CD3, CD8, FoxP3, PD-1, LAG-3, TIM-3) and myeloid cell (CD11b, CD14, CD15, LOX1, S100A9, CD68) subsets (n = 14 total). The association between T cell and myeloid cell subset density, prespecified immune scores (Immunosign 21; Immunoscore), and objective response was evaluated. T test values were based on Brightplex analysis. Results: Pretreatment tumor biopsy samples from 18 pts were analyzed (14 objective responders and 4 nonresponders). The pretreatment TME comprised all major myeloid and T cell subsets, with diverse distribution across samples analyzed. The median TME density of monocytes (CD11b+ CD15− CD14+; 1215 cells/mm2) and macrophages (CD68+; 530 cells/mm2) was greater than that of the total CD8+ T cell subset (312 cells/mm2). The pretreatment Immunosign 21 and Immunoscore scores associated positively with the density of all major T cell subsets and some myeloid subsets. The density of activated CD8+ T cells (PD-1+ LAG-3+/− TIM-3−) was most significantly associated with clinical response versus other T cell subsets. The density of nonactivated CD8+ T cells (PD-1− LAG-3− TIM-3−) and exhausted CD8+ T cells (PD-1+ LAG-3+ TIM-3+) were not significantly associated with response. Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusions: These results suggest that a TME associated with increased density of activated PD-1+ LAG-3+/− TIM-3− CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post–axi-cel.

PURPOSE Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication. PATIENTS AND METHODS Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution’s guidelines. Responses were assessed as per Lugano 2014 classification. RESULTS Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel–treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis. CONCLUSION The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

TPS7574 Background: Pts with LBCL who have persistent disease assessed by dynamic PET after rituximab-based induction therapy have an increased risk of death (Casasnovas, et al. Blood. 2017). Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of pts with relapsed/refractory LBCL with ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in pts with refractory LBCL, the objective response rate (ORR) was 91% (70% complete response [CR] rate) in pts with double-expressor or high-grade LBCL with ongoing responses in 48% after a median follow-up of 27.1 mos (Locke FL, et al. Lancet Oncol 2019). Furthermore, pts with fewer prior lines of therapy and lower tumor burden had higher rates of ongoing responses and manageable safety (Locke et al. ASCO 2018. 3039). ZUMA-12 will investigate the efficacy and safety of axi-cel as a first-line therapy in newly diagnosed pts with high-risk LBCL who have PET-positive disease after 2 cycles of induction therapy. Methods: This Phase 2 study has a planned enrollment of ≈40 pts aged ≥ 18 y with high-risk LBCL, defined by the presence of MYC and BCL2 and/or BCL6 translocations by FISH or an IPI score ≥ 3 any time before enrollment, and an ECOG performance status of 0 – 1. Before enrollment, pts must have a Deauville score of 4 – 5 (Barrington SF et al. J Clin Oncol. 2014) after 2 cycles of chemoimmunotherapy that includes an anti-CD20 monoclonal antibody and anthracycline. After leukapheresis, pts with bulky or rapidly progressing disease may receive optional non-chemotherapy bridging therapy. Following conditioning therapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days, pts will receive a single infusion of axi-cel at a target dose of 2 × 106 CAR T cells/kg. The primary endpoint is investigator-assessed CR rate per the Lugano classification (Cheson et al. J Clin Oncol. 2014). Key secondary endpoints include ORR, duration of response, event-free survival, progression-free survival, overall response, safety, relapse with CNS disease and levels of blood CAR T cells and serum cytokines over time. Accrual is ongoing. Clinical trial information: NCT03761056.

7517 Background: Axi-cel, an anti-CD19 CART cell therapy, achieved 83% ORR, 58% CR rate, with 39% PFS at 2 years in patients (pts) with relapsed refractory large B-cell lymphoma (LBCL) on the ZUMA-1 study (Locke, Lancet Oncology 2018). Data from a 17-center consortium showed response rates were similar in 274 pts treated with commercial axi-cel (Nastoupil, ASH 2018). Here, we performed retrospective analysis of outcomes in pts with progressive disease (PD) after axi-cel. Methods: Response status was determined by Cheson 2014 and reported as date of radiologic relapse. 274 pts were infused by December 26, 2018 with maximum follow-up of 14 months; 116 pts had PD as of Feb 1, 2019. Twelve sites provided additional data, detailing 85% of PD pts (n=99) with a median time to relapse of 54 days (IQR 16-120). Results: Pre axi-cel pt characteristics: median lines of therapy were 4 (range 2-11), 86% were Stage III/IV and 22% were ECOG >1. Following relapse, 60% (n=61) were biopsied and 70% (43/61) had CD19 expression measured. Thirty percent (13/43) were CD19 negative by: IHC (3/13), flow (2/13) or both (8/13). Seventy percent (n=71) received salvage therapy for PD. Median lines of salvage therapy was 1 (range 0-4). The most common therapies were Lenalidomide-based (30%), checkpoint inhibitors (30%), chemotherapy (20%) and radiation (10%). First salvage therapy ORR by regimen: checkpoint inhibitors = 24%, lenalidomide regimens = 20% and chemotherapy = 11%. One patient received allogeneic transplant. Twelve pts enrolled on clinical trial, with one receiving 2nd CAR-T. Median OS following relapse was 108 days (95% LCL 71). Nineteen pts relapsed <3 months after axi-cel and did not receive therapy with median OS 17 days (95% CI 7-49); 33 pts relapsed <3 months and received therapy with 114 day median OS (95% LCL 82). In contrast, 30 pts who relapsed >3 months post axi-cel and received therapy had estimated median OS >220 days (95% LCL 81). Conclusions: Patients with LBCL relapsing less than 3 months following axi-cel have extremely poor outcomes supporting the development of novel therapies. Therapy for relapse >3 months appears promising. JYS and SD contributed equally; APR, DBM and BTH contributed equally.