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Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment (Tx) of patients (pts) with R/R LBCL with ≥ 2 prior systemic therapies. In Cohorts 1+2 (C1+2) of the ZUMA-1 study, Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 11% and 32% of pts, respectively (Locke FL et al, Lancet Oncol 2019). A nonrandomized safety expansion cohort (Cohort 4 [C4]) evaluated the impact of earlier steroid use on CRS and NE rates. Here we present the primary analysis of ZUMA-1 C4 with a greater number of pts and longer follow-up (F/U). Eligible pts were leukapheresed, could receive optional bridging chemotherapy (not allowed in C1+2), and received conditioning chemotherapy before axi-cel infusion at a targeted 2 × 106 anti-CD19 CAR T cells/kg. C4 pts received early steroid intervention at Grade 1 NE and at Grade 1 CRS after 3 days of supportive care. Primary endpoints were incidence and severity of CRS and NEs. ORR and CAR T cell levels were compared across quartiles of tumor burden (TB). As of May 6, 2019, 41 pts had received axi-cel, with a median F/U of 8.7 mo. Pts who received bridging therapy prior to axi-cel (68%) all had evidence of disease after bridging, documented by a new baseline PET/CT scan. The median age was 61 y (range, 19 – 77 y; 32% ≥ 65 y). The majority of pts (63%) had DLBCL; 49% had an ECOG 1; 70% had disease stage III/IV; 68% were refractory to ≥ 2nd-line therapy; 63% had ≥ 3 prior lines of therapy; and 20% had relapsed after ASCT. C4 pts had a lower median TB by sum of product diameters (SPD; C4: 2100 mm2; C1+2: 3723 mm2) and lower pre-Tx serum LDH level than C1+2 pts. A greater proportion of C4 pts received steroids and tocilizumab vs C1+2 (73% and 76% vs 27% and 43%). Fewer C4 pts experienced Grade ≥ 3 CRS (2%) and NE (17%) than C1+2 pts. The ORR in C4 was 73% with a CR rate of 51%. Response was ongoing in C4 54% of pts with ≥ 6 mo F/U vs the 44% ongoing response rate at the primary analysis of C1+2 (also ≥ 6 mo F/U). Although most pts in C4 had lower SPDs than those in C1+2, responses were comparable when evaluated by TB. Median DOR was 8.9 mo, consistent with that observed for C1+2 (8.1 mo; Locke, AACR 2017; Figure). Median PFS was 11.7 mo; median OS was not reached. Peak CAR T cell levels were 42 cells/µL blood in C1+2 vs 59 cells/µL in C4. C1+2 had a median CAR AUC of 462 cells/µL × days vs 512 cells/µL in C4. CAR T cell expansion was comparable between cohorts when adjusted by TB. Levels of key NE-associated biomarkers including ferritin (pre- and post-Tx) and IL-2 (post-Tx) appeared lower in C4 than in C1+2. Earlier steroid use may reduce the rates of CAR T cell Tx-related CRS and NEs without affecting efficacy. Conclusions are limited by the nonrandomized study design and differences in population sizes and baseline characteristics between cohorts. Optimizing AE management is important to improve the benefit–risk profile of CAR T cell therapy. [ABSTRACT FROM AUTHOR]

Outcomes with salvage regimens in pts with MCL who progress after Bruton tyrosine kinase inhibitor (BTKi) therapy are poor. ZUMA-2 is a Phase 2, registrational, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL (1-5 therapies, including a BTKi). We present interim efficacy and safety results. Evaluate efficacy and safety of KTE-X19 in R/R MCL. Eligible pts (≥ 18 y) with R/R MCL had an ECOG of 0-1 and ≤ 5 prior therapies, including chemotherapy, an anti-CD20 antibody, and a BTKi. Pts underwent leukapheresis and conditioning chemotherapy followed by KTE-X19 infusion at 2 × 106 cells/kg. Bridging therapy with dexamethasone, ibrutinib, or acalabrutinib was permitted. The primary endpoint was objective response rate (ORR; complete response [CR] + partial response) assessed by an Independent Review Committee per the Lugano Classification (Cheson, et al. J Clin Oncol. 2014). Interim efficacy endpoints were investigator-assessed using the revised IWG Response Criteria for Malignant Lymphoma (Cheson, et al. J Clin Oncol. 2007). Key secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), frequency of adverse events (AEs), and blood levels of CAR T cells and cytokines. Sixty pts received KTE-X19; here, we present results in pts with ≥ 1 y follow-up. Updated results in all 60 pts will be reported in the presentation. As of May 30, 2018, 28 pts received KTE-X19 with ≥ 1 y follow-up (median, 13.2 mo). The median age was 65 y; 43% of pts had an ECOG score of 1; 21% had blastoid morphology; 82% had stage IV disease; 50% had intermediate/high-risk MIPI; and 86% received a median of 4 prior therapies. In 20 of 28 pts with available data, the median Ki-67 index was 38%. Eight pts received bridging therapy; all had disease present post-bridging. Investigator-assessed ORR was 86% (95% CI, 67-96) with a CR rate of 57% (95% CI, 37-76). As of May 30, 2018, 75% of responders remained in response, and 64% of treated pts had ongoing responses. The 12-month rates of DOR, PFS, and OS were 83% (95% CI, 60-93), 71% (95% CI, 50-84), and 86% (95% CI, 66-94), respectively; medians were not reached. The most common Grade ≥ 3 AEs were anemia (54%), platelet count decreased (39%), and neutropenia (36%). Grade 3/4 cytokine release syndrome (CRS) assessed by Lee et al. (Blood. 2014) and Grade 3/4 neurologic events (NE) occurred in 18% and 46% of pts, respectively, with no Grade 5 events. CRS and NE were generally reversible. There was 1 Grade 5 AE of organizing pneumonia. Median CAR T cell levels measured by peak and area under the curve were 99 cells/µL (range, 0.4-2589) and 1542 cells/µL (range, 5.5-27239), respectively. With ≥ 1 y follow-up, KTE-X19 demonstrated significant and durable clinical benefit, with a manageable safety profile in pts with R/R MCL for whom there are no curative treatment options. [ABSTRACT FROM AUTHOR]