P1197: AXICABTAGENE CILOLEUCEL (AXI-CEL) IN COMBINATION WITH RITUXIMAB FOR THE TREATMENT OF RELAPSED/REFRACTORY (R/R) LARGE B-CELL LYMPHOMA (LBCL): OUTCOMES OF THE PHASE 2 ZUMA-14 STUDY

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Background: Despite the success of axi-cel, ≈60% of patients have no response or relapse within ~2 y after treatment (Jacobson C, et al. ASH 2021. #1764), highlighting the need for more therapeutic strategies. In preclinical studies, rituximab augmented CD19 chimeric antigen receptor (CAR) T-cell function and increased tumor reduction and survival in murine models via synergistic targeting with CAR T-cells (Mihara K, et al. Br J Haematol. 2010). Aims: Here, we report outcomes of ZUMA-14, a Phase 2, multicenter study of axi-cel in combination with rituximab in pts with R/R LBCL after ≥2 lines of systemic therapy. Methods: Eligible patients were ≥18 y with R/R LBCL. Patients received one rituximab dose (375 mg/m2) on Day -5, a conditioning regimen of cyclophosphamide and fludarabine on Days -5, -4, and -3, and a single axi-cel infusion of 2×106 CAR T cells/kg on Day 0. Starting on Day 21 post–axi-cel infusion, patients received 1 rituximab dose every 28 days for up to 5 doses. The primary endpoint was investigator-assessed complete response (CR) rate. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and biomarker assessments. The analysis reported here occurred after all treated patients had ≥12 months of follow-up. Results: As of 12/2/21, 27 patients were enrolled, and 26 received axi-cel and ≥1 rituximab dose (15 patients received all 6 rituximab doses); 1 patient discontinued treatment due to an adverse event (AE). Median age was 63 y (range, 38-82), 54% were male, 81% had stage III/IV disease, 62% had extranodal disease, 38% had elevated lactate dehydrogenase, and 85% had an age-adjusted International Prognostic Index (aaIPI) ≥1 (35% aaIPI=2). The CR rate was 65% (95% CI, 44%-83%), and the ORR was 88% (95% CI, 70%-98%). With a median follow-up of 17 months, 65% of the patients had ongoing response, with 57% ongoing in CR. Medians for DOR, PFS and OS were not reached. The estimated DOR and PFS rates at 12 months were 64% and 56%, respectively. The estimated 12-month OS rate was 76%, and 6 patients (23%) died of progressive disease. Most patients (92%) experienced Grade ≥3 AEs. Grade ≥3 cytopenias were reported in 85% of patients, with 38% ongoing on Day 30. Grade ≥3 neurologic events (NEs) occurred in 4 patients (15%); there was no Grade ≥3 cytokine release syndrome (CRS). Median times to onset of CRS and NEs were 4 days (range, 1-7 days) and 6 days (range, 3-32 days), respectively, with median durations of 5 days (range, 2-15 days) and 7 days (range, 1-39 days). No patients experienced myelodysplastic syndrome. Median peak CAR T-cell levels were comparable to the ZUMA-1 pharmacokinetic profile. Immune-modulating cytokines, including granzyme B, IL-6, CXCL10, IFN-γ and IL-2, were induced in patients following axi-cel and rituximab infusion and were more prominently elevated in responders vs non-responders. Peak rituximab levels were also elevated in responders vs non-responders. Summary/Conclusion: Results from ZUMA-14 demonstrated that axi-cel in combination with rituximab elicited a high CR rate and durable PFS with no new safety signals detected in patients with R/R LBCL.

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