Axicabtagene Ciloleucel in Combination With Atezolizumab in Patients With Refractory Diffuse Large B-cell Lymphoma: The Phase 1/2 ZUMA-6 Trial

Purpose: Chimeric antigen receptor (CAR) T-cell therapies have improved outcomes in patients with relapsed/refractory large B-cell lymphoma (LBCL). However, up to two-thirds of these patients do not maintain long-term responses. The Phase 1/2 ZUMA-6 study investigated the feasibility of combining the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) with the PD-L1 inhibitor atezolizumab as a potential approach to increase treatment efficacy while maintaining acceptable safety. Methods: Patients with refractory diffuse LBCL received a single axi-cel infusion (2×106 cells/kg) followed by atezolizumab 1,200 mg intravenously every 21 days for 4 cycles. Primary endpoints were dose-limiting toxicities (DLTs; Phase 1) and complete response (CR) rate (Phase 2). Other efficacy and safety outcomes and pharmacokinetics/pharmacodynamics were assessed. Results: Overall, 34 patients received axi-cel plus atezolizumab in ZUMA-6. Median follow-up for the final analysis was 56.9 months. In Phase 1, 1 patient experienced DLTs (Grade 4 neutropenia and thrombocytopenia). Thirty patients (88%) experienced Grade ≥3 treatment-emergent adverse events. Three (9%) and 11 (32%) patients experienced Grade ≥3 cytokine release syndrome and neurologic events, respectively. In the final analysis, 15 patients (54%) had a CR. Median PFS and OS were 9.0 months and 32.2 months, respectively. Peak CAR T-cell and cytokine profiles were comparable to those previously reported for axi-cel monotherapy (ZUMA-1).< Conclusions: Axi-cel plus atezolizumab had a managable safety profile, with no new safety signals. Safety and efficacy of this combination were consistent with axi-cel monotherapy. Correlative analyses could inform as to which LBCL patients may benefit from axi-cel and immune checkpoint inhibitor combinations.