End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma

Abstract

Background Axi-cel is a US FDA-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for treatment of adult patients (pts) with relapsed or refractory large B cell lymphoma (LBCL) after ≥ 2 prior lines of therapy. The checkpoint proteins PD-1 and PD-L1 are expressed on CAR T cells and in the tumor microenvironment, and are upregulated after CAR T cell infusion (Cherkassky, et al. J Clin Invest . 2016; Galon, et al. ASCO 2017. #3025). This suggests that PD-L1 blockade could augment axi-cel activity. This end of Phase 1 analysis of ZUMA-6 examines the safety and preliminary efficacy of axi-cel in combination with the anti–PD-L1 antibody atezolizumab (atezo) in pts with refractory LBCL (NCT02926833). Methods Eligible pts (≥ 18 years) with refractory DLBCL must have received prior CD20-targeting and anthracycline-containing regimen and had ECOG ≤ 1 and adequate bone marrow and organ function. Pts received low-dose conditioning followed by axi-cel infusion (target dose of 2\u202f×\u202f10 6 cells/kg). Atezo was administered at 1200 mg every 21 days for 4 doses starting on Day 21, 14, and 1 post–axi-cel infusion for Cohorts 1, 2, and 3, respectively. Incidence of dose-limiting toxicities (DLTs) was the primary endpoint. Secondary endpoints included the frequency of adverse events (AEs), disease response, and pharmacokinetics. Results As of January 19, 2018, 12 pts have received axi-cel and ≥1 dose of atezo (3 in Cohort 1; 3 in Cohort 2, 6 in Cohort 3). Median age was 55 years (range, 30 – 66); median follow-up from axi-cel infusion was 4.4 months (range, 0.8 – 12.6). One pt in Cohort 3 experienced a DLT of Grade 4 thrombocytopenia and neutropenia lasting >30 days. All pts experienced at least 1 AE (92% Grade ≥ 3), with no apparent exacerbation or recurrence of axi-cel–related AE following atezo infusion. The most common grade ≥ 3 AEs were anemia (9/12, 75%), encephalopathy (5/12, 42%), and neutropenia (5/12, 42%). Grade ≥ 3 CRS and neurologic events occurred in 3 (25%) and 6 (50%) pts, respectively. The ORR in evaluable pts was 9/10 (90%), with 6 pts (60%) in CR and 3 (30%) in partial response (PR); 2/6 pts (33%) had converted to CR at month 6 and month 9 after initially achieving a PR. CAR T cell expansion (area under the curve D0-28 ) in pts with DLBCL was >2-fold higher in ZUMA-6 than the median observed in pts treated with axi-cel alone in ZUMA-1 (ZUMA-6: median, 823 cells/µL\u202f×\u202fdays, range, 99 – 2301; ZUMA-1: median, 357 cells/µL\u202f×\u202fdays, range, 5 – 11,507). Median CAR T cell levels remained higher than ZUMA-1 beyond 28 days. Conclusions PD-L1 blockade with atezo following axi-cel infusion has a manageable safety profile, with a low incidence of DLTs and no clinically significant increase in incidence of AEs. Encouraging efficacy results support the opening of Phase 2 of ZUMA-6 in which 22 pts will be treated according to the Cohort 3 schedule. Pharmacokinetic data suggest the potential for enhanced CAR T cell expansion.