Phase 1 Results from ZUMA-6: Axicabtagene Ciloleucel (axi-cel; KTE-C19) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma (DLBCL)

Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, has shown promising efficacy in refractory aggressive non-Hodgkin lymphoma in the ZUMA-1 trial with an objective response rate (ORR) of 82%, including 54% complete responses (CRs; Locke et al. AACR 2017. #9986). Checkpoint expression within the tumor environment, at baseline and post-CAR T cell infusion, suggests that checkpoint blockade could augment axi-cel activity (Galon et al. ASCO 2017. #3025; Vranic et al. PLOS One. 2016). ZUMA-6 is a phase 1/2 study evaluating the safety and efficacy of combination treatment with axi-cel and the anti-PD-L1 antibody, atezolizumab (atezo), in patients with refractory DLBCL (NCT02926833).

Methods: Eligible patients (≥ 18 years) had received ≥ 1 prior CD20-targeting and anthracycline-containing regimen with stable or progressive disease to last line of therapy or early relapse after autologous stem cell transplant, had an ECOG ≤ 1, and had adequate bone marrow and organ function. Patients received low-dose conditioning with fludarabine 30 mg/m²/day and cyclophosphamide 500 mg/m²/day × 3 days, followed by axi-cel infusion at a target dose of 2 × 10⁶ cells/kg. In the phase 1 portion of the study, in cohorts 1, 2, and 3, atezo 1200 mg was administered every 21 days for 4 doses starting on day 21, 14, and 1 post-axi-cel infusion, respectively. This report describes phase 1 results from the first 2 dosing cohorts. The primary endpoint of phase 1 was incidence of dose-limiting toxicities (DLTs) within 21 days from the first atezo dose. Secondary endpoints included frequency of adverse events (AEs), ORR, and biomarkers.

Results: As of the June 23, 2017 data cut-off, there were 6 patients dosed with axi-cel and atezo (3 in cohort 1; 3 in cohort 2). Median age was 52 years (range, 29-66). Patients had a median of 3 prior therapies (range, 2-4), 4 had disease progression as best response to last prior treatment before study entry, and 3 had an International Prognostic Index score of 3 or 4. No DLTs were observed in either cohort and there was no evidence of worsening or recurrent AEs consistent with cytokine release syndrome (CRS), neurologic events (NE), or other CAR T cell-related toxicities following atezo administration in either dosing schedule. All patients experienced at least 1 AE, the majority of which were cytopenias attributed to conditioning chemotherapy. The most common grade ≥ 3 AEs were anemia (67%), encephalopathy (67%), and hyponatremia (50%). Incidences of grade ≥ 3 CRS and NE were 33% and 67%, respectively. Five patients were evaluable for response; ORR was 100% (5/5) with 1 CR observed. One CR and 2 partial responses are ongoing. All 6 ZUMA-6 patients demonstrated a CAR T cell area under the curve in the first 28 days (AUC₂₈) that was over 2-fold higher than the median observed in patients with DLBCL enrolled in ZUMA-1 (ZUMA-6 range, 816-2301 days × cells/uL; ZUMA-1 median, 374 days × cells/uL). A second peak of > 2-fold over the pre-atezo level in serum concentrations of the immune-modulating cytokine interferon gamma was also observed 1 week after the first atezo infusion in 4/5 evaluable patients. Cohort 3 is currently enrolling and updated results, including those from cohort 3, will be presented.

Conclusions: In this ongoing phase 1 study, PD-L1 blockade with atezo following axi-cel infusion appeared to have a manageable safety profile, and translational evidence suggested an enhancing pharmacodynamic action on CAR T cells. Results collected thus far support further evaluation of the combination in the phase 2 portion of the study.