Interim Analysis of ZUMA-12: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) as First-Line Therapy in Patients (Pts) With High-Risk Large B Cell Lymphoma (LBCL)

Background: Pts with high-risk LBCL have poor outcomes with R‑CHOP chemoimmunotherapy (Sathyanarayanan, et al. ASH 2016. #106), and ≈50% of pts will not achieve long‑term disease remission (Coiffier, et al. ASH Ed Program. 2016), highlighting unmet need for new therapies. Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, was approved for treatment of adults with R/R LBCL after ≥ 2 lines of systemic therapies based on the pivotal study, ZUMA‑1 (Neelapu SS, et al. NEJM. 2017). ZUMA-12 is a Phase 2, multicenter, open-label, single-arm study of axi-cel as part of first-line therapy in pts with high-risk LBCL. Here, we present interim efficacy, safety, and pharmacokinetics (PK) results from ZUMA-12.

Methods: Eligible adults (≥ 18 y) met 2 criteria for high-risk LBCL: i) double- or triple-hit lymphoma by fluorescent in situ hybridization per investigator or LBCL with IPI score ≥ 3; and ii) positive interim PET per Lugano Classification (Cheson, et al. J Clin Oncol. 2014; Deauville score [DS] 4 or 5) after 2 cycles of an anti‑CD20 monoclonal antibody and anthracycline containing regimen, which served as a dynamic risk assessment. Pts with PMBCL were not eligible. Pts underwent leukapheresis (≥ 2 wks after prior systemic therapy) and optional non-chemotherapy bridging at investigator discretion, followed by conditioning chemotherapy (cyclophosphamide 500 mg/m²/d and fludarabine 30 mg/m²/d for 3 d) and a single axi-cel infusion (target dose, 2 × 10⁶ CAR T cells/kg). The primary endpoint was investigator-assessed complete response (CR) rate per Lugano. Key secondary endpoints included objective response rate (ORR), frequency of adverse events (AEs), and levels of CAR T cells and cytokines in blood and serum.

Results: As of July 15, 2020, 31 pts have been enrolled and treated, and as of January 24, 2020, in a planned interim analysis, 15 pts were treated with axi-cel with ≥ 3 mos of follow-up. Median age was 60 y (range, 39 – 86), 67% of pts were male, 73% had ECOG of 1, 40%/60% had DS4/5; 60% had double‑ or triple-hit status per investigator, and 67% had IPI score ≥ 3. Baseline characteristics were largely comparable to ZUMA-1 Cohort 1 except for lower median tumor burden in ZUMA-12 (ZUMA-1: 3897 mm² vs ZUMA-12: 1610 mm²).

Of 12 response-evaluable pts (pts with centrally confirmed high-risk LBCL who received axi-cel), the investigator-assessed ORR was 92% (95% CI, 62% – 100%) with a CR rate of 75% (95% CI, 43% – 95%); 75% of pts had ongoing responses at data cutoff. Of 15 pts treated (safety analysis set), the investigator-assessed ORR was 93% (95% CI, 68% – 100%) with a CR rate of 80% (95% CI, 52% – 96%); 86% of pts had ongoing responses at data cutoff.

Of 15 safety-evaluable pts, 80% experienced Grade ≥ 3 AEs. The most common Grade ≥ 3 AEs (≥ 25% of pts) were white blood cell count decreased (40%), anemia (27%), and encephalopathy (27%). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 20% and 27% of pts, respectively. All CRS and 10/11 NEs of any grade resolved (causally unrelated Grade 1 tremor was ongoing in 1 pt at data cutoff). Median time to onset of CRS was 4 d (range, 1 – 8), with median duration of 5 d (range, 2 – 12). Median time to onset of NEs was 9 d (range, 2 – 44), with median duration of 10 d (range, 1 – 40). Grade ≥ 3 infection was reported in 27% and Grade ≥ 3 neutrophil count decreased was reported in 20%. No Grade 5 AEs occurred.

Despite similar assessment schedule and methodology, median peak CAR T cell levels were greater in ZUMA-12 vs ZUMA-1 Cohort 1 (131 cells/µL [range, 10 – 555] vs 32 cells/µL [range, 1 – 1514]). Median CAR T cell expansion (AUC_0-28) was also greater in ZUMA-12 (1124 cells/µL × d [range, 147 – 4261]; ZUMA-1: 357 cells/µL × d [range, 5 – 11,507]). Median time to peak levels of CAR T cells in blood was 7 d after infusion. PK were similar in pts with double- or triple-hit lymphoma and IPI score ≥ 3.

Updated safety, efficacy, and PK results will be reported, along with product characteristics and levels of key cytokines.

Conclusion: ZUMA-12 is the first study evaluating CAR T cell therapy as first-line therapy in high-risk LBCL, which notably was defined by both histology and/or IPI and dynamic risk assessment with PET scan. Axi-cel demonstrated significant clinical benefit, with high ORR and CR rates and a manageable safety profile in pts for whom there is an unmet medical need. The study also provides new insights into the pharmacology of CAR T cell therapy for pts exposed to fewer prior therapies.