Axicabtagene ciloleucel: potential new second-line standard of care for patients with relapsed/refractory large B-cell lymphoma

May 2022 ASH 2021 Tom Feys

Two-year data from the ZUMA-7 trial primary analysis show that the CAR-T-cell therapy axicabtagene ciloleucel (axi-cel) significantly improved event-free survival compared to standard of care for patients with aggressive large B-cell lymphoma, meeting the trial’s primary endpoint. As axi-cel also demonstrated a manageable safety profile, these results might herald a paradigm shift in how large B-cell lymphoma is treated.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR-T cell therapy approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) after at least two lines of systemic therapy. Current standard of care (SOC) second-line treatment in the curative setting for patients with R/R LBCL consists of salvage chemotherapy, followed by consolidative high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). However, as many patients do not respond to or cannot tolerate second-line chemoimmunotherapy (CIT), or are not eligible for HDT-ASCT, their prognosis is poor. ZUMA-7 is the first randomised, global, multicentre phase III study of axi-cel versus SOC as second-line treatment in patients with R/R LBCL.

ZUMA-7 study design

Eligible patients were adults with LBCL, an ECOG performance status of 0–1, R/R disease within 12 months of adequate first-line CIT (including anti-CD20 monoclonal antibody and an anthracycline), and intended to proceed to HDT-ASCT. In total, 359 patients were randomised (1:1) to axi-cel or SOC, stratified by first-line treatment response and second-line age-adjusted IPI (sAAIPI). In the axi-cel arm, patients received a single infusion of 2 ×106 CAR-T cells/kg after conditioning (3 d; cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day). Optional bridging treatment was limited to corticosteroids (CIT was not allowed). In the SOC arm, patients received 2–3 cycles of an investigator-selected, protocol defined, platinum-based CIT regimen; patients with partial response (PR) or complete response (CR) proceeded to HDT-ASCT. Disease assessments by PET-CT per Lugano Classification occurred at time points specified from randomisation. Although there was no planned trial crossover between arms, patients not responding to SOC could receive CAR T-cell therapy off protocol. Primary endpoint of the ZUMA-7 study was event-free survival (EFS) by blinded central review. Key secondary endpoints were tested hierarchically and consisted of objective response rate (ORR) and an interim analysis of overall survival (OS). The OS primary analysis will be conducted after approximately 210 deaths or five years of follow-up.


Of the 180 patients randomised to the axi-cel arm, 94% received axi-cel treatment. In contrast, of the 179 patients randomised to SOC, only 36% received HDT-ASCT. Baseline characteristics were generally balanced between the two cohorts. Approximately 30% of patients were 65 years or older, 79% had stage III-IV disease, 74% had primary refractory disease and 45% had high sAAIPI (2–3). With a median follow-up of 24.9 months, the median EFS was significantly longer in patients in the axi-cel arm compared to those in the SOC arm (8.3 vs. 2.0 months, HR[95%CI]: 0.398[0.308-0.514], p< 0.0001), translating into Kaplan-Meier estimates of the 24-month EFS rates of 40.5% and 16.3%, respectively. EFS improvements with axi-cel versus SOC were consistent among key patient subgroups, including patients ≥65 years, patients with primary refractory disease and patients with double-hit or double expressor lymphoma. Also the ORR was significantly higher in the axi-cel arm (83% vs. 50%, Odds ratio [95%CI]: 5.31[3.1-8.9], p< 0.0001) with a complete response rate of 65%, twice as high as what was seen in the SOC arm (32%). Median OS, evaluated as a preplanned interim analysis, favoured axi-cel vs. SOC, although this difference did not meet statistical significance (not reached vs. 35.1 months, respectively; HR: 0.730; p= 0.027).

Grade ≥3 treatment-emergent adverse events occurred in 91% and 83% of patients in the axi-cel and SOC arms, respectively. During the protocol-specified reporting period, grade 5 adverse events occurred in seven patients in the axi-cel arm, with one death being investigator-attributed to axi-cel. There were two grade 5 adverse events in the SOC arm, both attributed to HDT and ASCT. In patients treated with axi-cel, grade ≥3 cytokine release syndrome (CRS) occurred in 11 (6%) patients (median time to onset 3 days; median duration 7 days) and grade ≥3 neurologic events (NEs) occurred in 36 (21%) patients (median time to onset 7 days; median duration 9 days). No grade 5 CRS or NEs occurred.


ZUMA-7 met its primary EFS endpoint, demonstrating a statistically significant and clinically meaningful improvement in efficacy with axi-cel versus second-line SOC in R/R LBCL. Nearly three times more patients in the axi-cel arm received definitive therapy versus the SOC arm. Axi-cel had a manageable safety profile that was consistent with previous studies. The results of the ZUMA-7 trial could therefore herald a true paradigm shift, with CAR-T cell therapy becoming a new second-line standard of care for patients with R/R LBCL.  


Locke F, et al. Primary Analysis of ZUMA‑7: A Phase 3 Randomized Trial of Axicabtagene Ciloleucel (Axi-Cel) Versus Standard‑of‑Care Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma. Presented at ASH 2021; Abstract 2.