Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma

Abstract

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.

Graphical abstract

Figure 1.

EFS, PFS, and time to progression. Kaplan-Meier estimates of (A) EFS, (B) PFS, and (C) time to progression by investigator assessment among the 101 patients with LBCL treated with axi-cel in cohorts 1 and 2 of phase 2.

Figure 2.

OS and disease-specific survival. Kaplan-Meier estimates of (A) OS and (B) disease-specific survival among 101 patients with LBCL treated with axi-cel in cohorts 1 and 2 of phase 2. One patient’s event time for OS was updated from month 42 to month 39 after data cutoff and is not reflected in this figure. DSS, disease specific survival.

Figure 3.

Early CAR T-cell expansion correlated with ongoing response. (A) Peak CAR T-cell levels and (B) AUC between days 0 and 28 among patients who received treatment who had evaluable samples who had an ongoing response after axi-cel infusion, along with those who relapsed after responding and those who did not respond to axi-cel. Ongoing response was defined as responders (CR or PR) who did not have PD or die by the data cutoff date. Four patients did not have evaluable postinfusion samples to allow for determination for CAR T-cell peak or AUC. The median is represented by the horizontal line within each box, and the 25th and the 75th percentiles are represented by the lower and upper borders, resepctively, of each box. AUC, area under the curve; PD, progressive disease, PR, partial response.