Long-Term Follow-Up of ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel in Patients with Refractory, Aggressive NHL

Patients with refractory non-Hodgkin lymphoma (NHL) experience poor outcomes to currently available therapies. In the SCHOLAR-1 pooled analysis of patients with refractory aggressive NHL, the objective response rate (ORR) was 26% (complete response [CR] rate was 7%), and the median overall survival (OS) was 6.3 months.¹ The primary analysis of ZUMA-1 demonstrated positive results, with an ORR of 82% and a CR rate of 54% after a single infusion of axicabtagene ciloleucel (axi-cel; anti-CD19 chimeric antigen receptor [CAR] T).^2,3 The safety profile was manageable, and with a median follow-up of 8.7 months, 44% of patients in ZUMA-1 were in ongoing response.⁴ At ASH 2017, the authors presented the 1-year follow-up of ZUMA-1 to confirm the stability of response following anti-CD19 CAR T-cell therapy as previously suggested.⁵ In addition, exploratory biomarker analyses were presented to understand the mechanisms of resistance to anti-CD19 CAR T-cell treatment.

Patients with refractory diffuse large B-cell lymphoma, transformed follicular lymphoma, or primary mediastinal large B-cell lymphoma were enrolled and dosed per Locke and colleagues.^2,3 Refractory disease was defined as progressive disease or stable disease (SD) as best response to last line of therapy, or relapse ≤12 months after autologous stem-cell transplant. The primary end point was ORR; key secondary end points included duration of response (DOR), OS, and incidence of adverse events (AEs). A key exploratory end point was to investigate the mechanisms of resistance using posttreatment tumor biopsies obtained at the time of relapse or progression.

An updated analysis of ORR was presented after median follow-up of 15.4 months. In these 108 patients, ORR and CR remained the same: 82% and 54%, respectively. More than one-third (38%) of the 60 patients with either partial response (PR) or SD at the first tumor assessment (2 months post‒axi-cel infusion) subsequently achieved CR up to 15 months postinfusion without additional therapy. The median time to conversion from PR to CR was 64 days.

Median DOR by best objective response was 11.1 months. In patients who achieved CR, median DOR has not been reached. Durable responses were noted in patients with and without detectable persisting CAR T-cells. After 15.4 months of follow-up, 56% of patients were alive and 42% of patients were progression-free.

With at least 6 months of follow-up, there have been no new axi-cel‒related cytokine release syndrome, neurologic events, or deaths. Most patients experienced hypogammaglobulinemia and B-cell aplasia, with 8% requiring intravenous immunoglobulin support during the study. Infections were the most common new-onset, treatment-emergent serious AEs, occurring in 8 patients (8%). All these infections resolved at the time of data cutoff.

Baseline and postprogression biopsies were evaluable by central review from 21 patients, and CD19 and PD-L1 immunohistochemistry results were tabulated. Seven of 21 (33%) patients with CD19-positive status at baseline developed CD19-negative disease at the time of disease progression. Sixty-two percent of patients who were evaluable for PD-L1 at the time of disease progression had PD-L1–positive disease. Of the 14 patients with CD19-positive samples at progression, 9 (64%) demonstrated PD-L1–positive tumor cells. Of the 7 patients with CD19-negative samples at progression, 2 had PD-L1–positive tumor cells.

The authors concluded that in the ZUMA-1 study, axi-cel demonstrated significant clinical benefit with manageable AEs in patients with refractory aggressive NHL and no curative treatment options. Loss of CD19 and gain of PD-L1 expression in tumors were identified as possible mechanisms of resistance following axi-cel treatment. Novel therapeutic strategies to overcome CD19 CAR T resistance and further improve outcomes in these patients are in development.

References

1. Crump M, et al. Blood. 2017;130:1800-1808.
2. Locke FL, et al. Mol Ther. 2017;25:285-295.
3. Locke FL, et al. AACR 2017. Abstract 9986.
4. Kochenderfer JN, et al. Mol Ther. 2017;25:2245-2253.
5. Neelapu SS, et al. ASH 2017. Abstract 578.