3-Year Follow-up Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

Introduction: Axi-cel, an autologous anti-CD19 CAR T-cell therapy, is approved for the treatment of adults with follicular lymphoma (FL) after ≥2 lines of prior therapy. ZUMA-5 is a Phase 2, multicenter, single-arm study of axi-cel in patients with R/R iNHL (FL and marginal zone lymphoma [MZL]). In the 2-year analysis of ZUMA-5, the overall response rates (ORR) in patients with FL and MZL were 94% (79% complete response [CR] rate) and 83% (63% CR rate), respectively (Neelapu et al. ASH 2021. Abstract 93). Here, we report updated clinical and pharmacologic outcomes from ZUMA-5 after >3 years median follow-up.

Methods: Eligible patients had R/R FL or MZL after ≥2 lines of therapy (including an anti-CD20 mAb plus an alkylating agent). At enrollment, patients underwent leukapheresis, followed by conditioning chemotherapy and a single axi-cel infusion (2×10⁶ CAR T cells/kg). The primary endpoint was ORR. Time-to-event endpoints were assessed by investigators in all enrolled patients. Exploratory analyses of lymphoma-specific survival were performed, where deaths unrelated to progression, axi-cel, or conditioning chemotherapy were not considered events of interest. Univariable and multivariable analyses were conducted using random forest analysis to rank the association of pharmacologic covariates with efficacy and toxicity.

Results: A total of 159 patients were enrolled (127 FL; 31 MZL) and 152 were treated with axi-cel (124 FL; 28 MZL). As of March 31, 2022, the median follow-up in enrolled patients was 40.5 months (range, 8.3-57.4; FL: 41.7, MZL: 31.8). ORR and CR rates were largely similar to the 2-year analysis. In all enrolled patients, median duration of response (DOR) was 38.6 months (FL: 38.6, MZL: not reached [NR]). Median DOR was NR in patients with a CR and was 4.9 months in those with a partial response. Median progression-free survival (PFS) was 40.2 months (FL: 40.2, MZL: NR). Median PFS among patients with FL with (n=70) or without (n=41) progression <2 years after initial chemoimmunotherapy (POD24) was 40.2 months and NR, respectively. Estimated 36-month PFS was largely consistent in all patients with iNHL, regardless of other high-risk characteristics, including ≥3 prior lines of therapy and double-refractory disease. Medians of time to next treatment and overall survival (OS) were not reached; 36-month OS rate was 75%. Medians of lymphoma-specific PFS and lymphoma-specific survival were not reached; 36-month rates were 65% and 89%, respectively.

Grade ≥3 adverse events (AEs) of interest occurring among treated patients since the 2-year analysis were largely in recently enrolled patients with MZL, including neurologic events in 1, cytopenias in 4, and infections in 2 (1 in FL). Since the 2-year analysis, 10 additional patients died due to progression (n=1), AEs (n=3; none related to axi-cel), and other causes (n=6).

Among treated patients, peak CAR T-cell levels were higher in those with ongoing responses at 36 months (53.9 cells/µL) than those who relapsed (29.6 cells/µL) or nonresponders (22.2 cells/µL). In patients with FL, peak levels of circulating CAR T cells normalized to baseline tumor burden in conjunction with elevated preinfusion inflammatory markers and regulatory T-cell (Treg)-related chemokines associated with relapse. Multivariable analyses in patients with FL, to be detailed in the presentation, further identified key covariates that differentially associated with efficacy and toxicity.

Conclusions: After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses in patients with R/R iNHL, with improved survival observed in patients with MZL. Late progression or death due to lymphoma or study treatment were uncommon and no new safety signals arose since the 2-year analysis. Preinfusion immunosuppressive Treg-related biomarkers associated with relapse in patients with FL.