作者
Sattva S. Neelapu,Julio C. Chávez,Alison R. Sehgal,Narendranath Epperla,Matthew L. Ulrickson,E. Bachy,Pashna N. Munshi,Carla Casulo,David G. Maloney,Sven de Vos,Ran Reshef,Lori A. Leslie,Olalekan O. Oluwole,Ibrahim Yakoub‐Agha,Rashmi Khanal,Joseph D. Rosenblatt,Jiali Yan,Qinghua Song,Weixin Peng,Christine Lui,Jacob Wulff,Rhine R. Shen,Soumya Poddar,Harry Miao,Sara Beygi,Caron A. Jacobson
摘要
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. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal