Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma.
Authors: Westin Jason , Oluwole Olalekan O. , Kersten Marie José , Miklos David Bernard , Perales Miguel-Angel , Ghobadi Armin , Rapoport Aaron , Sureda Anna , Jacobson Caron Alyce , Farooq Umar , van Meerten Tom , Ulrickson Matthew L. , Elsawy Mahmoud , Leslie Lori A. , Chaganti Sridhar , Dickinson Michael , Yang Yin , Schupp Marco Andreas , To Christina Ann , Locke Frederick L. 
Published: June 2023

LBA107 Background: In ZUMA-7 (NCT03391466), axicabtagene ciloleucel (axi-cel) was superior to standard of care (SOC; hazard ratio [HR], 0.398; P<.0001) in the primary analysis of event-free survival as second-line therapy in patients with early relapsed or refractory large B-cell lymphoma (R/R LBCL; Locke et al. NEJM. 2022). In a preplanned interim analysis, median overall survival (OS) was not reached in the axi-cel arm and was 25.7 mo in the SOC arm (HR, 0.71; 95% CI, 0.52-0.97; Locke et al. TCT 2022. Abstract 1). We now report the primary OS analysis of ZUMA-7. Methods: Study procedures and eligibility were previously reported. The intention-to-treat (ITT) primary OS analysis occurred 5 years after the first patient was randomized (01/25/2018) per protocol. A log-rank test stratified by randomization stratification factors compared OS between the 2 arms. In addition to the ITT analysis and to account for subsequent treatment with cellular immunotherapy off protocol in the SOC arm, prespecified sensitivity analyses of OS were conducted using the Rank-Preserving Structural Failure Time (RPSFT) and Inverse Probability of Censoring Weights (IPCW) models. Other endpoints included progression-free survival (PFS) per investigator assessment, OS in key subgroups, and safety. Results: In total, 359 patients were randomly assigned, 180 to axi-cel and 179 to SOC. As of 01/25/2023, at a median follow-up of 47.2 mo, axi-cel demonstrated a statistically significant improvement in OS over SOC (HR [95% CI], 0.726 [0.540-0.977]; stratified log-rank 1-sided P=0.0168 [efficacy boundary, 0.0249]). Median OS was longer with axi-cel vs SOC (not reached vs 31.1 mo, respectively); 48-mo OS estimates were higher with axi-cel (54.6% vs 46.0%, respectively). OS benefit with axi-cel vs SOC was consistent in prespecified key subgroups, including age ≥65 years, primary refractory, early relapse, high-grade B-cell lymphoma, and high second-line age-adjusted IPI. In the SOC arm, 102 (57%) patients received subsequent cellular immunotherapy off protocol. Prespecified OS sensitivity analyses, conducted to address the confounding effects of treatment-switching in the SOC arm, showed an even greater OS benefit with axi-cel vs SOC, with stratified HR (95% CI) of 0.608 (0.449-0.824) by RPSFT and 0.633 (0.409-0.981) by IPCW. PFS by investigator confirmed benefit of axi-cel over SOC (HR [95% CI], 0.506 [0.383-0.669]), with 48-mo PFS estimates of 41.8% vs 24.4%, respectively. No new cytokine release syndrome or neurologic events and no new treatment-related deaths occurred since the primary EFS analysis. The safety profile of axi-cel remained consistent with prior studies. Conclusions: Axi-cel as second-line therapy demonstrated a significant improvement in overall survival over historical standard of care in patients with early relapsed/refractory LBCL. Clinical trial information: NCT03391466 .