Axicabtagene Ciloleucel (Axi-Cel) Versus Standard of Care (SOC) in Patients with Primary Refractory or Early Relapsed Large B-Cell Lymphoma (LBCL)

Introduction Historically, patients (pts) with primary refractory and early relapsed LBCL had poor outcomes. Axi-cel showed superior overall survival (OS) vs SOC in the ZUMA-7 intention-to-treat primary OS analysis (NCT03391466; Westin et al. NEJM. 2023). Objectives To determine survival benefit of axi-cel over SOC in the prespecified pt groups of primary refractory vs relapsed disease ≤12 mo of first-line (1L) therapy in ZUMA-7, and assess correlates of efficacy outcomes. Methods Study design and pt eligibility were reported in Locke et al. NEJM . 2022. Pts were randomized 1:1, stratified by 1L therapy response and second-line (2L) age-adjusted IPI, to axi-cel or SOC (chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation in responding pts). As of 25 Jan 2023, OS, event-free survival (EFS) and progression-free survival (PFS) per investigator, and safety were reported for prespecified subgroup analysis. Pre-infusion tumor biopsies were used to assess levels of immune cell infiltrates by multiplex immunohistochemistry and gene expression signatures (GES) by Nanostring IO-360 TM and RNAseq. Results Of 180 and 179 pts randomized to axi-cel and SOC, 133 and 131 had primary refractory and 47 and 48 had early relapsed LBCL , respectively. Baseline characteristics for each group were generally balanced between arms and similar to all pts randomized in each arm. EFS and PFS (Fig. 1; HR [95% CI]) were improved with axi-cel vs SOC in primary refractory (EFS, 0.437 [0.326-0.585]; PFS, 0.550 [0.401-0.753]) and in early relapsed LBCL (EFS, 0.401 [0.241-0.668]; PFS, 0.445 [0.251-0.786]). OS appeared prolonged with axi-cel vs SOC in primary refractory (HR [95% CI], 0.828 [0.592-1.156]) and in early relapsed LBCL (HR [95% CI], 0.619 [0.321-1.193]). Pts with early relapsed LBCL appeared to have longer OS and PFS vs pts with primary refractory LBCL within the axi-cel arm (OS, median not reached vs 29.4 mo, respectively; PFS, median not reached vs 7.2 mo) and the SOC arm (OS, 52.0 vs 19.8 mo, respectively; PFS, 6.0 vs 2.9 mo). Safety profile of axi-cel in each group was consistent with that observed in overall pt arms. Significantly higher infiltration of CD4 and CD8 T cells ( P <.05; Fig. 2) as well as lower GES representative of hypoxia , glycolytic activity, and myeloid and stromal cells (Fig. 3) were observed in pts with early relapsed vs primary refractory LBCL. Conclusions Axi-cel markedly prolonged EFS, PFS, and OS over SOC in ZUMA-7 overall, and the magnitude of improvement was numerically greater in the early relapsed group compared with the primary refractory group. Differences in tumor immune contexture and metabolic pathways may contribute to improved outcomes in pts with early relapsed vs primary refractory disease. These findings support early referral of pts with relapsed and refractory LBCL for axi-cel as a preferred 2L SOC.

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