Abstract CT004: Product attributes of axicabtagene ciloleucel (axi-cel) that associate differentially with efficacy and toxicity in second-line large B-cell lymphoma
Authors: Filosto Simone , Vardhanabhuti Saran , Canales Miguel , Poiré Xavier , Lekakis Lazaros J. , de Vos Sven , Portell Craig A. , Wang Zixing , To Christina , Cheng Paul , Chou Justin , Bot Adrian , Shen Rhine , Westin Jason R. 
Published: June 2022

Abstract
Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapy. ZUMA-7, a global Phase 3 randomized study, showed superiority of axi-cel over standard second-line therapy (N=359; event-free survival [EFS] HR 0.398, P&lt;.0001; median EFS 8.3 vs 2 months; estimated 2-year EFS 41% vs 16%; objective response rate [ORR] 83% vs 50%, Locke et al. N Engl J Med. 2021). Here we report axi-cel pharmacokinetics (PK), pharmacodynamics (PD), and product attributes associated with ZUMA-7 clinical outcomes.
Methods: Samples from patients who received axi-cel (n=170) were analyzed. PK, PD, and axi-cel T-cell composition (naive, CCR7+CD45RA+; differentiated, CCR7-) were assessed for associations with safety and efficacy using previously described methodologies (Neelapu et al. NEJM. 2017; Locke et al. Blood Adv. 2020).
Results: The median (Q1, Q3; n=162) peak CAR T-cell level, time to peak, and area under the curve within the first 28 days of treatment (AUC0-28) were 25.8 cells/μL (8.2, 57.9), 8 days (8, 9), and 236.2 cells/μL*days (76.4, 758.0), respectively. CAR T-cell peak and AUC0-28 correlated with higher ORR (P=.0224 and .0054, respectively) and increased Grade (Gr) ≥3 neurologic events (NEs; P=.0006) but not with durability of response (P=.4894). Rapid transient increases in serum analytes, including granzyme B, ferritin, IL-6, IL-10, CXCL-10, IL-15, ICAM-1, and GM-CSF, occurred early (median peak ≤7 days) and were associated with increased Gr ≥3 NEs and Gr ≥3 cytokine release syndrome (CRS; P&lt;.05). Infusion products richer in naive-like T cells expressing CD27 and CD28 associated with increased EFS, ORR, and complete response (P&lt;.05). In contrast, infusion products richer in differentiated T cells (CCR7-) and with lower % of CCR7+CD45RA+ T cells associated with higher postinfusion peak levels and AUC0-28 of several proinflammatory and immunomodulatory serum analytes (eg, IL-15, ferritin, IFN-γ). Increased rates of Gr ≥3 NEs were found in patients who received axi-cel richer in CCR7- T cells (above median: 30% vs below median: 10%). Similarly, a trend of higher rates of Gr ≥3 NEs and CRS were observed in patients who received axi-cel that secreted higher levels of IFN-γ in co-culture with CD19-expressing targets.
Conclusions: Preinfusion axi-cel features and postinfusion PK/PD profiles in the randomized phase 3 ZUMA-7 trial were associated with safety and efficacy outcomes and supported that optimizing product composition towards a juvenile T-cell phenotype (CCR7+CD45RA+) may improve axi-cel therapeutic index. These findings could result in future trials to evaluate if preemptive interventions, including enrichment of naive T cells in the product, could improve outcomes. [SF and SV contributed equally]
Citation Format: Simone Filosto, Saran Vardhanabhuti, Miguel Canales, Xavier Poiré, Lazaros J. Lekakis, Sven de Vos, Craig A. Portell, Zixing Wang, Christina To, Paul Cheng, Justin Chou, Adrian Bot, Rhine Shen, Jason R. Westin. Product attributes of axicabtagene ciloleucel (axi-cel) that associate differentially with efficacy and toxicity in second-line large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT004.