Abstract
3023 Background: ZUMA-2 is a Phase 2 study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL (1 – 5 prior therapies, including a BTK inhibitor). In the primary efficacy analysis of ZUMA-2 (N = 60), the objective response rate was 93% (67% complete responses) and was generally comparable among high risk pts (Wang et al. ASH 2019 #754). CAR T cell levels in blood were associated with objective response (including minimal residual disease [MRD] negativity) and toxicity. Here, we describe a comparative analysis of KTE-X19 pharmacology profile in higher vs lower risk pts in ZUMA-2. Methods: Product attributes, CAR T cell and serum cytokine levels in blood, and their associations with clinical outcomes, were analyzed using previously described methods (Locke et al. Mol Ther 2017). MRD (10−5 sensitivity) was assessed by next-generation sequencing. Pharmacology data are reported for all 68 pts treated with KTE-X19 (2 × 106 cells/kg). Results: Manufactured KTE-X19 products showed a slight bias to CD8 and effector memory/effector phenotype. Median CD4/CD8 ratio was 0.7 (range, 0.04 – 3.7); T cell phenotypes included naive (median, 24.5%; range, 0.3 – 80.7), central memory (median, 12.8%; range, 2.3 – 51.6), effector memory (median, 24.5% (range, 0.8 – 70.3) and effector (median, 28.7%; range, 2.8 – 65.2). MRD negative (n = 24/29) vs positive pts (n = 5/29) at 1 mo post KTE-X19 had increased median cytokine levels, including IL-15, IL-2, IFN-γ, IL-10, and IL-6, peaking in serum within 7 days post treatment. Pts who were MRD negative by 1 mo post treatment also had increased median peak levels of Granzyme B and soluble PD-L1. Six pts developed Grade 4 neurologic events (NE), including 1 cerebral edema case; 3 had concurrent Grade 4 cytokine release syndrome. These pts had higher peak cytokine levels vs pts without Grade 4 NE, with lack of reversion to baseline by Day 28 of serum IL-6 and sVCAM-1. Peak CAR T cell in blood and serum cytokine levels were generally comparable in higher vs lower risk pts defined as TP53 mutated (n = 6/36) vs unmutated (n = 30/36), or high vs low Ki-67 proliferation index (PI; ≥ 30% [n = 40/49] and < 30% [n = 9/49]), consistent with the comparable clinical efficacy of KTE-X19 in these subgroups. Conclusions: PD profile of KTE-X19 associated with efficacy (MRD status at 1 mo) and treatment-related NE. In contrast to approved therapies, KTE-X19 showed comparable pharmacology and clinical outcomes in pts with higher vs lower risk MCL defined by TP53 mutation or Ki-67 PI. Clinical trial information: NCT02601313 .
Published Version
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