Pharmacological Profile and Clinical Outcomes of KTE-X19 By Prior Bruton Tyrosine Kinase Inhibitor (BTKi) Exposure or Mantle Cell Lymphoma (MCL) Morphology in Patients With Relapsed/Refractory (R/R) MCL in the ZUMA-2 Trial

Background: Patient (pts) with MCL who progress after BTKi therapy have a median overall survival of only 5.8 mo with salvage therapies (Martin, et al. Blood 2016). KTE-X19 is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy being evaluated in the Phase 2, registrational, multicenter ZUMA-2 study of pts with R/R MCL after 1 – 5 prior therapies, including a BTKi. In the primary analysis of ZUMA-2 (N = 60), the objective response rate (ORR) with KTE-X19 treatment (median follow-up 12.3 mo) was 93% (67% complete response [CR] rate; Wang et al. N Engl J Med 2020). Here, we describe a comparative analysis of KTE-X19 pharmacology profile and outcomes by MCL morphology and prior BTKi exposure (ibrutinib [Ibr] and/or acalabrutinib [Acala]), accompanied by basic product attribute characterization.

Methods: Eligible pts with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of 2 × 10⁶ anti-CD19 CAR T cells/kg (Wang et al. N Engl J Med 2020). Product attributes, CAR T cell levels in blood, and cytokine levels in serum were assessed using methods previously described (Locke et al. Mol Ther 2017). Clinical outcomes are reported in the 60 efficacy-evaluable pts; product attributes and pharmacology data are reported for all 68 treated pts (data cutoff 7/24/2019). Additional pharmacodynamic and cytogenetic data were generated and will be presented.

Results: At baseline, 40 pts (59%) had classical MCL, 17 (25%) had blastoid MCL, and 4 (6%) had pleomorphic MCL as assessed by investigator. Before study entry, 52 pts (76%) had prior Ibr, 10 (15%) had prior Acala, and 6 (9%) had both; 88% had BTKi-refractory disease.

In manufactured KTE-X19 products, median (range) CD4/CD8 ratios for pts with classical, blastoid, or pleomorphic MCL were 0.7 (0.04 – 2.8), 0.6 (0.2 – 1.1), or 0.7 (0.5 – 2.0), respectively. Product T cell phenotypes (median [range]) included less differentiated CCR7+ T cells (classical 40.0% [2.6 – 88.8]; blastoid 35.3% [14.3 – 73.4]; pleomorphic 80.8% [57.3 – 88.8]) and effector + effector memory CCR7- T cells (classical 59.9% [11.1 – 97.4]; blastoid 64.8% [26.6 – 85.7]; pleomorphic 19.2% [11.1 – 42.7]). Median (range) interferon (IFN)-γ levels by coculture in pts with classical, blastoid, or pleomorphic MCL were 6309.5 pg/mL (424.0 – 20,000), 6510.0 pg/mL (2709.0 – 18,000), or 7687.5 pg/mL (424.0 – 12,000), respectively. In pts with classical, blastoid, or pleomorphic MCL, median (range) peak CAR T cell levels were 77.6 cells/µL (0.2 – 2241.6), 35.0 cells/µL (0.2 – 2589.5), or 144.9 cells/µL (39.2 – 431.3), respectively. ORR/CR rates were 93%/65% in pts with classical MCL, 88%/53% in those with blastoid MCL, and 100%/75% in those with pleomorphic MCL. The 12-mo survival rates in pts with classical, blastoid, or pleomorphic MCL were 86.7%, 67.9%, or 100%, respectively. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events occurred in 15% and 38% of pts with classical MCL, 6% and 8% of pts with blastoid MCL, and 25% and 50% of pts with pleomorphic MCL.

For pts who received prior Ibr, Acala, or both, median CD4/CD8 ratios in manufactured KTE-X19 products were 0.7 (range, 0.04 – 3.7), 0.6 (range, 0.3 – 1.2), or 1.0 (range, 0.7 – 1.9), respectively. Product T cell phenotypes (median [range]) included less differentiated CCR7+ T cells (Ibr 39.3% [2.6 – 86.4]; Acala 42.7% [16.3 – 88.8]; both 49.5% [14.3 – 83.0]) and CCR7- effector + effector memory T cells (Ibr 60.6 [13.7 – 97.4]; Acala 57.3% [11.1 – 83.8]; both 50.6% [17.0 – 85.7]). Median (range) levels of IFN-γ by coculture in pts with prior Ibr, Acala, or both was 6496.0 pg/mL (424.0 – 20,000), 5972.5 pg/mL (2502.0 – 18,000), or 7985.5 pg/mL (2709.0 – 12,000), respectively. For pts with prior Ibr, Acala, or both, median (range) peak CAR T cell levels were 95.9 (0.4 – 2589.5), 13.7 (0.2 – 182.4), or 115.9 (17.2 – 1753.6), respectively. ORR/CR rates were 94%/65% in pts with prior Ibr, 80%/40% in pts with prior Acala, and 100%/100% in pts with both BTKis. The 12-mo survival rates in pts with prior Ibr, Acala, or both were 81%, 80%, or 100%, respectively. Grade ≥ 3 CRS and neurologic events occurred in 17% and 31% of pts with prior Ibr, 10% and 10% of pts with Acala, and 0 and 67% of pts with both BTKis.

Conclusions: All subgroups defined by MCL morphology or prior BTKi drew clinical benefit from KTE-X19 treatment, with lower post-treatment CAR T cell levels in pts with blastoid morphology or previously treated with Acala alone.