Axicabtagene Ciloleucel NHL Data Presented as FDA Weighs Approval

Virginia Powers, PhD
Published: Wednesday, Jun 14, 2017

Sattva S. Neelapu, MD

Sattva S. Neelapu, MD

Patients with refractory aggressive non-Hodgkin lymphoma (NHL) lacking curative treatment options demonstrated high response rates and durable responses plus a manageable safety profile following treatment with axicabtagene ciloleucel (axi-cel; KTE-C19) in a primary analysis of the phase II ZUMA-1 trial.

ZUMA-1, the first multicenter trial of the anti-CD19 chimeric antigen receptor (CAR) T cell axi-cel, met the primary endpoint of best ORR. The best ORR in the modified intent-to-treat (mITT) population of 101 patients with NHL was 82% (P <.0001); of responding patients, 54% achieved complete response (CR) and 28% of patients achieved partial response (PR).

Response was durable at 8.7 months of follow-up with 44% of responding patients maintaining response and 39% of patients remaining in CR.

These findings from the primary analysis of ZUMA-1 were presented at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland.

A cohort of 77 patients with diffuse, large, B-cell lymphoma (DLBCL) demonstrated an ORR of 82% with 49% of these patients achieving CR. A second cohort of 20 patients with refractory primary mediastinal B-cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL) demonstrated an ORR of 83%, with 71% of the responders achieving CR.

“These responses were consistent across key covariates, including age, disease stage, IPI risk score, the presence of extranodal, or bulky disease, and in a subgroup of patients with refractory disease,” pointed out Sattva S. Neelapu, MD, associate professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine, at the University of Texas MD Anderson Cancer Center. Neelapu explained that axi-cel is CD19-directed CAR T-cell therapy with CD3zeta/CD28–based signaling domains.

“There is a significant unmet need in non-Hodgkin lymphoma, which is the most common hematologic malignancy in the US,” he said.

In the phase II ZUMA-1 trial, adult patients were enrolled in 2 cohorts consisting of 72 patients with DLBCL and 20 patients with PMBCL or TFL. Axi-cel was successfully manufactured in 110 (99%) patients, with an average turnaround time from apheresis to the clinical site of 17 days.

Following low-dose conditioning with cyclophosphamide/fludarabine, a target dose of 2 × 106 anti-CD19 CAR T cells was administered to 101 (91%) patients; the patients had a median age of 58 years (range, 23-76), 67% were male, 85% had stage III-IV disease, 47% had IPI 3-4, and 59% of patients were ECOG PS 0-1. Most (69%) patients had received 3 or more prior lines of treatment, 54% had been refractory to 2 consecutive lines of therapy, and 21% of patients had relapsed within 12 or fewer months of receiving an autologous stem cell transplant (ASCT). No bridging therapy was allowed in ZUMA-1.

The primary endpoint for this analysis was ORR in the combined DLBCL, PMBCL, and TFL population. Key secondary endpoints were duration of response (DOR), overall survival (OS), levels of CAR T and cytokines, and safety. The primary analysis was done when the first 92 patients treated had at least 6 months of follow-up.

Response rates were also consistent between DLBCL molecular subgroups based on the cell of origin, as determined by the Nanostring Lymphoma Subtyping Test. Of 69 patients with evaluable samples, 25% of patients had activating B-cell (ABC) subtype, 17% were germinal center B-cell (GCB) subtype, and 4% remained unclassified. The ORR was 75% in ABC patients and 88% in patients GCB subtype; of responding patients, 59% and 57% of ABC and GCB patients achieved CR, respectively. This CR is ongoing in 35% of ABC patients and 47% of GCB patients.

These responses were durable; at 8.7 months of follow-up, 44% of patients in the overall mITT population demonstrated an ongoing response and 39% of patients maintained CR. The median duration of response (DOR) was 8.2 months (95% CI, 3.3 months–not reached [NR]) in the overall population. The median DOR was not reached for patients achieving CR (95% CI, 8.2 months–NR), and the median DOR for PR was 1.9 months (95% CI, 1.5–2.1).

Median progression-free survival was 5.9 months (95% CI, 3.4–9.8), and median OS was not reached at a median follow-up of 8.7 months (95% CI, 10.5– NR). The 6-month OS rate was 80% in ZUMA-1.

The levels of CAR T-cells peaked within 7 to 14 days of axi-cel treatment. The expansion of CAR T-cells was associated with the ORR, area under the curve (AUC) fold = 5.4, and with the presence of grade ≥3 neurologic events, AUC fold = 2.6 but not with cytokine release syndrome (CRS), AUC fold = 1.3.

In the primary safety analysis of 101 patients, the most frequently occurring grade ≥3 adverse events (AEs) were anemia in 43% of patients, neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (32%), decrease white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%).

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