Axicabtagene Ciloleucel NHL Data Presented as FDA Weighs Approval

Sattva S. Neelapu, MD, associate professor, The University of Texas MD Anderson Cancer Center

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%).

The rate of CRS in the primary analysis showed a decrease to 13% from the rate demonstrated in the preliminary analysis; 43% of patients with CRS received tocilizumab and 27% received corticosteroids to resolve CRS. The rate of neurologic events was 28% in the primary assessment. Greater CAR T-cell levels were observed in patients requiring tocilizumab or steroids for AE management but no impact on response was noted.

“This is consistent with reports showing CAR T-cell expansion associated with grade ≥3 neurologic events,” he commented.

“Both CRS and neurologic events were generally reversible and all CRS events resolved excepting one case each of hemophagocytic lymphohistiocytosis and cardiac arrest, which were fatal,” commented Neelapu. One death that was unrelated to treatment was due to pulmonary embolism.

The FDA granted a priority review to axi-cel for transplant-ineligible patients with relapsed or refractory NHL, based on data from this study. An application for approval of axi-cel as a treatment for patients with relapsed/refractory DLBCL in Europe has also been submitted.

The ZUMA-1 trial was funded by Kite Pharma and by a grant from the Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program®.

Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel (AXI-CEL; KTE-C19) in patients with refractory aggressive non-Hodgkin Lymphomas (NHL): primary results of the pivotal trial ZUMA-1. Presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. doi: 10.1002/hon.2437_7.