FDA Submission Completed for Axicabtagene Ciloleucel in NHL

Arie Belldegrun, MD, FACS

A biologics license application (BLA) has been submitted for axicabtagene ciloleucel (KTE-C19) as a potential treatment for transplant ineligible patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL), according to Kite Pharma, the developer of the CAR T-cell therapy.

UPDATE 5/26/2017: FDA Grants Priority Review to KTE-C19 for Non-Hodgkin Lymphoma

The BLA was based on findings from the phase II ZUMA-1 study, in which axicabtagene ciloleucel demonstrated an objective response rate (ORR) of 82% and a complete response (CR) rate of 54% for patients with NHL. Responses were seen across subgroups in the study, including those with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL).

The application was completed following a rolling submission of data, which was permitted as part of a breakthrough therapy designation received in December 2015. Given the unmet need, it is likely that the BLA will receive a priority review, under which the FDA would decide 4 months earlier than a standard review. The FDA will assign a regulatory timeline within 60 days. Kite anticipates a launch in 2017.

"We look forward to working closely with the FDA during the review of axicabtagene ciloleucel and the possibility of bringing this therapy to patients with aggressive NHL whose outlook is dismal with current therapy," Arie Belldegrun, MD, chairman, president, and chief executive officer of Kite, noted in a statement.

Interim results from ZUMA-1 were presented at the 2016 ASH Annual Meeting, with an update presented at the 2017 BMT Tandems Meeting in February. The primary analysis of the trial will be presented at the upcoming 2017 AACR Annual Meeting.

In the trial, patients were enrolled into 2 cohorts consisting of those with DLBCL (cohort 1) and those with PMBCL/TFL (cohort 2). All patients had chemorefractory disease, with roughly 80% refractory to their last line of chemotherapy, and the remainder relapsing within 12 months of autologous transplant. Patients had received a median of 3 prior therapies.

Prior to infusion of axicabtagene ciloleucel, a conditioning regimen of fludarabine and cyclophosphamide was administered. Axicabtagene ciloleucel was administered as a single infusion of modified autologous T cells at a target dose of 2 x 10⁶ CAR-positive T cells/kg.

The median follow-up for the primary analysis was 8.7 months, with most patients having data available for 6 months. There were 4 patients who experienced a CR but did not have assessment data available for 6 months. For the primary analysis, these individuals were classified as non-responders, suggesting the response rates could be higher.

The primary endpoint of the phase II study was ORR, which was significantly satisfied across the full study (P <.0001). After 6 months, 41% of patients continued to respond, with a CR rate of 36% and a partial response (PR) rate of 5%. There was one incidence of a PR transitioning to a CR after 9 months, suggesting longer follow-up could alter these numbers.

Across the full duration of the study, those with DLBCL (n = 77) had an ORR of 82% and a CR rate of 49%. In the PMBCL/TFL group (n = 24), the ORR was 83% and the CR rate was 71%. After 6 months of follow-up, the ORR in the DLBCL group was 36%, which included a CR rate of 31%. In the TFL/PMBCL group, the 6-month ORR rate was 54%, with a CR rate of 50%. Median overall survival was not yet reached.

The most common grade ≥3 adverse events (AEs) were anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%). There were 3 fatal events in the study, 2 of which were deemed related to axicabtagene ciloleucel: hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome (CRS). The third death was from pulmonary embolism.

Data from 93 patients were available for the interim analysis from the ZUMA-1 trial, whereas the primary assessment contained data for 101 patients. With more patients assessed, the rate of CRS declined from 18% at the interim assessment to 13% for the primary analysis. Additionally, neurologic events dropped from 34% in the interim analysis to 28% in the primary assessment. There continued to be no cases of cerebral edema.

Kite also announced plans to also file for potential approval for axicabtagene ciloleucel as a treatment for patients with relapsed/refractory DLBCL in Europe. This application is anticipated later this year.