Axicabtagene ciloleucel (KTE-C19; axi-cel) has been granted a priority review by the FDA for transplant-ineligible patients with relapsed or refractory non-Hodgkin lymphoma.
David Chang, MD, PhD
Axicabtagene ciloleucel (KTE-C19; axi-cel) has been granted a priority review by the FDA for transplant-ineligible patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to Kite Pharma, the developer of the CD19-directed chimeric antigen receptor (CAR) T-cell therapy.
The priority review was based on data from the phase II ZUMA-1 study, which was presented at the 2017 AACR Annual Meeting. In the study, axicabtagene ciloleucel demonstrated an objective response rate (ORR) of 82% and a complete response (CR) rate of 54%. After 8.7 months of follow-up, 39% of patients continued to have a CR.
Under the priority review program, the FDA will decide on the biologics license application (BLA) for axicabtagene ciloleucel 4 months earlier than a standard review. The deadline for the approval, under the Prescription Drug User Fee Act, is November 29, 2017, according to Kite.
"Patients with refractory aggressive NHL face a dire prognosis with only a 50% chance of surviving six months. This underscores the urgent medical need for these patients and why every day matters, from development to manufacturing to clinical experience," David Chang, MD, PhD, executive Vice president of Research and Development and Chief Medical Officer of Kite. "We firmly believe in the potential for axicabtagene ciloleucel to address this need and forge a new path for the future of cell therapy."
In the ZUMA-1 trial, patients were enrolled into 2 cohorts consisting of those with diffuse large B-cell lymphoma (DLBCL; n = 77) and those with primary mediastinal B-cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL; n = 24). 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 106CAR-positive T cells/kg.
All patients had chemorefractory disease and had received a median of 3 prior lines of therapy, with 54% refractory to 2 consecutive lines of therapy. Overall, 79% of patients were refractory to their last line of chemotherapy without having received prior autologous stem cell transplant (ASCT) while the remainder had relapsed within 12 months of ASCT.
Those with DLBCL had an ORR of 82% and a CR rate of 49%. After 8.7 months of follow-up, the ORR in the DLBCL group was 36%, which included a CR rate of 31%. In the PMBCL/TFL group, the ORR was 83% and the CR rate was 71%. The 8.7-month ORR rate was 67%, with a CR rate of 63%.
Across all patients (N = 101), the median duration of response was 8.2 months. For those with a CR, the median duration of response was not yet reached. The median overall survival (OS) was not yet reached at the time of the analysis. The 6-month OS rate was 80%.
"Many of these responses are durable. In fact, at the time of the data cutoff, 44% of patients remain in remission," lead investigator Frederick L. Locke, MD, medical oncologist at Moffitt Cancer Center, toldTargeted Oncologyat the 2017 AACR Annual Meeting. "In patients who did obtain a CR, the median duration of response has not yet been reached. We have a lower bound at a 95% confidence interval of 8.2 months."
At the primary analysis of 101 patients, the rate of cytokine release syndrome (CRS) dropped to 13% versus 18% at the interim assessment, which included 93 patients. Additionally, neurologic events dropped from 34% in the interim analysis to 28% in the primary assessment. Overall, 43% of patients received tocilizumab and 27% received corticosteroids to resolve CRS.
There were 4 fatal events in the study, 3 of which were deemed related to axicabtagene ciloleucel. The first two reported were from hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of CRS. In early May, the company noted that a patient had died from cerebral edema in the setting of grade 3 CRS with multiorgan failure. The unrelated death was from pulmonary embolism.
"It is important to note that the toxicities that we sawCRS and neurological events—are generally reversible," said Locke. "These are going away within 1 month of the therapy, so we think that this is a therapy that can be safely administered across multiple centers for patients who are really without other treatment options."
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.
Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.
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%).