Axicabtagene ciloleucel (KTE-C19; axi-cel) was granted a priority review by the Food and Drug Administration (FDA) for the treatment of 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 2 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 percent and a complete response (CR) rate of 54 percent. After 8.7 months of follow-up, 39 percent 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 four months earlier than a standard review. The deadline for the approval, under the Prescription Drug User Fee Act, is Nov. 29, 2017, according to Kite.
"Patients with refractory aggressive NHL face a dire prognosis with only a 50 percent 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, M.D., Ph.D., 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 two cohorts consisting of those with diffuse large B-cell lymphoma (DLBCL; 77 patients) and those with primary mediastinal B-cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL; 24 patients). 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.
All patients had chemorefractory disease and had received a median of three prior lines of therapy, with 54 percent refractory to two consecutive lines of therapy. Overall, 79 percent 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 percent and a CR rate of 49 percent. After 8.7 months of follow-up, the ORR in the DLBCL group was 36 percent, which included a CR rate of 31 percent. In the PMBCL/TFL group, the ORR was 83 percent and the CR rate was 71 percent. The 8.7-month ORR rate was 67 percent, with a CR rate of 63 percent.
Across all patients (101 patients), 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 six-month OS rate was 80 percent.
"Many of these responses are durable. In fact, at the time of the data cutoff, 44 percent of patients remain in remission," lead investigator Frederick L. Locke, M.D., medical oncologist at Moffitt Cancer Center, told CURE at 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 percent confidence interval of 8.2 months."
The most common grade 3 or higher adverse events (AEs) were anemia (43 percent), neutropenia (39 percent), decreased neutrophil count (32 percent), febrile neutropenia (31 percent), decreased white blood cell count (29 percent), thrombocytopenia (24 percent), encephalopathy (21 percent) and decreased lymphocyte count (20 percent).
At the primary analysis of 101 patients, the rate of cytokine release syndrome (CRS) dropped to 13 percent versus 18 percent at the interim assessment, which included 93 patients. Additionally, neurologic events dropped from 34 percent in the interim analysis to 28 percent in the primary assessment. Overall, 43 percent of patients received tocilizumab and 27 percent 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 saw—CRS and neurological events—are generally reversible," said Locke. "These are going away within one 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.