This is only the second CAR T-cell therapy ever approved by the FDA. It is a development that moves cancer treatment in general another step forward into the future.
“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases. In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer,” Scott Gottlieb, MD, FDA Commissioner, said in a statement. “This approval demonstrates the continued momentum of this promising new area of medicine and we’re committed to supporting and helping expedite the development of these products."
The approval was based on complete remission (CR) rates in the phase II ZUMA-1 trial. In the single-arm ZUMA-1 study, which was presented at the 2017 AACR Annual Meeting, axi-cel demonstrated an objective response rate (ORR) of 82% and a CR rate of 54%. After 8.7 months of follow-up, 39% of patients remained in CR. The median duration of response in those with a CR was not reached at the time of the assessment (95% CI, 8.1-not estimable). The label for the medication lists the ORR as 72% and the CR rate as 51% (95% CI, 41%-62%).
Kite Pharma, which was recently acquired by Gilead, plans to market axi-cel at a list price of $373,000. The company plans to manufacture the treatment in El Segundo, California, which was the facility used for the ZUMA-1 trial, wherein cells were successfully manufactured 99% of the time and the median turnaround time was 17 days.
In the ZUMA-1 trial, patients were enrolled into 2 cohorts consisting of those with DLBCL (n = 77) and those with PMBCL or TFL (n = 24). Prior to infusion of axi-cel, a conditioning regimen of fludarabine and cyclophosphamide was administered. Axi-cel 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 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. The median overall survival (OS) was not yet reached at the time of the analysis. The 6-month OS rate was 80%.
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%). Cytokine release syndrome occurred in 13% of patients and neurologic events were experienced by 28% of patients. To treat these events, 43% of patients received tocilizumab and 27% received corticosteroids.
There were 4 fatal events in the study, 3 of which were deemed related to axi-cel. The first 2 reported were from hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of CRS. In early May 2017, 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.
The CAR T-cell therapy was approved with a boxed warning regarding CRS. To address the risk of CRS and neurologic toxicities, the FDA approved axi-cel with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). Additionally, certification and training will be required before hospitals will be cleared to administer the T cell therapy. The required training will focus on identifying and managing CRS and neurologic toxicity.
"It is important to note that the toxicities that we saw—CRS and neurological events—are generally reversible," lead investigator Frederick L. Locke, MD, medical oncologist at Moffitt Cancer Center, told Oncology Nursing News at the 2017 AACR Annual Meeting. "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."
Axi-cel is the second CAR T-cell therapy approved by the FDA, with the first approval arriving in late August for patients with acute lymphoblastic leukemia. The FDA anticipates that more agents in this class will gain approval in the future and is taking steps to establish a system for evaluation of these adaptive T-cell therapies. Axi-cel was approved following a priority review and under the FDA's breakthrough therapy program.
"We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine. That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies," said Gottlieb. "We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.”