Yescarta was granted FDA approval for use in adults with relapsed or refractory non-Hodgkin lymphoma. This is only the second CAR T-cell therapy ever approved.
The FDA has approved a novel immunotherapy for the treatment of adult non-Hodgkin lymphoma that has relapsed or become resistant to other therapies. Yescarta (axicabtagene ciloleucel) is the second chimeric antigen receptor (CAR) T-cell therapy approved by the FDA to treat cancer. The first was approved Aug. 30 to treat acute lymphocytic leukemia in people under 25.
Yescarta targets the protein CD19, a driver of non-Hodgkin lymphoma. It was approved based on complete remission (CR) rates in the phase 2 ZUMA-1 trial.
The approval was specifically for use after two prior therapies by those with large B-cell lymphoma, a category that includes non-Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL). Additionally, the CAR T-cell therapy is indicated for primary mediastinal large B-cell lymphoma (PMBCL), high grade B-cell lymphoma and DLBCL transformed from follicular lymphoma (TFL).
“This therapy is a new option for patients with relapsed or refractory large B-cell lymphoma who have run out of treatment options and face a dire prognosis,” said Louis J. DeGennaro, Ph.D., president and chief executive officer of The Leukemia & Lymphoma Society (LLS). “Early on, LLS recognized the potential of CAR T therapy, and we are proud to be part of making this historic approval possible.”
In the single-arm ZUMA-1 study, Yescarta demonstrated an objective response rate (ORR) of 82 percent and a CR rate of 54 percent. After 8.7 months of follow-up, 39 percent of the patients who initially experienced a CR maintained that status. The CAR T-cell therapy was approved with a boxed warning regarding cytokine release syndrome (CRS), a potential serious or severe side effect caused by the immune system attacking healthy organs, which occurred in 13 percent of patients in the trial.
“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,” FDA Commissioner Scott Gottlieb, M.D., 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."
In the ZUMA-1 trial, patients were enrolled into two cohorts consisting of those with DLBCL (n = 77) and those with PMBCL or TFL (n = 24). Prior to infusion of Yescarta, a conditioning regimen of the chemotherapies fludarabine and cyclophosphamide was administered. Yescarta was administered as a single infusion of modified versions of the patients’ own T cells at a specified target dose.
All patients had disease that was resistant to chemotherapy and had received a median of three prior lines of therapy, with 54 percent resistant to two consecutive lines of therapy. Overall, 79 percent of patients had not received prior transplant of their own stem cells and had disease that was resistant to their most recently received line of chemotherapy. The remainder had disease that had relapsed within 12 months of receiving such stem cell therapy.
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 (N = 101), the median duration of response was 8.2 months. For those with a CR, the median duration of response had not yet been reached. The median overall survival (OS) had not yet been reached at the time of the analysis. The six-month OS rate was 80 percent.
The most common grade serious or severe side effects 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). In addition to CRS, neurologic events were experienced by 28 percent of patients. To treat these events, 43 percent of patients received Actemra (tocilizumab), a monoclonal antibody approved for the treatment of rheumatoid arthritis that has been found to help with these types of side effects, and 27 percent received corticosteroids.
There were four fatal events in the study, three of which were deemed related to Yescarta. The first two reported were due to an immunodeficiency known as hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of CRS. In early May 2017, the company noted that a patient had died from brain swelling in the setting of serious CRS with multiorgan failure. The unrelated death was from pulmonary embolism.
To address the risk of CRS and neurologic toxicities, the FDA approved Yescarta with a risk evaluation and mitigation strategy, which includes elements to assure safe use. 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.
"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.”
The United States list price of Yescarta is $373,000.