The US Food and Drug Administration (FDA) has approved the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta) for the treatment of de novo and transformed diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, and high grade B-cell lymphoma in adults who have failed or relapsed after two or more prior treatments.
This is the second CAR T-cell therapy approved by the FDA, following the approval of tisagenlecleucel (Kymriah) for pediatric acute lymphoblastic leukemia.
“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,” said FDA Commissioner Scott Gottlieb, MD, in a press release. “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. 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. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.”
ZUMA-1, the multicenter clinical trial that led to the approval of axicabtagene ciloleucel, included over 100 adult patients with refractory or relapsed large B-cell lymphoma. Patients were treated with a single infusion of axicabtagene ciloleucel. The overall response rate was 72%. More than half of the patients (51%, 95% CI, 41%–62%) achieved a complete remission. Median duration of response was non estimable at a median of 7.9 months follow-up.
“With CAR T therapy, we are re-engineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” said ZUMA-1 co-lead investigator Frederick L. Locke, MD, of the Moffitt Cancer Center in Tampa, Florida, in a press release. “Many of the patients that received CAR T therapy had already relapsed several times with traditional treatments such as chemotherapy or hematopoietic stem cell transplant. Now, thanks to this new therapy many patients are in remission for months.”
Thirteen percent of patients in ZUMA-1 experienced grade 3 or higher cytokine release syndrome (CRS) and 31% of patients experienced neurologic toxicities. The most common grade 3 or higher adverse events (AEs)—occurring in more than 10% of patients—included CRS, encephalopathy, febrile neutropenia, fever, hypotension, hypoxia, and infections. Serious AEs occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias (such as anemia, neutropenia, and thrombocytopenia), and serious infections. Fatal cases of CRS and neurologic toxicity occurred in the trial. Side effects from treatment with axicabtagene ciloleucel usually appear within the first 1–2 weeks, though some may occur later.
Axicabtagene ciloleucel is being approved with a risk evaluation and mitigation strategy (REMS) due to the risk of CRS and neurologic toxicities. Hospitals and associated clinics that dispense axicabtagene ciloleucel are required to be certified, with staff training involved to recognize and manage neurologic toxicities and CRS for those prescribing, dispensing, or administering the agent. Patients must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop.