ON OCTOBER 18, the U.S. Food and Drug Administration (FDA) approved axicabtagene ciloleucel (Yescarta), a cell-based gene therapy, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Axicabtagene ciloleucel, a chimeric antigen receptor (CAR) T-cell therapy, is the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma. (On August 30, 2017, the FDA approved the CAR T-cell immunotherapy, tisagenlecleucel [Kymriah], for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.)
A Scientific Paradigm
“[OCTOBER 18 ] 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. “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 FDA] 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.”
Axicabtagene Ciloleucel Indications
AXICABTAGENE CILOLEUCEL is approved for use in adult patients with large B-cell lymphoma after at least two other kinds of treatment have failed, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.
Each dose of axicabtagene ciloleucel is a customized treatment created using a patient’s own immune system to help fight the lymphoma. The patient’s T cells are collected and genetically modified to include a new gene that targets and kills the lymphoma cells. Once the cells are modified, they are infused back into the patient.
“The approval of axicabtagene ciloleucel brings this innovative class of CAR T-cell therapies to an additional group of cancer patients with few other options—those adults with certain types of lymphoma that have not responded to previous treatments,” said Peter Marks, MD, PhD, Director of the FDA’s Center for Biologics Evaluation and Research (CBER).
Safety and Efficacy
THE SAFETY AND EFFICACY of axicabtagene ciloleucel were established in a multicenter clinical trial of more than 100 adults with refractory or relapsed large B-cell lymphoma (ClinicalTrials.gov Identifier NCT03105336). The complete remission rate after treatment with axicabtagene ciloleucel was 51%.
Treatment with axicabtagene ciloleucel has the potential to cause severe side effects. It carries a boxed warning for cytokine-release syndrome, which is a systemic response to the activation and proliferation of CAR T cells causing high fever and flu-like symptoms, and for neurologic toxicities. Both cytokine-release syndrome and neurologic toxicities can be fatal or life-threatening. Other side effects include serious infections, low blood cell counts, and a weakened axicabtagene ciloleucel usually appear within the first 1 to 2 weeks, but some side effects may occur later.
Because of the risk of cytokine-release syndrome and neurologic toxicities, axicabtagene ciloleucel is being approved with a risk evaluation and mitigation strategy, which includes elements to assure safe use. The FDA is requiring that hospitals and their associated clinics that dispense axicabtagene ciloleucel be specially certified. As part of that certification, staff involved in the prescribing, dispensing, or administering of axicabtagene ciloleucel are required to be trained to recognize and manage cytokine-release syndrome and nervous system toxicities. Also, 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.
To further evaluate the drug’s long-term safety, the FDA is also requiring the manufacturer to conduct a postmarketing observational study involving patients treated with axicabtagene ciloleucel.
Efficacy, Affordability, and Safety
DAVID MALONEY, MD, PhD, Medical Director of Cellular Immunotherapy at Fred Hutchinson Cancer Research Center and Medical Director of the Bezos Family Immunotherapy Clinic at Seattle Cancer Care Alliance, commented, “While the [FDA’s] first approval of a CAR T-cell therapy impacted a relatively small number of pediatric and young adult patients, [this] decision opens the door for a cellular immunotherapy to treat adults with aggressive lymphoma. Thousands of lives will likely be saved in the next few years because of it.”
He continued, “The current CAR T-cell therapies need to become more effective, more affordable, and safer. We need to understand why they do not work for certain people, why they only work in select types of cancer, and why they can cause severe, occasionally fatal, side effects.
The FDA granted axicabtagene ciloleucel Priority Review, Breakthrough Therapy, and Orphan Drug designations. The application was reviewed using a coordinated, cross-agency approach. The clinical review was conducted by the FDA’s Oncology Center of Excellence, while CBER conducted other aspects of review and made the product approval determination. ■