Perspective from Joshua Brody, MD
October 19, 2017
4 min read

FDA approves Yescarta, second-ever CAR T-cell therapy, for certain B-cell lymphomas

Perspective from Joshua Brody, MD
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The FDA approved axicabtagene ciloleucel as the first chimeric antigen receptor T-cell therapy to treat adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

Axicabtagene ciloleucel (Yescarta; Kite, Gilead) is the second chimeric antigen receptor (CAR) T-cell therapy approved by the FDA — following the approval of tisagenlecleucel T-suspension (Kymriah, Novartis) for the treatment of children and young adults with B-cell acute lymphoblastic leukemia — and the first therapy of this type approved for some non-Hodgkin lymphomas.

“Today is an important day for patients with relapsed or refractory large B-cell lymphoma who have run out of options and have been waiting for new treatments that may help them in their fight against cancer,” John Milligan, PhD, president and CEO of Gilead Sciences, said in a press release. “With the combined innovation, talent and drive of the Kite and Gilead teams, we will rapidly advance cell therapy research and aim to bring new options to patients with many other types of cancer.”

The indication for axicabtagene ciloleucel — a CD19-directed genetically modified autologous T-cell immunotherapy — includes patients with diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

However, the agent is not indicated for the treatment of patients with primary central nervous system lymphoma.

“The FDA approval of Yescarta is a landmark for patients with relapsed or refractory large B-cell lymphoma. This approval would not have been possible without the courageous commitment of patients and clinicians, as well as the ongoing dedication of Kite’s employees,” Arie Belldegrun, MD, FACS, founder of Kite, said in a press release. “We must also recognize the FDA for their ability to embrace and support transformational new technologies that treat life-threatening illnesses. We believe this is only the beginning for CAR T therapies.”

The FDA based its decision in part on data from the ZUMA-1 pivotal trial, designed to evaluate axicabtagene ciloleucel in 101 adults with relapsed or refractory large B-cell lymphoma.

Overall, 72% of patients treated with a single infusion responded to therapy, including 51% (95% CI, 41-62) of patients who achieved complete response.

At a median follow-up of 7.9 months, patients who experienced complete remission had not reached an estimated median duration of response (95% CI: 8.1-not estimable).

“With CAR T therapy, we are reengineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” co-lead investigator Frederick L. Locke, MD, vice chair of the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center, said in the 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 experienced grade 3 or higher cytokine release syndrome and 31% had neurologic toxicities.

The most common grade 3 or worse toxicities included febrile neutropenia, fever, cytokine release syndrome, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections.

Serious adverse reactions — which occurred in 52% of patients — included cytokine release syndrome, neurologic toxicity, prolonged cytopenias and serious infections.

Because fatal cases of cytokine release syndrome and neurologic toxicity occurred, the FDA approved axicabtagene ciloleucel with a risk evaluation and mitigation strategy. Hospitals and clinics that dispense the therapy must receive special certification that involves training staff to recognize and manage cytokine release syndrome or nervous system toxicities. Patients also must be informed about serious adverse events and the need to return to treatment site at the development of serious symptoms.

“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, MD, said 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.”

Gottlieb noted the FDA plans to release a comprehensive policy with plans to support the development of cell-based regenerative medicine, which is how the agency will apply its 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,” he added. – by Kristie L. Kahl