FDA NewsPerspective

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

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

 

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.”

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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

 

    Perspective
    Joshua Brody

    Joshua Brody

    Aggressive lymphomas are diagnosed in tens of thousands of Americans each year and with recent advances, the majority of these patients can be cured with standard chemoimmunotherapy or stem cell transplantation. Unfortunately, these therapies fail for approximately one out of three of those diagnosed, and the remaining treatment options are generally unable to cure the disease. The early results we have seen with CAR T cells in the past 5 years are easily the most potent therapy ever tested for these patients with 30% to 40% achieving and maintaining complete remission for months, possibly years. Some of the earliest patients treated more than 5 years ago are still in remission and appear to be cured. The success is a testament to the many scientists, physicians and others who developed this almost-science-fictional therapy.

    The process removes immune, or T, cells from a patient, inserts a synthetic CAR gene — actually a chimera of five genes “cut and pasted” together — into the T cells to create CAR T cells that are reinfused into the patients 2 to 3 weeks later. Back in the patient, the CAR allows the T cells to specifically target and then eliminate the cancer cells, just as T cells would normally target and eliminate virus-infected cells.

    The activation of these anticancer T cells can sometimes hyperactivate them, making them release chemicals, or cytokines, which cause a sepsis-like condition that can be extremely dangerous; these effects generally occur only in the first 2 weeks after the infusion. Thereafter, the CAR T cells can live inside the patient for months or years, continuing to fight any residual cancer cells, hence their description as a “living medicine.”

    Unquestionably, the results are transformational for how we treat these patients and, at best, will transform an incurable disease setting into a potentially curable one. The remaining question is how we will be able to expand this approach to treat patients with other types of lymphoma, leukemia, myeloma, and eventually common cancers like breast, prostate and lung cancers.

    • Joshua Brody, MD
    • Director of the Lymphoma Immunotherapy Program, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai

    Disclosures: Brody reports no relevant financial disclosures.