FDA Calls for New Boxed Warning on All CAR-T Products

The FDA has called for new boxed warnings on the labeling of all approved chimeric antigen receptor (CAR) T-cell therapies over a potential risk for secondary T-cell malignancies.

Six B-cell maturation antigen (BCMA)- or CD-19-directed CAR T-cell agents are approved for hematologic cancers. If the agency gets its way, the boxed warning would indicate that “T-cell malignancies have occurred following treatment with BCMA- and CD-19-directed genetically modified autologous T-cell immunotherapies,” including with:

• Idecabtagene vicleucel (Abecma): a BCMA-directed therapy indicated for multiple myeloma
• Lisocabtagene maraleucel (Breyanzi): a CD19-directed product for large B-cell lymphoma (LBCL, including diffuse large B-cell lymphoma [DLBCL], high-grade B-cell lymphoma, and primary mediastinal LBCL), and follicular lymphoma
• Ciltacabtagene autoleucel (Carvykti): a BCMA-directed agent for multiple myeloma
• Tisagenlecleucel (Kymriah): a CD-19-directed therapy for B-cell precursor acute lymphoblastic leukemia (ALL), LBCL (including DLBCL and high grade B-cell lymphoma), and follicular lymphoma
• Brexucabtagene autoleucel (Tecartus): a CD19-directed product for mantle cell lymphoma and B-cell precursor ALL
• Axicabtagene ciloleucel (Yescarta): a CD19-directed agent for LBCL (including DLBCL, primary mediastinal LBCL, and high grade B-cell lymphoma) and follicular lymphoma

In the full prescribing information, a new warning would note that “mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes.”

Since the initial approvals of these agents, the first in 2017, the FDA has “become aware of the risk of T-cell malignancies, with serious outcomes, including hospitalization and death, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies,” the agency said in its letters to drugmakers Kite Pharma, Novartis, Janssen, Juno, and Bristol Myers Squibb.

The new action follows an announcement by the FDA last November stating that it was investigating what it called a “serious risk” of T-cell malignancies in patients treated with CAR T-cell therapies.

At the time, the FDA said it had received 19 reports of T-cell malignancies, including CAR-positive lymphomas, from clinical trials and postmarketing adverse event data sources.

“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, the FDA continues to investigate the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death,” the FDA said in a press release on Tuesday.

Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” the agency continued. “In the event that a new malignancy occurs following treatment with these products, clinicians are encouraged to contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing for the presence of the chimeric antigen receptor transgene.”

The companies now have 30 days to submit proposed changes to their products’ safety labels, or submit a statement saying they don’t believe changes are warranted, and why.

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