FDA Requests Black Box Warning for Approved CAR-T Therapies Over Secondary Cancer Concern

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As per US law Section 505(o)(4), the manufacturers are required to make the requested changes, respond with a modified version of the requested changes for review, or respond with a rebuttal within 30 days of the FDA's ask.

UPDATE: January 24, 2024, 10:07 AM  The FDA's letter to Kite Pharma regarding brexucabtagene autoleucel (marketed as Tecartus) has been updated on the FDA's website with revised language. In the letter, the FDA notes that the revision—dated January 23, 2024—supersedes the original language. References to T-cell malignancies having occurred following treatment with Tecartus specifically have been removed with the warnings now simply referring to BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies in general. Notably, the boxed warning now reads: "T-cell malignancies have occurred following treatment with BCMA- and CD19- directed genetically modified autologous T-cell immunotherapies."

January 23, 2024  The FDA has requested that black box warnings related to secondary cancer risks be added to all 6 of the chimeric antigen receptor T-cell (CAR-T) therapy products currently approved by the agency for use in the United States.1-6 The FDA issued separate letters to each of the relevant companies for the therapies on January 19, 2024. These CAR-T products target either the antigen CD19 or B-cell maturation antigen (BCMA).

These products include Bristol Myers Squibb (BMS) and 2seventybio’s idecabtagene vicleucel (ide-cel; marketed as Abecma); BMS’s lisocabtagene maraleucel (liso-cel; marketed as Breyanzi); Janssen and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; marketed as Carvykti); Novartis’s tisagenlecleucel (tisa-cel; marketed as Kymriah); Kite Pharma’s brexucabtagene autoleucel (brexu-cel; marketed as Tecartus); and Kite Pharma’s axicabtagene ciloleucel (axi-cel; marketed as Yescarta).

The language of the requested warnings takes the following form and is to be included as a Boxed Warning, noting that “T-cell malignancies may occur following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies,” with each product’s name listed in the letter. The agency also requests additional references to T-cell malignancies be added to the 'WARNINGS AND PRECAUTIONS' sections of for each of the 6 CAR-T products' labels: “T cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including [product name]. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes.”

As per US law Section 505(o)(4), the companies are required to make the requested changes, respond with a modified version of the requested changes for review, or respond with a rebuttal within 30 days of the letters’ issuance. The changes are deemed to constitute new safety information by the agency.

“Since [the product was approved], we have 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,” Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, the signed author of the letters, wrote in each.1-6 “FDA identified postmarketing adverse event and clinical trial reports describing [the] occurrence of mature T-cell malignancies, including CAR-positive tumors, following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies... Furthermore, we consider the serious risk of T-cell malignancy to be applicable to all BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies.”

Several months ago, in November 2023, the FDA announced that it was investigating the risk of T-cell malignancies in patients who have received BCMA-directed or CD19-directed autologous CAR T-cell immunotherapies.7 At the time, according to the FDA Adverse Event Reporting System (FAERS) database, there had been 12 instances of T-cell lymphoma in patients treated with approved CAR T-cell therapies. These cases have been seen in patients treated with Kymriah (n = 7), Yescarta (n = 3), Carvykti (n = 1), and Breyanzi (n = 1). Despite this, at the time of this announcement, the FDA stated that the overall benefits of the marketed CAR-T products continue to outweigh their potential risks for their approved uses.

This article originally appeared in CGTlive.

References
1. Safety Labeling Change Notification Letter - ABECMA (idecabtagene vicleucel). News release. FDA. January 19, 2024. Accessed January 23, 2024. https://www.fda.gov/media/175623/download?attachment
2. Safety Labeling Change Notification Letter - BREYANZI (lisocabtagenemaraleucel). News release. FDA. January 19, 2024. Accessed January 23, 2024. https://www.fda.gov/media/175622/download?attachment
3. Safety Labeling Change Notification Letter - CARVYKTI (ciltacabtagene autoleucel). News release. FDA. January 19, 2024. Accessed January 23, 2024. https://www.fda.gov/media/175624/download?attachment
4. Safety Labeling Change Notification Letter - KYMRIAH (tisagenlecleucel). News release. FDA. January 19, 2024. Accessed January 23, 2024. https://www.fda.gov/media/175625/download?attachment
5. Safety Labeling Change Notification Letter - TECARTUS (brexucabtagene autoleucel). News release. FDA. January 19, 2024. Accessed January 23, 2024. https://www.fda.gov/media/175626/download?attachment
6. Safety Labeling Change Notification Letter - YESCARTA (axicabtagene ciloleucel). News release. FDA. January 19, 2024. Accessed January 23, 2024. https://www.fda.gov/media/175627/download?attachment
7. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. November 28, 2023. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous?utm_medium=email&utm_source=govdelivery
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