FDA Calls for Boxed Warnings on CAR-T Therapies Regarding Secondary Cancer Risks

The FDA’s safety probe of CAR-T therapies has resulted in a call to add a class-wide boxed warning to these medicines, alerting patients and prescribers of their potential risk of secondary T-cell malignancies.

All six commercial CAR-T therapies will be affected, including J&J’s Legend Biotech-partnered Carvykti (ciltacabtagene autoleucel), Novartis’ Kymriah (tisagenlecleucel), BMS’s Abecma (idecabtagene vicleucel) and Breyanzi (lisocabtagene maraleucel) and Gilead’s Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel).

The FDA on Friday sent out six letters to their respective manufacturers notifying them that the drug class has been associated with the risk of developing secondary cancers “with serious outcomes, including hospitalization and death.”

“FDA identified postmarketing adverse event and clinical trial reports describing occurrence of mature T cell malignancies, including CAR-positive tumors, following treatment with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies,” the regulator said in the letters, while stopping short of establishing a causal connection between treatment and the secondary cancers.

The companies now have 30 days to either submit their proposed changes to their products’ safety labels or file a rebuttal statement if they disagree with the FDA’s assessment.

The FDA first announced that it was looking into the safety of CAR-T therapies in November 2023, after it had flagged instances of T-cell malignancies in patients who had been treated with these products. One such case, according to the regulator, was a CAR-positive lymphoma.

At the time, the FDA said that the benefits of CAR-T therapies still outweigh their potential risk but also noted that patients and participants receiving the treatment through clinical trials “should be monitored life-long for new malignancies.”

However, in response to the FDA’s safety investigation, oncologists have come out in defense of CAR-T therapies asserting that secondary blood malignancies are rare and that their risk is not enough to outweigh the treatment’s benefit for patients whose cancers have already progressed after chemotherapy and radiation.

“I doubt you will meet a CAR-T treating physician who will change their practice due to this warning,” Rahul Banerjee, a physician-researcher specializing in multiple myeloma at the Fred Hutchinson Cancer Center in Seattle, told BioSpace in a December 2023 interview.

Meanwhile, the FDA’s probe has triggered similar reviews by health regulatory authorities around the world, including the U.K.’s Medicines and Healthcare products Regulatory Agency, the E.U.’s European Medicines Agency and South Korea’s Ministry of Food and Drug Safety.

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