FDA wants classwide boxed warning on all commercial CAR-T therapies amid secondary cancer safety probe

As many have feared, the FDA’s investigation into secondary T-cell cancers following treatment with existing CAR-T therapies is poised to lead to a classwide black box warning.

For all six commercial CAR-T therapies, the FDA is requiring label updates to include T-cell malignancies in the boxed warning section of each product’s label, according to the agency’s separate notification letters dated Jan. 19 to Bristol Myers Squibb, Gilead Sciences’ Kite Pharma, Johnson & Johnson and Novartis. A black box warning is the most serious safety alert on a medication’s label.

The products involved are Bristol’s Abecma and Breyanzi, Kite’s Yescarta and Tecartus, J&J’s Legend Biotech-partnered Carvykti and Novartis’ Kymriah. The products are separately approved to treat multiple myeloma, large B-cell lymphoma, among other blood cancers.

Specifically, the U.S. agency wants the companies to include a paragraph in those boxed warnings to say, “T-cell malignancies may occur following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including,” followed by the product’s name. The same language is also required as part of the “secondary malignancies” item in the less prominent “Warnings and Precautions” section of a drug’s label.

The required label update comes less than two months after the FDA unveiled an investigation into secondary T-cell malignancies among patients who received BCMA- or CD19-targeted CAR-Ts. The agency at the time labeled the risk as “serious” based on cases it had received from clinical trials and postmarketing surveillance. The FDA from the outset said that it deemed the potential risk as applicable to all currently approved CAR-T products. Based on those descriptions, industry watchers have speculated that a classwide boxed warning would likely come next.

Now, the FDA has determined that the T-cell malignancy safety signal “should be included in the labeling for all BCMA- and CD19-directed genetically modified autologous T cell immunotherapies,” the letters show.

That language suggests that even future CAR-T contenders that fits the description will be subject to the same boxed warning. Gracell’s BCMA/CD19 dual-targeting GC012F, which is the centerpiece of AstraZeneca’s $1 billion acquisition of the Chinese biotech, is one such product. Meanwhile, the FDA’s distinction of “autologous” therapies offers a relief for companies such as Allogene Therapeutics that are working on allogeneic, or so-called "off-the-shelf," CAR-T therapies. 

The companies now have the option to meet the FDA’s demand and submit a supplement to offer the changes verbatim or file a supplement with different wording. Alternatively, the companies may submit a rebuttal statement detailing their disagreements. Whichever pathway they choose, the companies must submit a response within 30 days or face potential enforcement action, including monetary penalties and forced change of label.

As the FDA is asking for a classwide change, J&J will “work with the agency to update the Carvykti prescribing information,” a J&J spokesperson told Fierce Pharma. With more than 2,000 patients having been treated with Carvykti worldwide, J&J remains confident in the favorable benefit-risk profile of Carvykti, the spokesperson added.

In a unique label update a month ago, Carvykti was slapped with an additional boxed warning item, which describes “secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia” following treatment with the BCMA CAR-T.

Separately, Novartis told Fierce Pharma that it will update Kymriah’s label in accordance with guidance from the FDA. The Swiss pharma pointed to 10,000 patients that have received Kymriah worldwide, saying it has not found sufficient evidence to declare a causal relationship between the CD19 therapy—which is the first FDA-approved CAR-T—and secondary T-cell malignancies.

A Bristol Myers spokesperson said the company is “evaluating next steps on the labels for Abecma and Breyanzi.” The company, which got the CAR-T therapies from its acquisition of Celgene in 2019, also said it hasn’t found a causal relationship between its products and T-cell cancers.

Gilead is “reviewing FDA’s changes and will determine appropriate next steps in the interest of patients and healthcare providers,” a company spokesperson said. Gilead’s latest analysis of more than 15,500 patients treated with Yescarta and more than 2,700 patients treated with Tecartus didn’t establish a causal role in the development of T-cell malignancies, the spokesperson said.

The fact that the FDA is allowing the products to stay on the market mirrors the agency’s prior comment that their benefit-risk profiles remain favorable in their existing indications.

In a commentary published in Nature Medicine a few days ago, several cell therapy experts, including CAR-T pioneers Bruce Levine, Ph.D., and Carl June, M.D., from Penn Medicine also suggested that treatment centers should continue to use those commercial CAR-T products based on existing safety information. The researchers noted that the “rate of T-cell malignancies observed is far lower than that seen with some other treatments.”

But it’s unclear how the perceived risk of secondary malignancies might affect the FDA’s calculation of benefit and risk as those BCMA and CD19 CAR-T therapies move into earlier lines of therapy. J&J and Legend’s application for Carvykti as a second-line multiple myeloma therapy is currently under FDA review, and the agency will convene an advisory committee meeting to discuss Bristol’s bid to move Abecma into the third-line setting. Gilead is running the Zuma-23 trial that’s testing Yescarta as first-line treatment in patients with high-risk large B-cell lymphoma.