FDA investigates 'serious risk' of secondary cancer following CAR-T treatment

In a blow to CAR-T therapies, the FDA is investigating a “serious risk” of patients developing new cancers after treatment with these highly efficacious oncology drugs.

The FDA unveiled the probe Tuesday. The agency said it has received reports of T-cell malignancies, including CAR-positive lymphoma, among patients who received BCMA- or CD19-directed CAR-T cell immunotherapies.

Some patients involved have had to be hospitalized or died, according to the agency. The cases stem from clinical trials and postmarketing adverse event surveillance, the FDA said.

The FDA has determined that the potential risk is applicable to all currently approved CAR-T therapies, as T-cell malignancies have occurred after patients received several different products. The FDA is now weighing potential regulatory action—even as the potential risk of developing secondary cancer is already included as a class warning on the labels of the CAR-T therapies.

Currently marketed CD19 CAR-Ts include Yescarta and Tecartus from Gilead Sciences’ Kite Pharma, Novartis’ Kymriah and Bristol Myers Squibb’s Breyanzi. Johnson & Johnson and Legend Biotech’s Carvykti is a competitor to BMS’ Abecma in the BCMA space. A search of the FDA’s adverse events reporting system showed T-cell lymphoma cases for Breyanzi, Carvykti, Kymriah and Yescarta.

In a statement to Fierce Pharma, a Gilead spokesperson said the company is “confident in the overall safety profile of both Tecartus and Yescarta.” The sister therapies have so far reached 17,700 patients, with no evidence to date that suggests a causal role linking them with the development of new malignancies, the spokesperson added. 

“We have a rigorous process in place to continuously monitor for and report adverse events to regulatory authorities,” the Gilead representative said. “We have fully cooperated with the FDA’s request for an analysis of our data related to this inquiry.”  

For Kymriah, Novartis also expressed confidence in its CD19 offering’s benefit-risk profile. With more than 10,000 patients treated, Novartis has not identified a causal relationship between Kymriah and secondary malignancies, the company said in a separate statement.

BMS noted that among the 4,700 patients it has treated with Abecma or Breyanzi, none developed CAR-positive T-cell malignancy. The company is responding to the FDA’s requests for information, a BMS spokesperson said, and it remains confident in the safety profile and clinical value of its cell therapies.


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In its statement, Legend Biotech noted that T-cell malignancies may occur among multiple myeloma patients even without CAR-T treatments. The company cited an incidence rate between 0 to 554 per 100,000 patients across multiple databases between 2018 and 2022. Besides, other myeloma-related treatments such as alkylators, immunomodulatory drugs and autologous stem cell transplantation are associated with an increased risk of secondary cancer. 

J&J said it has shared Carvykti post-treatment surveillance data with the FDA and is working with the agency to assess this safety signal. Carvykti has so far been used in 2,000 patients with a favorable benefit-risk profile, a J&J spokesperson said.

In a Tuesday note to investors, analysts at Willima Blair said they view the T-cell lymphoma risk as low, pointing to the small number of cases. For example, Yescarta only had three T-cell lymphoma cases in the FDA’s adverse event database, although the analysts acknowledged that the FDA might have received more reports.

Over the last several years, CAR-T therapies have transformed care for several blood cancers. When used as a second-line treatment for large B-cell lymphoma, Gilead’s Yescarta reduced the risk of disease progression, death or the need for a new therapy by 60.2% compared to standard of care, which involves chemotherapy and stem cell transplant. J&J and Legend’s Carvykti demonstrated a massive 74% benefit in delaying tumor progression or death when compared with a standard combo therapy in patients with multiple myeloma who had previously tried one to three lines of therapy.

For now, the FDA believes the benefits of these therapies continue to outweigh their risks, but the agency said it’s investigating the T-cell malignancy cases. This comment suggests the FDA doesn’t plan to withdraw any approvals at this point.

Although secondary cancer is a known risk, the FDA’s probe marks a new hurdle to the CAR-T class, which has already had some difficulties reaching more patients. Yescarta, for example, missed analyst consensus in the third quarter thanks to a relatively low level of adoption in second-line large B-cell lymphoma despite strong clinical data.

First approved by the FDA in October 2017, Yescarta is currently the world’s best-selling CAR-T therapy, generating $1.13 billion in the first nine months of 2023.

Meanwhile, BMS and J&J/Legend have been struggling to provide enough supply to meet demand for their BCMA therapies. Thanks to competition and a manufacturing operation pause, BMS recorded a sequential sales decline for Abecma in the third quarter.

The cancer risk is believed to stem from the viral vectors used to deliver cell and gene therapies. For CAR-T therapies, a patient’s own T cells are drawn out and genetically modified to be able to identify cancer cells based on specific biomarkers such as CD19 and BCMA. While the viral vector can deliver the genetic payload, it might also cause cancer when inserting genetic material into a person’s genome, especially near cancer-related DNA sequences or suppressors.

The FDA has required manufacturers of cell therapies to conduct 15-year, long-term studies to monitor their safety profiles. Cancer cases and patient deaths in the past have prompted the FDA to halt clinical trials of cell and gene therapies.

Editor's Note: The story has been updated with additional comments from BMS, J&J, Legend and Novartis.