J&J, Legend’s Carvykti slapped with FDA black-box warning over secondary cancer risk

As the FDA investigates a safety signal for approved CAR-T therapies, the agency has upgraded a warning about secondary cancers following the use of Johnson & Johnson and Legend Biotech’s Carvykti. 

The boxed warning on Carvykti’s label includes a new item stating that “secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred following treatment with Carvykti.” Legend disclosed the label update in a securities filing Thursday.

A boxed warning is the FDA’s most serious safety-related warning for drugs on the market. Previously, the risk of secondary malignancies was listed in the “Warnings and Precautions” section of Carvykti’s label. This section is lower and not as prominent as a boxed warning.

The warning upgrade followed the recording of MDS and AML events in 10 of 97 patients (10.3%) who received Carvykti in the CARTITUDE-1 study, as well as cases in the post-marketing setting, Legend said in the filing. Nine of the 10 patients have died after developing bone marrow abnormalities. The time to myeloid neoplasm onset ranged from about half a year to about three years after treatment.

All 10 patients were heavily pretreated with four to 18 prior therapies, and some had genetic mutations before getting the BCMA-targeted CAR-T.

Carvykti’s label update comes less than a month after the FDA launched an investigation into the potentially “serious risk” of patients developing new cancers after treatment with marketed CAR-T therapies. Although they’re both centered on secondary cancers after treatment with the cell therapies, the two events appear unrelated.

While the warning for Carvykti centers on MDS and AML, the FDA is looking into a newly identified risk of T-cell malignancies that arise after CAR-T treatment in its broader probe.

When unveiling the safety investigation in late November, the FDA said it's determined that the potential risk of T-cell malignancies is applicable to all existing CAR-T therapies on the market. Carvykti’s label update looks specific to the J&J-Legend multiple myeloma drug.

Simultaneously on Thursday, Gilead Sciences’ Kite Pharma announced an FDA label update for its large B-cell lymphoma CAR-T Yescarta. The CD19-targeted drug’s prescribing information now includes overall survival data from the phase 3 Zuma-7 trial showing that Yescarta reduced the risk of death by 27.4% compared with standard of care as second-line treatment. In Yescarta’s renewed label, secondary malignancies remain in the less severe “Warnings and Precautions” section.

As the FDA’s investigation came to light, industry watchers have suggested that the agency might eventually add T-cell malignancies to all existing CAR-Ts’ black-box warnings.

In response to a Fierce Pharma inquiry, Bristol Myers Squibb declined to provide an update on any potential label changes for its BCMA-targeted Abecma and CD19-directed Breyanzi. A spokesperson said the company does not disclose details of regulatory discussions.

An article published in November in the journal Blood described a 51-year-old male patient in Carvykti’s CARTITUDE-4 trial who developed CAR-positive T-cell lymphoma after Carvykti treatment. Although the CAR-positive nature of the case is a concerning sign, no conclusion has been made about whether Carvykti caused the secondary cancer.

The researchers who reported the case noted that other genetic mutations could have driven the rare malignancy, but they also acknowledged that a contribution from the CAR insertion could not be ruled out.

J&J and Legend are working with the FDA in its probe, a J&J spokesperson said, adding that it “would be inappropriate to speculate on any potential outcome until the agency has concluded its investigation.”

Still, the company remains confident in the $5 billion-plus peak sales estimate for Carvykti, according to the spokesperson.