Updated: FDA’s safety review on CAR-Ts culminates in new boxed...

Updated: FDA’s safety review on CAR-Ts culminates in new boxed warnings of secondary cancerAmber TongSenior EditorThe FDA has told Novartis, Gilead, Bristol Myers Squibb and Johnson & Johnson to add boxed warnings on the labels of six CAR-T therapies noting the risks of secondary cancer.The agency caused a stir in the CAR-T space when it revealed the safety review in November, which came as a surprise to many. Secondary cancers are a known but uncommon risk of many anti-cancer treatments; most scientists, clinicians and companies said they remain rare and are a relatively small risk factor for an otherwise effective drug class.In December, Johnson & Johnson partner Legend Biotech updated its label with a caution about “secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia” within the boxed warning, following reported cases in the clinical and postmarketing settings. But the FDA is now saying the companies need to add warnings about a different type of secondary cancer, namely T cell malignancies.advertisementadvertisement“(W)e consider the serious risk of T cell malignancy to be applicable to all BCMA- and CD19-directed genetically modified autologous T cell immunotherapies,” the agency wrote in its safety label change notification letters dated Jan. 19.Notably, while five of the six letters sought the addition of warnings that T cell malignancies “have occurred following treatment with BCMA- and CD19- directed genetically modified autologous T cell immunotherapies,” the letter to Gilead on Tecartus contained slightly different language, noting that such cases “may occur.”The companies have 30 days to submit proposed changes to the label. In response to an Endpoints News query, Gilead said it’s still reviewing the changes.“The FDA has recommended updated safety language for each individual label,” a Gilead spokesperson in a statement “However, it’s premature to discuss any specific labeling language as the labels will not be considered final until after the 30-day period.”The FDA stopped short of suggesting that there’s a causal relationship between CAR-T therapy and secondary cancer, writing only that T cell malignancies have occurred following CAR-T treatment.Novartis said in a statement to Endpoints that it will update the label, but it “has not found sufficient evidence to support the causal relationship between Kymriah and secondary T-cell malignancies to date and remains confident in the favorable benefit/risk profile of Kymriah.”“More than 10,000 patients have been treated with Kymriah worldwide in clinical studies and the post-marketing setting since the August 2017 approval of Kymriah in the United States,” it wrote. “We are fully committed to patient safety and will continue to work closely with the FDA.”Whether regulators believed that CAR-T therapies, which have primarily been used to treat blood cancer, directly caused secondary cancer has been a closely watched point of contention. Earlier this month, CBER Director Peter Marks said some cases may have been causal as the CAR construct had been found in the “malignant clone.” However, he emphasized that the benefits still outweighed the risks of CAR-T therapy.Across six similarly worded letters addressed to companies behind CAR-Ts — one for each therapy — regulators noted that the cases were identified during postmarketing use. At last count, the FDA was investigating 22 cases of blood cancer developing after CAR-T treatment.“Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure,” the letters read.Among the six CAR-Ts currently on the market, Novartis’ Kymriah, Gilead’s Yescarta and Tecartus, as well as Bristol Myers’ Breyanzi, are directed against CD19, while J&J/Legend’s Carvykti and BMS’ Abecma hit BCMA.Editor’s note: Story updated to clarify the differences between Legend’s December update to Carvykti’s label and the FDA update; and to note the wording in the Tecartus letter