CLINICAL DEVELOPMENT IN ONCOLOGY C
himeric antigen receptor (CAR)-T cell therapies have always carried a risk of causing secondary malignancies, but
until now that risk has been somewhat theoretical. In the last two months, since the FDA launched an investigation into the risk of developing secondary cancers following the administration of CAR-T cell therapies, a volley of safety updates has increased the scrutiny of these innovative therapies. One month after the FDA opened its
investigation, Johnson and Johnson and Legend Biotech reported data from the Phase II CARTITUDE-1 trial (NCT03548207) showing that myeloid neoplasms occurred in 10 out of 97 patients following treatment with its CAR-T cell therapy Carvykti (ciltacabtagene autoleucel; cilta-cel). Nine of these 10 patients died after developing myeloid neoplasms. In December, the companies added a boxed warning stating the risk of developing secondary hematological malignancies following treatment with Carvykti. Then, on 19 January, the FDA sought to add
boxed warnings for secondary T-cell malignancies to all approved CAR-T therapies, including Carvykti. A few days later, the agency updated the proposed label for Gilead Sciences’ CAR-T treatment Tecartus (brexucabtagene autoleucel) to a general class-wide boxed warning instead of the specific warning that was previously issued. While there is potential for correlation, there is not enough information to infer any causation, says Dr. Bruce Levine, Barbara and Edward Netter Professor in Cancer Gene Therapy at the Perelman School of Medicine at the University of Pennsylvania. Levine is credited as a co-inventor of the first CAR-T to get an FDA nod: Novartis’s Kymriah (tisagenlecleucel). “Although there have been cases with T-cell lymphomas and other secondary T-cell malignancies, some of these were positive for the CAR transgene and there are multiple unknowns.”
Difficulty in defining a causal relationship Dr. Rahul Banerjee, oncologist and assistant professor at Fred Hutchinson Cancer Center, explains that many of the patients who have developed secondary T-cell malignancies in the CARTITUDE-1 trial have been on other treatments that are known to predispose patients to secondary cancers, including
“Although there have been cases with T-cell lymphomas and other secondary T-cell malignancies, some of these were positive for the CAR transgene and there are multiple unknowns”
chemotherapies like lenalidomide, bendamustine, and fludarabine. Given the fact that these patients may have received other therapies in prior years that could be coming to the forefront, it is hard to say what effects are due to a CAR-T and what are not, he adds. Banerjee highlights a discussion surrounding
this issue at the premier haematology meeting—American Society of Hematology (ASH) Annual Meeting & Exposition—which took place in December 2023, shortly after the news of the FDA investigation broke. In the case of one patient from the Phase III CARTITUDE-4 study (NCT04181827) with relapsed/refractory (R/R) multiple myeloma being treated with Carvykti, a CAR-T cell lymphoma was observed. However, Banerjee says it appeared as if the cells were potentially predisposed and destined to become a T-cell lymphoma, even before CAR-T therapy was administered. In that particular case, those T-cells had many risk factors, including a genetic predisposition that probably meant that they were destined to become T-cell lymphoma cells in that patient’s lifetime, Banerjee adds. Levine says longer survival because of
patients receiving CAR-T therapies creates an “immortal time bias” in this specific population. Often, patients receiving CAR-T therapies are in the R/R setting and have no other good options. However, “patients are now surviving, and we don’t know the frequency of secondary malignancies that would ordinarily occur in this population,” Levine adds.
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