FDA Warns on CAR-Ts, but Benefits Outweigh Risks for Now

Reprinted with AIS Health permission from the February 2024 issue of Radar on Specialty Pharmacy

A couple of months after the FDA revealed that it was investigating the risks of chimeric antigen receptor T cell (CAR-T) immunotherapies, the agency is seeking updated language in their labels warning about those risks. However, the fact that the FDA is allowing the therapies to remain on the market suggests that their overall benefits outweigh their potential risks, says one industry expert.

In late November, the FDA revealed that it was investigating the risks of CAR-T therapies following reports of T cell malignancies in people who had undergone treatment with the agents. Less than two months later, the agency issued safety labeling change notification letters to the six available B cell maturation antigen (BCMA)-directed or CD-19 directed autologous CAR-Ts, which cover a range of hematologic cancers:

Abecma (idecabtagene vicleucel) from Bristol Myers Squibb and 2seventy bio, Inc.;
Breyanzi (lisocabtagene maraleucel) from Bristol Myers Squibb unit Juno Therapeutics, Inc.;
Carvykti (ciltacabtagene autoleucel) from the Janssen Pharmaceutical Companies of Johnson & Johnson and Legend Biotech USA, Inc.;
Kymriah (tisagenlecleucel) from Novartis Pharmaceuticals Corp.;
Tecartus (brexucabtagene autoleucel) from Gilead Sciences Inc.'s subsidiary Kite Pharma, Inc.; and
Yescarta (axicabtagene ciloleucel), also from Kite.

The FDA initially sent the letters on Jan. 19, and the updated language was essentially the same for all of them: "T cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including [product name]."

However, on Jan. 23, the agency issued an updated letter to Kite for Tecartus, requiring a warning that "T cell malignancies have occurred following treatment with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies" without mentioning Tecartus specifically.

A spokesperson for the FDA's Center for Biologics Evaluation and Research (CBER) told the Pink Sheet that officials held teleconferences with each sponsor to discuss the labeling changes, but they did not disclose any details on the conversations. The initial Tecartus letter "was removed from FDA's website to incorporate updates consistent with the required class labeling changes," said CBER.

AIS Health and the Pink Sheet are part of the same parent company, Norstella.

"This revised letter may seem to indicate that even though the FDA views secondary T-cell cancers as a class effect, Tecartus itself has not seen such cases reported," observes Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth.

In a Jan. 24 article in the New England Journal of Medicine, Nicole Verdun, M.D., director of the FDA's CBER Office of Therapeutic Products, and Peter Marks, M.D., Ph.D., director of CBER, explained that as of the end of 2023, the FDA was aware of 22 cases of T cell cancers that happened after treatment with CAR-T therapies. Of those, among the 14 with adequate data, secondary cancers have occurred within two years of CAR-T treatment, and cases have been reported for five of the six available agents — presumably not for Tecartus.

Verdun and Marks noted that the CAR-T agents have "well-described safety concerns" such as cytokine release syndrome that already are included in the products' labels.

Kymriah was the first CAR-T therapy to receive FDA approval, which was granted Aug. 30, 2017.

"In three cases for which genetic sequencing has been performed to date, the CAR transgene has been detected in the malignant clone, which indicates that the CAR-T product was most likely involved in the development of the T-cell cancer," wrote Verdun and Marks. "With more than 27,000 doses of the six approved products having been administered in the United States, the overall rate of T-cell cancers among people receiving CAR-T therapies appears to be quite low, even if all reported cases are assumed to be related to treatment. But relying on postmarketing reporting may lead to underestimates of such cases."

The FDA is trying to gather as much information as possible but has inadequate samples for many of the lymphomas. They request that providers caring for people who have received CAR-T cells report any new cancers to the therapies' manufacturers and the FDA.

"The FDA has stated that the overall benefits of the CAR-T therapies continue to outweigh their potential risks," says Szczotka. "The initial approvals of each of these products included postmarketing requirements to conduct 15-year long-term follow-up observational studies to assess the long-term safety and the risk of secondary malignancies occurring after treatment. Patients should be monitored life-long for new malignancies."

Were Lymphomas Misdiagnosed?

Research analysts from Cantor Fitzgerald, however, shared a different take on the secondary malignancies. "We theorize that these 'T cell lymphomas' seen after CAR-T therapy were misdiagnosed and were actually part of the original malignancy!" they wrote in a Jan. 3 research note. "While unique surface markers of B cells, plasma cells and T cells are very helpful in identifying specific cell types, they are not always reliable in the setting of malignancies, where B cells and plasma cells can start to look like T cells."

In addition, they said, T cell receptor (TCR) and B cell receptor (BCR) sequencing are not always reliable "due to the potential expression of TCR by B cells and myeloma cells in the context of malignancy (an important and surprising finding). Therefore, we suspect many T-cell lymphoma cases found in the context of CAR-T therapy are misdiagnosed — relying on inaccurate markers and TCR sequencing."

Also lending credence to their hypothesis, they asserted, is the low incidence rate of T cell lymphoma cases.

All of the current therapies are autologous, meaning that they are manufactured from a patient's own immune cells, but allogeneic — or off-the-shelf — CAR-T therapies are in development. Both kinds of CAR-T agents are under investigation for the treatment of not only cancerous indications but also noncancerous conditions such as autoimmune diseases like lupus. Indeed, data reported at the recent American Society of Hematology annual meeting showed promising results in those conditions.

However, the Cantor Fitzgerald analysts claimed that if their hypothesis is correct, "it would generally exonerate the autoimmune CAR-T programs, as these patients do not have any malignant clones to begin with! Therefore, we believe that 'T-cell lymphoma' is not a potential risk for the autoimmune CAR-T programs."

Could Warnings Hamper Agents' Uptake?

In light of the safety warnings, could the use of CAR-Ts be negatively impacted?

"The FDA has not stated that every one of the reported cases [of secondary malignancies] has been shown that CAR-T therapy led to the malignancies, but rather that this is a safety signal," points out Szczotka. "The FDA has stated that the benefits of CAR-T therapies continue to outweigh the risks, and this will likely continue to guide therapy choices."

He tells AIS Health, a division of MMIT, that people who require CAR-Ts "often have a high chance of mortality from their current cancer type, and CAR-T therapies offer hope of a potential greater response rate and response durability after failure of initial therapies. From the currently available data, the risk of developing treatment-induced T-cell lymphoma appears to be extremely low. The proposed label changes will help support clinician discussion with patients on the risks associated with therapy and enhance the clinical decision-making process, but it would be anticipated that current utilization of these therapies for appropriate patients will continue."

The fact that the FDA is allowing the CAR-Ts to remain on the market supports their favorable benefit/risk profile and use as treatment options, asserts Szczotka. That said, as the agents move into earlier lines of therapy, the perceived risk of secondary malignancies could impact that profile.

According to Szczotka, "the FDA will likely have a higher level of scrutiny and add additional time for the approval process for more detailed reviews. Both Legend Biotech and Bristol Myers Squibb have disclosed that the FDA will convene the Oncologic Drugs Advisory Committee to review their respective applications for earlier line treatments of their CAR-T therapies (i.e., Carvykti use in a second-line multiple myeloma setting and Abecma for earlier lines of triple-class exposed relapsed or refractory multiple myeloma).

"The impact of this revised safety warning is that this will likely push CAR-T manufacturers to develop more safe versions and conduct further and more detailed safety reviews of clinical studies and monitoring for future applications and indications," he states.

For now, though, with CAR-Ts' current indications in later line settings, "health plans and payers will continue to ensure that the appropriate patients will continue to have access to these treatments as later lines of therapies," maintains Szczotka. "Product positioning by payers will likely not significantly impact current product positioning. Payers will continue to monitor the available clinical information and FDA guidance to ensure that the products remain safe and clinically effective, and the proper patient monitoring is being conducted."

Contact Szczotka via Caroline Chambers at cchambers@cpronline.com.

By Angela Maas