An FDA announcement last year of an investigation into the risk of patients developing secondary cancers following the treatment of CAR-T cell therapies sent shock waves across the industry. The probe led to classwide black boxed warnings on existing CAR-T products’ labels.
Now, less than a year later, the FDA is reconsidering those serious safety warnings with plans to change them potentially, Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER), said in an interview with Fierce Pharma.
“We are in the process right now of reevaluating the need for the current labeling on these products,” Marks said. “You may see some actions, in some cases, removing warnings, in some cases, adding warnings, changing warnings.”
“There may be things that are specific to a specific CAR construct,” Marks said. “There may be other things that are perhaps seem to be more general across, for instance, the CD19 CAR-T cells.”
The six meds involved are Gilead Sciences’ Yescarta and Tecartus, Bristol Myers Squibb’s Breyanzi and Abecma, Johnson & Johnson and Legend Biotech’s Carvykti, and Novartis’ Kymriah. They have been approved to treat various types of blood cancers including large B-cell lymphoma and multiple myeloma.
Following the FDA’s high-profile scrutiny, complaints have been murmured among cell therapy developers and industry watchers that the FDA overreacted.
The agency pounced on cases of secondary T-cell malignancies captured in its voluntary adverse event report system. An FDA analysis by Marks and Nicole Verdun, M.D., who leads therapeutic products at CBER, found 22 cases of T-cell cancers following treatment with a CAR-T product as of the end of 2023. A slightly earlier Nature Medicine study in January noted 20 reports out of an estimated 34,400 CAR-T receivers.
As the authors of the Nature Medicine article pointed out, “the rate of T-cell malignancies observed is far lower than that seen with some other treatments.” Marks and Verdun, in their article, also said the cases “appear to be relatively rare.”
Multiple studies have since looked into the risk of secondary cancers after CAR-T therapies. A meta-analysis published recently in the journal Clinical Cancer Research found that the rate of secondary cancer was no greater among patients treated with CAR-T than those on traditional standard of care.
The industry complained that the FDA treated CAR-T unfairly while there are drugs with larger or similar numbers of secondary cancer reports that are being marketed without this boxed warning item. Besides, people with blood cancers already have various risk factors related to the secondary development of cancer in the first place.
“Was it perhaps a bit of an overreaction? In retrospect, maybe,” Marks said in the interview. “But if you saw the rate at which the reports were coming in at the time, there was concern.”
One main reason the FDA got scared was the agency initially “didn’t have a good handle on” the background rate of some secondary cancers, Marks explained.
“Any time we have gene therapy in the mix, we tend to be a little extra cautious,” the FDA official said.
“I think it was a good lesson,” Marks said. “The point […] is really well taken, which is that for lymphomas, a risk of 1 in 10,000 or 1 in 5,000 for a secondary lymphoma, or 1 in 1,000, is probably fully acceptable when in this salvage setting where the standard chemotherapies are associated oftentimes with […] even 1% of 2% of secondary malignancies.”
“The good news is, I think we now can go back, we can tune things up,” Marks said. “And we have this under our belt, this experience going forward, because I’m sure we’re going to have more safety signals in the future as we have more novel products.”
The FDA’s secondary cancer boxed warnings for the six commercial CAR-T meds for blood cancers have also put into question the commercial opportunities for CAR-T therapies that are being developed for autoimmune diseases.
The FDA was concerned back then because the CAR-T field was expanding beyond cancer treatment, and the secondary malignancy problem could carry over to other disease settings, Marks explained.
So far in lupus patients, cytokine release syndrome, a potentially dangerous side effect that’s also included in the boxed warnings of existing CAR-T therapies, appears to be milder than that seen in cancer patients. “So I think hopefully we’ll see kind of a reasonable safety profile here,“ Marks said. “I think understanding baseline data is really important, and also understanding … the totality of a field is sometimes very important."
Marks pointed to lupus, which is a hot disease area in which CAR-T drugs are being tested. Here, a secondary malignancy rate of 1 in 1,000 or 5,000 could probably be acceptable in severe patients, Marks said, “comparing to other products and comparing to the nature of these diseases which kill people.”
Marks encouraged biopharma companies to continue their CAR-T programs for autoimmune diseases and come talk to the FDA early if they start to see safety signals.
“I think this, in particular, is an area where why we are very interested in kind of revisiting this boxed warning because I think it may make a real difference here in the level of comfort that people will have in that space of nonmalignant disease,” Marks said.
Editor's note: This story was based on a fireside chat conducted in October as part of the Fierce Cell & Gene Virtual Event. The full interview, including remarks by Peter Marks, M.D., Ph.D., on the controversial approval of Sarepta Therapeutics' gene therapy Elevidys, intra-agency consistency, the working guidance on Platform Designation, AI and more, will go live Wednesday, Nov. 20.