As FDA probes CAR-T safety, expert meeting for Bristol's Abecma could serve as key guidepost

The revelation of an FDA investigation into whether CAR-T treatments can cause cancer sent shockwaves across the cell therapy world Tuesday. As industry watchers deliberate the implications, one upcoming meeting could offer precious clarity from drug regulators.

The meeting of the FDA’s oncology drugs advisory committee to deliberate Bristol Myers Squibb’s application for Abecma in earlier treatment of multiple myeloma will be “an important milestone in understanding evolving regulatory stances on non-relapse risks with CAR-T” therapies, Leerink Partners analysts said in a Tuesday note.

BMS said the FDA will discuss overall survival data from Abecma’s KarMMa-3 trial during the meeting. As the FDA has yet to set a date, Leerink analysts suspected that the agency might be considering including Johnson & Johnson and Legend Biotech’s rival drug Caryvkti in the discussion, as well.

A Legend spokesperson told Fierce Pharma Wednesday that the company hasn’t received any communication from the FDA about a potential advisory committee meeting for Carvykti’s earlier-line application.

Abecma and Carvykti are BCMA-targeted CAR-T therapies that have each shown an impressive ability to prevent myeloma progression. But CAR-Ts also come with significant toxicities, and the FDA views patient survival as a measurement of both efficacy and safety.

For years, the possibility of patients developing secondary cancer has been discussed mostly as a theoretical risk for CAR-T therapies that use viral vectors as their delivery vehicles. As the Leerink team noted, rates of T-cell lymphoma in clinical trials were too low to draw any conclusions. The FDA’s investigation, unveiled Tuesday, now demonstrates actual reports of T-cell malignancies.

Across all six FDA-approved CAR-T therapies, drugmakers have reported treating about 34,400 patients worldwide. The FDA has identified 19 cases of T-cell malignancies following CAR-T treatment, although the number of CAR-positive lymphoma cases—and whether there’s any causal relationship—remains unclear.

As Legend’s spokesperson pointed out, blood cancer patients who received CAR-Ts had also received other treatments, such as chemotherapy, which is also associated with an increased risk of secondary cancer. The FDA hasn’t yet responded to a request for comment.

Given the small number of cases, analysts at Leerink and William Blair viewed the overall risk of T-cell lymphoma as low, especially for drugs that have shown a strong overall survival benefit, like Gilead Sciences’ CD19-targeted Yescarta. The FDA also said the benefits of these CAR-T products continue to outweigh their risks, but the agency is weighing potential regulatory actions.

Currently, secondary malignancies are listed in the “warnings and precautions” section of every CAR-T therapy’s label. Should the FDA take regulatory action, the Leerink team argued the agency would most likely flag the risk in a black-box warning, which is the highest level of a safety alert on a medication’s label. That wouldn’t be too big a problem, given CAR-Ts already have several boxed warnings, including for potentially life-threatening cytokine release syndrome and neuro toxicities.

Alternatively, the FDA could decide to restrict CAR-T use to high-risk patients or to later-line treatment settings, the Leerink analysts said. Such actions would limit these products’ commercial potential in a meaningful way.

“A worst-case scenario is that today’s FDA announcement portends increased scrutiny and higher risk/benefit bar for CAR-T in earlier lines and settings beyond oncology,” the Leerink analysts wrote in their note Tuesday.

What’s more, the FDA’s probe could start to shift doctors’ attention to the long-term safety profile of these drugs. For now, safety differentiation is secondary to topline efficacy results in most doctors’ evaluation of treatment choice, serving only as a “tie-breaker” between two products with comparable efficacy, the Leerink analysts observed.

As part of the initial approvals for CAR-T therapies, the FDA has required the companies to conduct 15-year follow-up studies to assess the long-term safety and the risk of secondary malignancies.