FDA Raises Concerns Over Carvykti and Abecma Clinical Trial Deaths Ahead of CAR-T Advisory Hearing

Federal drug regulators are raising concerns over clinical trial deaths among patients given Carvykti and Abecma, indicating that the deaths appear to be linked to side effects of the CAR-T therapy drugs.

In January, the U.S. Food and Drug Administration (FDA) ordered several manufacturers to add black box warnings to the entire class of medications, indicating that the CAR-T therapy may increase the risk of T cell malignancies, which can result in hospitalization and death.

The decision came after the agency’s researchers found 22 cases of secondary cancer linked to CAR-T side effects, following an investigation that started in November of last year.

FDA Advisory Meeting To Review Side Effects of Carvykti, Abecma

The concerns will be outlined during an FDA advisory committee meeting today, which is being convened to discuss whether Carvykti, manufactured by Johnson & Johnson, should be approved as a second-line treatment for myeloma, and Bristol Myers Squibb’s Abecma, which is being considered as a third-line therapy treatment.

The hearing is highly anticipated by stakeholders because it will give them a glimpse into how the FDA will approach the safety of the drugs after the new cancer warnings. The advisors are expected to focus on the overall survival data from recent clinical trials on the two drugs.

While the FDA often heavily considers the findings of its’ advisory committees when making regulatory decisions, the agency is not obligated to follow their recommendations.

Ahead of the hearing, federal regulators submitted briefing documents for both Abecma (PDF) and Carvykti (PDF) to the Oncologic Drugs Advisory Committee meeting, asking the group to review deaths seen in phase 3 clinical trials for both drugs, but focusing particularly on Abecma.

“FDA seeks the Committee’s discussion of the benefits and risks of treatment with ABEMCA in the indicated population,” the agency’s investigators indicated. “In particular, FDA is interested in the Committee’s opinion regarding the higher rate of early deaths in the ide-cell arm, in the context of a statistically significant progression-free survival benefit in the KarMMa-3 trial.”

FDA officials found that while the KarMMa-3 trial linked Abecma to a 51% reduction of myeloma progression or death, it also was linked to as high as a 9% increased risk of death. In addition, they found that 98% of Abecma patients in the standard of care arm of the clinical trial reported suffering an adverse event.

The most common adverse events linked to Abecma were neutropenia, infection, fever, hypertension, hypoxia and kidney failure.

FDA investigators also found that 11% of Carvykti patients died of adverse events which appeared during the treatments. However, some of those deaths were linked to cases of COVID-19. In addition, 8% of patients given Carvykti died of disease progression, compared to only 2% of patients given standard therapy.

The FDA report notes that the Carvykti trial, CARTITUDE-4, met its primary endpoints, however, indicating the benefits may still outweigh the potential health risks.

CAR-T Therapy Drug Problems

The CAR-T treatments were approved under a requirement that the FDA conduct a 15-year observational study, to assess the potential for long-term adverse health outcomes and secondary malignancies that could occur after treatment.

The FDA began an investigation into CAR-T cancer risks in November, due to concerns over secondary cancer rates.

By December 31, the agency had found 22 cases of T-cell cancers linked to treatment with CAR-T products, including T-cell lymphoma, T-call large granular lymphocytosis, peripheral T-cell lymphoma and cutaneous T-cell lymphoma. All of the cases examined in detail to date appear to have manifested within two years of treatment.

Some of the cases are still under investigation, but cancer incidents have been reportedly linked to five of the six CAR-T cell drugs on the market, including Abecma, Breyanzi, Carvykti, Kymriah and Yescarta. The sixth drug, Tecarus, had no cases of cancer linked to it, but the FDA required it to also carry a black box warning anyway.

As a result of the risks associated with side effects of Carvykti and other CAR-T treatments, the FDA currently recommends that patients or clinical trial participants receiving these treatments be monitored for the rest of their life by a health care professional for new cancers that may develop.