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An increased risk of early death has created uncertainty about the risk-benefit ratio of two CAR T-cell therapies for relapsed/refractory multiple myeloma, which an FDA advisory committee will consider on Friday.

Both ciltacabtagene autoleucel (cilta-cel, Carvykti) and idecabtagene vicleucel (ide-cel, Abecma) produced positive results in pivotal trials supporting supplemental approval requests. However, in the randomized CARTITUDE-4 trial, 14% of patients assigned to cilta-cel died during the first 10 months of follow-up as compared with 12% among patients treated with standard-of-care (SOC) therapies. Additionally, more patients in the cilta-cel arm died in association with adverse events (AEs, 11% vs 8%).

In a report prepared for the Oncologic Drugs Advisory Committee (ODAC), FDA staff members said the adequacy of exploratory analyses to identify mitigation strategies require further discussion.

"FDA has granted approval to drugs that demonstrate a statistically significant and clinically meaningful effect on progression-free survival [PFS] in the context of an acceptable risk profile," staff members wrote. "Because of the higher rate of early deaths in the cilta-cel arm, it is unclear whether the overall benefit-risk assessment is favorable; specifically, whether additional data is needed to support such an assessment."

FDA staff came to the same conclusion after reviewing data from the KarMMa-3 trial of ide-cel. The results showed that 18% of patients randomized to the CAR T-cell therapy died within the first 9 months as compared with 11% in the control group. A safety analysis showed that more patients in the ide-cel arm died of AEs during the first 90 days (2.7% vs 1.6%).

CARTITUDE-4 involved 419 patients with relapsed/refractory myeloma, randomized to cilta-cel or one of two SOC regimens. The primary endpoint was PFS, and the results showed the median had yet to be reached in the cilta-cel arm (22.8 months to not evaluable) versus 12 months with standard therapy. The difference represented a 59% reduction in the PFS hazard in favor of cilta-cel (95% CI 0.30-0.56, P<0.0001).

A preliminary survival analysis showed the median overall survival (OS) had yet to be reached with cilta-cel as compared with 26.7 months with standard therapy. Kaplan-Meyer curves showed the hazards pattern crossing at about 11 months, with the cilta-cel arm having lower survival prior to 11 months.

KarMMa-3 included 386 patients with relapsed/refractory myeloma, randomized 2:1 to the CAR T-cell therapy or one of five FDA-approved doublet or triplet regimens. The primary endpoint was PFS, and the results showed a median of 13.3 months with ide-cel versus 4.4 months with SOC therapy, representing a 51% reduction in the hazard ratio (95% CI 0.379-0.647, P<0.0001). A preliminary OS analysis showed a median of 32.8 months with ide-cel versus not reached in the control arm (HR 1.093, 95% CI 0.727-1.645).

Sponsors for both drugs are seeking approval for earlier-line use of their CAR T-cell therapies in relapsed/refractory myeloma. Both therapies currently have approval for patients who have received four or more prior lines of therapy.

While the FDA is not required to follow the advice of its advisory committees, it typically does.

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