The FDA has raised concerns about early clinical trial deaths as part of two applications that aim to move the CAR-T therapies Carvykti and Abecma into earlier lines of treatment for multiple myeloma.
In both cases, the FDA noted increased rates of death for the CAR-T cell therapies compared with standard drug combinations in the first few months of their respective phase 3 trials. The pattern of early deaths attributed not to disease progression but to adverse events is especially concerning to the agency.
The agency appears more worried about Abecma than Carvykti, according to the briefing documents (PDF, PDF) prepared for an advisory committee meeting this Friday.
Despite the drugs’ huge benefits in delaying tumor progression, the FDA is asking experts on its oncologic drugs advisory committee (ODAC) to discuss whether the negative trend in overall survival early in the studies is “acceptable in the context of the clinical benefit.”
Input from outside oncology experts will help the agency decide on whether to approve Johnson & Johnson’s Carvykti as a second-line myeloma treatment and Bristol Myers Squibb’s Abecma a third-line therapy. Moving up in the treatment sequence from the current fifth-line setting is critical for the drugs’ long-term trajectories.
Between the two BCMA-directed CAR-Ts up for regulatory scrutiny, Carvykti appears to be in better shape. In a prespecified test that measured events eight weeks after patient randomization, Carvykti led to a 74% reduction in the risk of progression or death versus standard combinations. In a standard analysis of all progression-free survival events from the time of randomization, the risk reduction was also statistically significant at 59%, according to the FDA.
Carvykti also showed a positive trend toward prolonging patients’ lives. At an interim analysis with a data cutoff of Nov. 1, 2022, the CARTITUDE-4 trial had accrued about a third of deaths for a planned final overall survival analysis; it linked Carvykti to a 22% reduction in the risk of death at the time. The survival benefit widened to 43% as of Dec. 13, 2023, when about half of deaths had happened for a final analysis, according to a briefing document (PDF) by J&J.
However, the FDA’s staffers noted that patients assigned to receive Carvykti were more likely to die than their control-arm peers in the first 11 months of participation in the study. Carvykti flipped the disadvantage after that time. The two arms’ overall survival curves therefore crossed at around 11 months.
Safety findings
In a safety analysis, 11% of Carvykti patients died of treatment-emergent adverse events, higher than the 8% in the standard therapy arm, the FDA observed. But it’s worth noting that COVID-19 accounted for 3.7% of the Carvykti’s trial arm's deaths, versus 0.5% for the control arm. Treatment-emergent side effects don’t necessarily equate to treatment-related events.
What’s more, the FDA also pointed out the fact that a higher proportion (8%) of patients in the Carvykti arm died before disease progression compared to the standard therapy arm (2%).
J&J attributed the imbalance in overall survival to patients in the Carvykti arm who had not received the CAR-T therapy in time, and not to toxicity. After further evaluations of various factors that could also have led to the imbalance, J&J said it found differences in the intensity of pretreatment bridging therapies, although it acknowledged that the exact contribution of this factor is unknown.
The situation looks relatively good for Carvykti because the drug’s overall survival benefit widened over time, and the FDA is wondering whether additional data might better support a favorable benefit-risk assessment.
FDA's Abecma review
Abecma seems to be in more trouble. For one, the FDA noted the same problem of early deaths in BMS’ KarMMa-3 trial. But in this case, “additional follow-up of overall survival even if statistically significant, is unlikely to overcome the increased risk of early deaths,” the FDA’s reviewers said in a briefing document.
KarMMa-3 previously showed that Abecma could cut the risk of progression or death by 51% over standard combination therapies. When that progression-free survival analysis was made, nearly half of deaths had happened for a final overall survival readout, and Abecma was linked to a preliminary 9% increased risk of death.
In a December update, when about three-quarters of deaths occurred before a final analysis, the overall survival trend improved but remained negative at 1%.
An analysis by the FDA found that more patients in the Abecma arm had died than those in the control group up to around 15 months.
BMS performed various exploratory analyses to identify factors that might have accounted for the early deaths, arguing that toxicity and manufacturing delays didn’t contribute to the observed early deaths.
The early deaths were driven by patients who didn’t live to receive Abecma at all, and manufacturing turnaround times were similar in the early deaths and the overall population, the company said in its briefing document (PDF).
Instead, the New Jersey pharma, like J&J, pointed to bridging therapy as a possible culprit in the survival results. The trial protocol on bridging therapy led to a long time without anti-myeloma treatment in the Abecma arm, which didn’t seem to adequately control the disease in some patients with high-risk features, BMS noted.
BMS also blamed a high 56% crossover rate in which patients in the control arm later received Abecma upon disease progression. After adjusting for patient crossovers, Abecma could have shown a positive overall survival trend, according to BMS.
But the FDA argued that BMS’ analyses “rely on unverifiable and questionable model assumptions, limiting their interpretability.”