Carvykti, Abecma secure FDA panel support for earlier-lines of myeloma
15 Mar 2024
Clinical ResultCell TherapyPhase 3Drug Approval
Outside advisors to the FDA voted that the benefits of a pair of CAR-T cell therapies outweigh their risks when used to treat multiple myeloma (MM) in earlier-line settings, paving the way for both to be approved for a broader swathe of the patient population.
In an all-day meeting Friday, advisory committee members discussed filings for Johnson & Johnson and Legend Biotech's Carvykti (ciltacabtagene autoleucel) as well as fellow BCMA-targeting therapy Abecma (idecabtagene vicleucel), which is co-marketed by Bristol Myers Squibb and 2seventy bio.
The final tally for Carvykti was 11-0 that its risk-benefit profile is favourable for second-line myeloma use based on the CARTITUDE-4 trial. However, the expert panel was not unanimous on its recommendation for Abecma in the third-line setting based on data from the KarMMa-3 study, voting 8-3 in its favour.
FDA flags early deaths
Friday's meeting follows concerns expressed this week by FDA scientists that both Carvykti and Abecma were associated with an increased risk of early death compared to standard care in their respective pivotal Phase III trials, despite each meeting their primary endpoints of progression-free survival (PFS).
Abecma, the subject of the afternoon panel discussion, was approved in 2021 for relapsed/refractory MM after four or more prior lines of therapy. Bristol Myers Squibb is looking to move it into the third-line setting based on KarMMa-3, which showed a 51% benefit on PFS.
The morning AdCom session was focused on Carvykti, which has been approved in the US since 2022 for fifth-line patients. Johnson & Johnson and Legend are now looking to have it authorised as a second-line option based on CARTITUDE-4, which showed a striking 74% reduction in disease progression or death versus standard therapy.
In a presentation at the meeting, Jordan Schechter, vice president of R&D for innovative medicine at Johnson & Johnson, acknowledged an "imbalance" in early overall survival (OS) events, with seven deaths in the Carvykti arm compared to one in the standard of care arm within the first three months after randomisation. However, he said six of the deaths in the Carvykti arm were in patients who progressed before they received the infusion, and so they had never actually received the drug.
Schechter noted that there was increasing separation in the survival curves with time. At a December 2023 cut-off, after a median follow-up of close to 29 months, the hazard ratio (HR) for OS was 0.57 in favour of Carvykti, with 48 deaths compared to 77 deaths in the standard care arm.
Front-loaded risk
Some panel members noted that Carvykti appears to have a "front-loaded risk" that looks similar to other medical procedures, such as allogeneic transplant, where the upfront burden is known and accepted because, down the road, there is an overall benefit in survival.
"Something that's lost in the curves, but really came out in the discussion… is that the PFS is really a freedom of treatment. Some of the benefit here is indeed being able to get a therapy and then kind of coasting for a while," committee chair Ravi Madan said.
Torn on Abecma data
Prior to the meeting, Bristol Myers Squibb chief medical officer Samit Hirawat suggested the study's crossover design and the impact of bridging therapies – the treatments patients receive as they wait, often weeks, for their CAR-Ts to be manufactured – likely impacted the OS results. During Friday’s presentation, the company said that at 31 months of OS follow-up, the average survival time was similar between treatment arms, just a little over 23 months for both Abecma and the standard regimen.
"This was a challenging one," commented panel member Daniel Spratt, who was a no vote and suggested it would be hard to justify an "over half-a-million-dollar expense for zero days, on average, life gained over a 31-month period."
Meanwhile, Bristol Myers Squibb also said early deaths were driven by patients who had not yet received Abecma. Thirty patients died in the Abecma arm at six months, including in 17 who had not yet received the treatment, versus nine for standard regimens. At nine months, the number rose to 45 deaths with Abecma, including 20 who had not received the treatment, compared to 15 for standard care.
"It is not a direct [Abecma]-related mortality," said Eric Bleickardt, head of late clinical development for cell therapies at Bristol Myers Squibb. However, FDA scientist Poornima Sharma who spoke at the meeting noted that patients who died within nine months of randomisation did so at different steps in the process toward getting Abecma, such as during leukapheresis or bridging therapy.
Panel member Jorge Nieva suggested much of the issue around bridging likely stemmed from the clinical trial process itself. "I think in the real world, where collection and manufacturing could occur early in the course of disease, it may be less of an issue… That's something where real-world evidence may help us in the future."
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