Two CAR T-cell therapies for multiple myeloma won favorable recommendations for earlier use in the disease during a day-long meeting of the FDA Oncologic Drugs Advisory Committee (ODAC).
By an 11-0 vote, ODAC recommended that FDA approve ciltacabtagene autoleucel (cilta-cel, Carvykti) for use as second-line therapy in certain patients with myeloma. Later in the day, the panel voted 8-3 in favor of approving idecabtagene ciloleucel (ide-cel, Abecma) for second-line treatment. The FDA is not bound by advisory committee decisions but usually follows the recommendations.
The favorable recommendations followed considerable discussion about an early mortality risk — and the potential cause — seen in pivotal trials of both therapies. In the end, the ODAC panel found that the benefits of earlier use of the therapies outweighed the risk.
“The data from CARTITUDE-4 [the cilta-cel pivotal trial] are still somewhat immature, but it appears to be favorable in its totality at this time,” said ODAC chair Ravi Madan, MD, of the National Cancer Institute in Bethesda, Maryland. “While the risk of early death, often prior to therapy, is not ignored in this discussion or this vote, it does seem to be outweighed by the long-term potential benefits here.”
“Ideally, emphasis in the further development of this therapy could be placed in better understanding how to optimize bridging therapy and guarding against infection,” he added.
The panel found the data for ide-cel slightly less compelling, not just because of the early mortality hazard but by the lack of survival benefit in the pivotal KarMMa-3 trial, despite a large progression-free survival (PFS) advantage for the CAR T-cell therapy.
“The risks are that PFS — [based on] the data we have now — appears transient and there is no clear benefit that early is better than later,” said Daniel Spratt, MD, of the UH Seidman Cancer Center in Cleveland, who cast one of the “no” votes. “Those that do cross over had favorable OS [overall survival], so there’s not a clear benefit of earlier intervention. There are numerically greater early deaths. I still believe there is uncertain potential of worse OS that crossover doesn’t explain, but we don’t have all of the events.”
“Speaking to real-world data, I think there’s a whole other side where providers would need to tell their patients, based on this data, there’s potentially over a half-million-dollar expense for a zero day, on average, life gained over a 31-month period,” Spratt continued. “My vote is based on the follow up we have today. I think with longer follow-up, it may change the PFS curves coming together, as well as the OS. I would strongly encourage industry to demonstrate a valid surrogate endpoint for their patient data to identify this.”
Jorge Nieva, MD, of the USC Norris Comprehensive Cancer Center in Los Angeles, voted “yes,” despite concern about a lack of plateau in the PFS curve.
“There is certainly a benefit there that’s prolonged,” he said. “The quality-of-life benefit made it convincing to me that patients actually d0 benefit from this therapy. I do think that much of the issue around bridging, which I think is a reason for some of the problems here, is in a way an artifact of the clinical trial process. In the real world, where collection and manufacturing could occur earlier in the course of disease, it may be less of an issue for patients. I think that’s something where real-world evidence may help us in the future.”
Both cilta-cel and ide-cel have approval for patients who have progressed on four or more prior lines of therapy. Janssen (cilta-cel) submitted a supplemental biologics license application (sBLA) to use the therapy in patients who have received at least one prior line of therapy (including a proteasome inhibitor and an immunomodulator) and are lenalidomide (Revlimid) refractory. Celgene/Bristol Myers Squibb is seeking approval for use of ide-cel in relapsed/refractory myeloma previously treated with an immunomodulator, a proteasome inhibitor, and an anti-CD38 antibody.
Trial Data
Support for the cilta-cel sBLA came from the phase III CARTITUDE-4 trial comparing the CAR-T therapy versus investigator’s choice of standard care in lenalidomide-refractory patients. The primary analysis showed a 74% reduction in the hazard for progression or death (P
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