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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<0.001) in favor of cilta-cel. The key secondary analysis showed a 43% reduction in the survival hazard in favor of the CAR T-cell therapy.

In a report prepared for ODAC, FDA staff raised concern about an increased risk of death during the first 10 months in the cilta-cel arm. The difference was driven by a higher mortality related to progressive disease prior to the start of study therapy, 4.8% in the cilta-cel arm versus 0.5% in the control group. Beyond 10 months, the cilta-cel arm had a 9.1% mortality (1.4% from progressive disease) versus 11.3% (7.1% from progressive disease) in the control arm.

The early mortality hazard was due to "not getting the treatment or inadequate bridging or delay or COVID," said Ranjana Advani, MD, of Stanford University in California. "Not completely understood, but I think overall it was a very positive trial with a significant benefit for most patients."

Christopher Lieu, MD, of the University of Colorado Cancer Center in Aurora, found the PFS "tail" and duration of response with cilta-cel particularly striking.

"If patients have a chance to get a durable response while being off therapy, the question is whether or not the patients are willing to undertake the risk for early progression or death," said Lieu. "It's not trivial. There's no question these patients are going to experience cytokine release syndrome, the possibility of [neurologic toxicity], and other long-term toxicities."

"If there's only a minimal improvement in PFS, the answer is always 'no'" Lieu continued. "However, if there's a chance for a long, durable response while not receiving toxic therapy during that response time, the answer may be 'yes,' -- and I honestly think the answer probably will be 'yes' -- for patients who may want just a chance at a longer time off treatment for multiple myeloma. Therefore, I believe the risk-benefit profile is favorable."

An early mortality hazard also was at the center of discussion for ide-cel, but the issue was complicated by the lack of survival benefit despite more than a three-fold difference in PFS favoring the CAR T-cell therapy. Unlike CARTITUDE-4, the KarMMa-3 trial allowed cross between groups. A prespecified sensitivity analysis that accounted for the increased crossover rate in the control arm yielded a substantial difference in median OS (41.4 vs 23.4 months). FDA staff contended that sensitivity analyses do not provide compelling evidence of an OS benefit.

As in the cilta-cel analysis, deaths during the first 9 months of the KarMMa-3 trial were driven by an imbalance before the start of randomized therapy (eight of 18 with ide-cel vs none of 11 in the control arm). Mortality after the start of treatment was actually lower in the ide-cel arm (10 among 254 patients vs 11 among 132 in the control group).

Despite the reservations some panelists expressed, the participants did have clear areas of agreement, said Madan, who cast one of the "no" votes.

"The PFS data here is very encouraging and great for patients," said Madan. "The bridging regimen really need to be optimized, which may be across the field, but it's something everybody agreed on. I think that for those people who had concerns and voted "no," it was more from a lack of later outcomes, whether it was survival despite the crossover or lack of plateau. That was less of a concern for the people who voted "yes," who felt that the time off from therapy was valuable and that perhaps in time, all the bridging issues would be worked out."

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