Ahead of a high-stakes FDA meeting to review CAR-T data in multiple myeloma, Legend Biotech CEO Ying Huang, Ph.D., laid out some of his expectations about the event.
For one, the Legend CEO expects that the advisory committee meeting will largely focus on overall survival efficacy results, rather than the FDA’s CAR-T safety probe that’s playing out in parallel to the company’s label expansion application for Johnson & Johnson-partnered Carvykti.
The FDA’s oncologic drugs advisory committee will convene this Friday to review Legend and J&J’s high-stakes bid to move their Carvykti into second-line treatment of multiple myeloma. Experts will also discuss Bristol Myers Squibb’s submission for rival drug Abecma in the third-line setting. The two applications will be discussed separately in morning and afternoon sessions.
Because the sessions are separate, “it’s not necessarily a panel on the CAR-T class,” Huang said during a Monday call with analysts and investors. “I believe each application will be discussed and also debated by the KOLs and also the agency on its merit.”
The meeting will focus on patient survival data from the medicines’ clinical trials. But it also comes as the FDA pushes for boxed warnings highlighting the risk of patients developing secondary T-cell cancers on the labels of all commercial CAR-T drugs.
Despite the boxed warning issue, the meeting will focus on Carvykti’s overall survival benefit rather than any specific toxicities, Huang said Monday.
However, because the FDA views overall survival as a measurement of both efficacy and safety, and because some patient deaths were not related to tumor relapse, the topic of toxicity will inevitably be included in the discussion.
Legend’s announcement in January about the FDA’s plan to convene an advisory committee meeting—and its focus on overall survival—was a bit surprising. An interim analysis of the CARTITUDE-4 trial previously showed a positive trend toward a 22% reduction in the risk of death for Carvykti—compared with standard combinations—in multiple myeloma patients who had tried one to three prior lines of therapy.
Since that first interim analysis, performed with data cut on Nov. 1, 2022, Legend and J&J have submitted to the FDA two more updates on overall survival, the CEO said Monday. The most recent data cut occurred on Dec. 13, 2023, according to Huang.
“We firmly believe that Carvykti provides overwhelming benefit in the [progression-free survival] and also overall survival endpoints here,” Huang said.
For its part, BMS will need to defend Abecma, which showed no life extension benefit—and instead a negative 1% trend in overall survival—compared with standard combinations in the KarMMa-3 study in patients who had previously tried two to four prior lines of treatment.
BMS has attributed the lack of overall survival showing to a high, 56% crossover rate in which patients in the control arm went on to receive Abecma after disease progression. However, the FDA’s oncology department appears unwilling to tolerate any negative trend in overall survival, even if trial crossover is to blame.
“[W]hile crossover and lack of power may attenuate the ability to detect an OS difference, they should not result in a negative effect on the observed OS,” a group of FDA staffers, including the agency’s oncology chief, Richard Pazdur, M.D., wrote in a recent article published in the Journal of Clinical Oncology.
By comparison, Carvykti’s CARTITUDE-4 does not allow for patient crossovers. This may raise some eyebrows given the FDA’s support for crossover trial designs, as well as possible questions about whether the lack of crossover actually gave Carvykti its survival edge.
Although the control arm patients cannot receive Carvykti following progression under the trial’s protocol, they can access commercially available therapies, including the two commercial CAR-Ts or bispecifics, or even enroll in new clinical studies, Huang noted. The FDA is expected to release more data on those patients later this week. A direct comparison between Carvykti and a subset of control patients who subsequently received a commercial CAR-T may clarify the drug’s overall survival profile in an earlier-line setting.
Huang said he doesn’t expect the crossover restriction to be a focus of Friday’s debate because J&J and Legend had frequent communications with the FDA about the trial protocol before its initiation.
In addition to moving into earlier lines of treatment, J&J and Legend also hope to expand Carvykti’s manufacturing qualification measurements so that fewer products will be deemed out of specification. In the last nine months, Carvykti’s out-of-spec rate is in the “teens range,” Huang said, referring to the partners’ rate of production failures.
Carvykti has recently become the market leader between the two BCMA CAR-T therapies. Full-year net sales of Carvykti reached $500 million last year, versus $472 million for Abecma. In the U.S., with the drugs’ current late-line approvals, Carvykti holds about 80% of the market share at treatment centers that offer both therapies, Steve Gavel, Legend’s commercial chief for the U.S. and Europe, said during Monday’s call.
Carvykti’s failure to capture the remaining 20% of the market is largely due to supply constraints, Gavel said. Lately, J&J and Legend have been busy expanding their capacity despite uncertainty around the outcome of their earlier-line application with the FDA.
The companies’ cell processing site in Ghent, Belgium, in January produced the first batch of Carvykti for clinical use, and commercial production is expected to commence in the second half of the year, Huang said. Plus, construction on a second manufacturing facility in Belgium is expected to be complete at the end of the year.
The pair also aims to apply for two capacity increases at their New Jersey plant with the FDA this year, Huang added, although he declined to offer any details other than the stated goal to achieve an annual capacity of 10,000 doses by the end of 2025.