In a major win for Johnson & Johnson and Legend Biotech, their star CAR-T therapy Carvykti showed it can prolong the lives of patients with previously treated multiple myeloma.
J&J and Legend announced the “statistically significant and clinically meaningful” overall survival win Tuesday from the phase 3 CARTITUDE-4 trial, which compared Carvykti with standard combination therapies in myeloma patients who had tried one to three prior lines of therapy. The standard regimens used in the study included either Takeda’s Velcade or J&J’s Darzalex in their combinations with Bristol Myers Squibb’s Pomalyst and the corticosteroid dexamethasone.
Even before Tuesday’s positive readout, Carvykti had in April won the FDA’s approval as a second-line therapy for multiple myeloma based on CARTITUDE-4 data showing the BCMA-targeted CAR-T can lower the risk of disease progression or death by 59% versus standard therapies.
Now, the overall survival showing puts Carvykti further ahead of BMS’ rival CAR-T, Abecma, which is approved as a third-line treatment and without evidence of a life extension benefit.
In the phase 3 KarMMa-3 study, Abecma demonstrated a 51% progression-free survival improvement compared with standard combinations in patients who had failed at least two prior lines of therapy. But investigators found no sign of an overall survival benefit before adjusting for control patient crossovers. Given the maturity of the data, KarMMa-3 likely won’t meet statistical significance on the overall survival metric.
Meanwhile, Carvykti’s overall survival win wasn’t a complete surprise. During a prior data cut in late 2023, when about half of deaths had happened for the planned final survival analysis of CARTITUDE-4, Carvykti was linked to a premature 43% reduction in the risk of death, which marked an improvement from the 22% reduction recorded when about a third of deaths had happened. The expanding effect size gave J&J and Legend the hope that a statistically significant win was within reach.
A detailed analysis of CARTITUDE-4 will be presented at an upcoming medical meeting and submitted to regulatory authorities worldwide, J&J and Legend said.
A definitive overall survival benefit could also help Carvykti relieve concerns left from an early death signal flagged by the FDA. Before handing out the second-line approval, the FDA noted that in the first 10 months from randomization, patients assigned to receive Carvykti in CARTITUDE-4 were numerically more likely to die than their control-arm peers. This increased early mortality concern now lives as the first item in the “Warnings and Precautions” section of Carvykti’s label. Abecma has a similar warning.
A group of external advisers to the FDA argued that Carvykti’s longer-term benefits outweigh that early problem, and the agency, in approving Carvykti, agreed.
In another positive development for Carvykti and the CAR-T class, the FDA recently reduced the reporting requirements for all existing CAR-Ts under a safety monitoring program called Risk Evaluation and Mitigation Strategies (REMS).
CAR-T drugs are available only through REMS because of their risks of potentially dangerous cytokine release syndrome (CRS) and neurological toxicities. But, given the experience accrued so far with these individualized cell therapies, the FDA figured that the REMS program should be modified to minimize the burden on the healthcare delivery system. The agency therefore removed the requirement to report adverse events suggestive of CRS or neurological toxicities to the REMS.
With the second-line approval and an expanded patient population, J&J and Legend are working to strengthen their supply of Carvykti with the goal to double capacity by the end of 2024 compared to 2023. Together with the second-line nod, the FDA also widened the specifications for manufacturing Carvykti, which could improve its production success rate.
Besides bringing additional internal capacity online, J&J and Legend recently also tapped Novartis to make Carvykti for commercial and clinical use.