FDA Approves Earlier Use of CAR-T Products for Myeloma

The FDA expanded the labels of two CAR T-cell products for multiple myeloma, allowing their use in earlier lines of treatment for relapsed or refractory disease.

Ciltacabtagene autoleucel (cilta-cel; Carvykti) is now approved as a second-line therapy for patients who are refractory to lenalidomide (Revlimid), an immunomodulatory agent, and whose prior line of therapy also included a proteasome inhibitor, Johnson & Johnson announced.

Idecabtagene vicleucel (ide-cel; Abecma), meanwhile, is now approved as a third-line option for patients with triple-class-exposed disease, meaning they have been treated with an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, said Bristol Myers Squibb.

FDA's move followed a recent meeting of the Oncologic Drugs Advisory Committee (ODAC), held due to concerns over an early increased risk for death compared with standard regimens in trials of the two B-cell maturation antigen (BCMA)-targeted agents. But ultimately, ODAC members said the benefits outweighed the risks in these earlier lines, with votes of 11-0 for cilta-cel and 8-3 for ide-cel.

Carvykti

Expanded approval of cilta-cel was based on findings from CARTITUDE-4, a phase III study that randomized 419 patients with lenalidomide-refractory myeloma to cilta-cel or one of two standard-of-care regimens: pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone; or daratumumab (Darzalex), pomalidomide, and dexamethasone.

At a median follow-up of 15.9 months, median progression-free survival (PFS) was not reached in the cilta-cel group as compared with 11.8 months in the standard-care group (HR 0.26, 95% CI 0.18-0.38, P<0.001). Rates of overall response (85% vs 67%) and complete response (73% vs 22%) were both superior with the CAR-T product.

"Carvykti demonstrated remarkable efficacy as a personalized, one-time infusion in the earlier treatment of relapsed/refractory multiple myeloma as shown through the CARTITUDE-4 study results," said investigator Binod Dhakal, MD, of the Medical College of Wisconsin in Milwaukee, in a statement from the drugmaker. "With this approval, I'm excited for patients who may have the opportunity for a treatment-free period for their multiple myeloma as early as first relapse, with the hope of eliminating the burden of having to be on continuous treatment while living with this challenging disease."

Despite the PFS benefits in the trial, 14% of patients assigned to cilta-cel died during the first 10 months of follow-up as compared with 12% among those in the standard-of-care arm. However, overall survival rates at 12 months were similar (84.1% vs 83.6%).

In the safety cohort, which also included similar patients from another cilta-cel trial, cytokine release syndrome (CRS) of any grade occurred in 84% of patients, including grade ≥3 events in 4%.

Abecma

The third-line approval of ide-cel was based on findings from the KarMMa-3 trial, which included 386 patients randomized 2:1 to either the CAR-T product or a standard regimen for myeloma chosen based on prior treatment history:

• Daratumumab, pomalidomide, and dexamethasone
• Daratumumab, bortezomib, and dexamethasone
• Ixazomib (Ninlaro), lenalidomide, and dexamethasone
• Carfilzomib (Kyprolis) and dexamethasone
• Elotuzumab (Empliciti), pomalidomide, and dexamethasone

The phase III study demonstrated a significant improvement in PFS for patients receiving the one-time infusion of ide-cel (median 13.3 vs 4.4 months; HR 0.49, 95% CI 0.38-0.65, P<0.0001), meeting the primary endpoint.

Furthermore, 71% of patients on the CAR-T product responded versus 42% of those assigned to standard care (P<0.001), with complete responses occurring in 39% and 5%, respectively. Responses with ide-cel proved durable, reaching a median 14.8 months for all responders and 20 months for complete responders.

"The results of the KarMMa-3 study are remarkable, especially given the historic outcomes with standard regimens for these patients with relapsed or refractory disease," said Al-Ola A. Abdallah, MD, of the University of Kansas Medical Center , in a statement from Bristol Myers Squibb. "With this approval, these patients now have an opportunity to be treated at an earlier line of therapy with a potentially transformative therapy that offers significantly improved progression-free survival for this difficult-to-treat disease that has had no established treatment approach."

Unlike cilta-cel, ide-cel will carry a warning about an early risk of death. In KarMMa-3, 18% of patients in the ide-cel arm died within 9 months of randomization versus 11% in the standard regimen arm, with nearly half of the deaths in the ide-cel arm occurring prior to infusion.

In the safety cohort, CRS occurred in 89% of patients, including grade ≥3 events in 7% and three CRS-related deaths (0.9%). Neurotoxicity occurred in 40% of patients, including grade 3 events in 4%, two grade 4 cases, and one neurotoxicity-related death.

Safety Warnings

Both products carry boxed warnings over the risks for secondary hematologic malignancies (including T-cell malignancies), CRS, immune effector cell-associated neurotoxicity syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenias. Cilta-cel also carries a boxed warning for parkinsonism and Guillain-Barre syndrome.

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