Anitocabtagene autoleucel (anito-cel), an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, produced responses in all treated patients in a phase I study of heavily pretreated relapsed or refractory multiple myeloma, with 79% achieving a complete response. Frigault et al reported the findings in The New England Journal of Medicine.
Anito-cel uses a synthetic d-domain binder designed to detach from BCMA relatively quickly after binding. The investigators also performed laboratory studies to explore whether those binding characteristics might help explain the therapy’s clinical activity and safety profile.
Study Details
The first-in-human study of anito-cel enrolled 40 patients with relapsed or refractory multiple myeloma who had received at least three previous lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, or had triple-class refractory disease. Thirty-eight patients ultimately received the CAR T-cell therapy.
Patients received either 100 × 106 or 300 × 106 CAR-positive T cells. The lower dose was selected as the recommended phase II dose because safety and efficacy appeared similar between the two dose levels.
The population was heavily pretreated, with a median of four previous lines of therapy. All patients had triple-class refractory disease, 68% had penta-drug refractory disease, 32% had extramedullary disease, and 29% had high-risk cytogenetic abnormalities.
The primary endpoints were adverse events during the treatment period and selection of the recommended phase II dose. Response, duration of response, progression-free survival, overall survival, and minimal residual disease (MRD) status were also evaluated.
Key Findings
At a median follow-up of 38.1 months, all 38 treated patients had achieved a response. Thirty patients, or 79%, had a complete response, and 92% achieved a very good partial response or better.
“Anito-cel induced rapid, deep, and durable responses with MRD negativity … in a population of patients with heavily pretreated relapsed or refractory multiple myeloma,” the investigators wrote.
The median duration of response was 29.1 months, and the median progression-free survival was 30.2 months. An estimated 57% of patients remained progression free at 24 months. Median overall survival had not been reached, and 65% of patients were alive at 36 months.
Among 28 patients who could be evaluated for minimal residual disease (MRD), 89% had no detectable disease at a sensitivity of 10-5, or about 1 cancer cell in 100,000 cells. Among patients with sustained MRD negativity for at least 12 months and sufficient follow-up, none had experienced disease progression or death through 33 months after infusion.
Safety findings were a major focus of the phase I study. All treated patients experienced at least one adverse event, and 97% had an event of grade 3 or higher, most commonly cytopenias.
At the recommended phase II dose, cytokine-release syndrome occurred in 94% of patients, but all events were grade 1 or 2. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 19%, including one grade 3 event. No delayed or non-ICANS neurologic toxicities were reported, including no cases of Parkinson-like movement disorders, cranial-nerve palsy, Guillain–Barré syndrome, or colitis.
Grade 3 or higher infections occurred in 16% of treated patients, with no infection-related deaths. Three patients developed myelodysplastic syndrome after anito-cel; all had been heavily pretreated and had received subsequent myeloma therapy, and investigators considered the events unrelated to anito-cel.
In laboratory studies, anito-cel’s BCMA binder detached from its target more quickly than the comparator binder but still killed myeloma cells similarly. It also triggered less cytokine release and showed less unintended activation. The investigators said these findings may help explain the relatively favorable neurologic safety profile seen with anito-cel in this study, although they do not establish that it is safer than other BCMA-directed CAR T-cell therapies.
The authors also cautioned that the study was small and single-arm and was not statistically powered for comparisons among BCMA-directed CAR T-cell products. Anito-cel is being evaluated further in the phase II iMMagine-1 and phase III iMMagine-3 trials.
Michael R. Bishop, MD, of the University of Chicago, is the corresponding author of the study.
DISCLOSURE: The study was funded by Arcellx and Kite, a Gilead company. For full disclosures of the study authors, visit nejm.org.
