CAR-T with synthetic binder shows ‘very promising’ results in advanced multiple myeloma
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A novel chimeric antigen receptor T-cell therapy induced responses in the first 12 evaluable patients with relapsed or refractory multiple myeloma treated in a phase 1 dose-escalation trial.
Results of the study — presented during the virtual ASCO Annual Meeting — showed all but one patient who received CART-ddBCMA had an ongoing response to therapy as of the data cutoff date.
CART-ddBCMA (Arcellx) is an autologous, gene-edited CAR T-cell therapy that targets the B-cell maturation antigen (BCMA) on the surface of cancer cells.
The investigational agent has been granted both fast track and orphan drug designations by the FDA for patients with relapsed or refractory multiple myeloma.
The CAR T-cell therapy uses a novel synthetic binding domain to target BCMA, unlike the animal-derived or humanized binders used in other BCMA-directed CAR-T constructs, according to Matthew J. Frigault, MD, assistant professor and clinical director of the cellular therapy service at Mass General Cancer Center, and member of the Cell Therapy Next Peer Perspective Board.
“It has been engineered to not cause an immune response,” he told Healio. “The binder on CART-ddBCMA was made so that it is less immunogenic and may not be recognized by the host immune system as readily.”
The phase 1, multicenter ARC-101 study enrolled 16 patients with relapsed or refractory multiple myeloma at one of two dose levels. Study participants were either triple-refractory or received at least three previous treatment regimens — including proteasome inhibitors, immunomodulatory agents and anti-CD38 antibodies.
Frigault reported results of the first 12 treated patients. Six (median age, 73 years; range, 66-75; n= 3 men; median prior lines of therapy, five) received the first dose level of 100 × 106 CAR T cells, and six (median age, 60 years; range, 53-65; n = 5 men; median prior lines of therapy, four) received 300 × 106 CAR T cells.
Patients received CART-ddBCMA after undergoing lymphodepletion chemotherapy with 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine.
Safety as measured by incidence of treatment-related adverse events and dose-limiting toxicities served as the study’s primary endpoint. Secondary endpoints included clinical response based on International Myeloma Working Group criteria, minimal residual disease (MRD) status, duration of response, PFS and OS.
Median follow-up was 197 days (range, 29-449), with a data cutoff date of April 14.
Results showed cytopenias were the most common grade 3 or grade 4 treatment-related adverse events, experienced by all patients in the study. However, no patients experienced grade 3 or grade 4 infections after infusion.
Cytokine release syndrome occurred in 11 of the 12 patients; however, only one patient — who received the higher dose level — had grade 3 CRS. One patient in the lower-dose group had grade 1 to grade 2 neurotoxicity and one patient in the higher-dose group had grade 3 neurotoxicity. Researchers reported no dose-limiting toxicities.
Frigault said he was “very encouraged” by the safety results so far, especially for a study population he described as older and having a heavy disease burden.
“I think it is very promising despite the small numbers in the study,” he told Healio. “I am very optimistic that patients will tolerate this therapy well.”
Efficacy results showed an overall response rate of 100%. Six patients had a complete response to therapy, including five with a stringent complete response.
Four of the stringent complete responses occurred in the lower-dose group. This result, coupled with the favorable safety profile, led the researchers to choose the 100 × 106 CAR T-cell dose level for further study, Frigault said.
Patients continue to be enrolled at the lower dose level and a phase 2 study is planned, he added.
Ten patients had MRD-negative status as of their last follow-up, and 11 had ongoing responses to therapy as of the data cutoff date.
Frigault said responses seen so far in this study are clinically meaningful and have been demonstrated even by patients who received previous BCMA-targeted therapy.
“We are seeing ongoing responses past a year,” he told Healio. “Our very first patient remains in response around 450 days since infusion.”
These early results show the safety and efficacy of CART-ddBCMA to be on par with that of other BCMA-directed CAR T-cell therapies for multiple myeloma.
"We need more time to evaluate the durability of the responses in this study,” Frigault said, “but I think all this looks very promising.”
Perspective
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Lisa Butterfield, PhD
The early data presented by Frigault and colleagues show very promising response rates for the 12 patients reported, although some systemic toxicity common to adoptive cell therapies were observed and treated. There are no translational or correlative data reported thus far. The biology of the infused T cells will be interesting and important, and there may be different critical quality attributes for these cells and their novel receptors compared with commercially approved CAR T cells and their engineered constructs. There may be different in vivo trafficking patterns observed in this setting, as well, and the early clinical success will support such investigations.
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Frigault MJ, et al. Abstract 8015. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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