A novel chimeric antigen receptor (CAR) T-cell therapy induced complete and durable responses in a phase I trial involving patients with heavily pretreated multiple myeloma.
Of 33 patients treated with bb2121, a B-cell maturation antigen (BCMA)-directed product, 85% achieved an objective response, reported James N. Kochenderfer, of the National Cancer Institute in Bethesda, Maryland, and colleagues.
And the agent induced complete and stringent complete responses in 9% and 36%, respectively, they wrote in the New England Journal of Medicine.
“The exciting thing with what was reported with bb2121 is that patients truly are having deep responses,” Sarah Holstein, MD, PhD, of the University of Nebraska Medical Center in Omaha, told MedPage Today. “For many of these patients these responses lasted an average of about a year.”
Median duration of response was 10.9 months in the study, progression-free survival (PFS) was 11.8 months, and all responders who could be evaluated for minimal residual disease (MRD) reached MRD negativity.
Holstein, who was not involved in the research, said the study provides the “first benchmark” for CAR T-cell therapy in multiple myeloma. “From now on, all future CAR T-cell studies are going to refer to this.”
And she noted that other trials of active agents in patients with heavily pretreated disease have yielded response durations “best measured in the 3- to 6-month range,” and with responses not typically as deep as those in the present study.
To that point, the authors highlighted a study of single-agent daratumumab(Darzalex) with a response rate of 29% and median PFS of 3.7 months, as well as a study on pomalidomide (Pomalyst) plus dexamethasone that showed a response rate of 31% and median PFS of 4 months. Similarly, the FDA recently convened an advisory committee to review whether selinexor, an agent that combined with dexamethasone elicited responses in roughly 26% of pretreated myeloma patients, should receive regulatory approval.
Holstein said the next step will be to see if CAR T-cell therapies in earlier lines of myeloma therapy will result in even better responses for patients than current approaches (studies in these settings are ongoing with bb2121 and another BCMA-targeting CAR T-cell agent).
“The million dollar question — or perhaps more, given the cost of these drugs — is really the durability of these responses,” she said. “At this point it’s too early to say that patients are being cured, but even if we can get patients several years’ worth of treatment-free time, that would be an incredible thing for this field.”
Study Details
From 2016 to 2018, the open-label phase I study enrolled 36 patients with relapsed or refractory multiple myeloma at centers across the U.S. who then underwent leukapheresis. Eligible patients had to have been treated with a minimum of three previous lines of therapy, including an immunomodulatory agent and a proteasome inhibitor, but most were far more heavily pretreated than that — median of 7 prior therapies in the dose-escalation group and 8 in an expansion cohort. All patients had been exposed to bortezomib (Velcade) and lenalidomide (Revlimid), and 91%, 94%, and 92% had exposure to carfilzomib (Kyprolis), pomalidomide, and daratumumab, respectively.
The CAR T-cell therapy was successfully manufactured in all patients, but three experienced disease progression prior to the infusion and were unable to receive bb2121.
“Sometimes the problem with CAR T-cell therapy is the amount of time that it takes between collecting the patients’ cells and then finally re-infusing them, and sometimes the myeloma can’t be controlled and patients get too sick to then receive the product,” said Holstein. “Overall, the majority of patients who enrolled in the study in fact received CAR-T therapy, which is a really important point.”
Grade 3/4 adverse events (AEs) were mostly hematologic in nature and included neutropenia (85%), leukopenia (58%), thrombocytopenia (45%), and anemia (45%). Cytokine release syndrome occurred in 76% of patients but were mostly grade 1/2 (70%). Two grade 3 cases (the remaining 6%) resolved within 24 hours. Grade 1/2 neurologic toxicity occurred in 39% of patients, and one reversible grade 4 neurologic event was reported in a patient 11 days post-infusion.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the authors wrote.
“There really were no alarming off-target toxicities that were seen — that’s always a concern because the cellular therapy is so effective,” said Holstein. “Even though BCMA is expressed on plasma cells, there’s always the concern that very low expression in other tissues could be affected by the CAR-Ts, but certainly there’s no indication of that here.”
Prior to the single CAR-T infusion, patients underwent lymphodepletion with fludarabine and cyclophosphamide. During the dose-escalation phase of the study, patients were given CAR T-cell doses ranging from 50×106 to 800×106. During the expansion portion of the trial, doses ranged from 150×106 to 450×106. In all, most patients received the 450×106 dose (n=19). Complete responses were seen in all doses of 150×106 and above. At data cutoff, six of the 15 complete responders had relapsed.
Tumor BCMA expression did not appear to have an impact on treatment response, the authors noted. At the 450×106 dose, response rates were similar among patients with tumor BCMA expression levels below 50% and in those with expression levels of 50% and above.
BCMA “is a member of the tumor necrosis factor superfamily of proteins that is primarily expressed by malignant and normal plasma cells and some mature B cells, making it a potential target for multiple myeloma,” Kochenderfer’s team explained.
Holstein said that since BCMA has been identified as a target in multiple myeloma, the CAR T-cell therapy field has moved along quickly. Current FDA-approved CAR T-cell therapies — such as those for diffuse large b-cell lymphoma and acute myeloid leukemia — target CD19, but myeloma cells really don’t express CD19, she said.
The study was funded by Bluebird Bio and Celgene.
Kochenderfer reported relationships with Celgene, Kite/Gilead, and disclosed patents related to BCMA targeting CAR T-cell therapy. Co-authors disclosed relationships with other industry entities and several are employed by either Bluebird Bio or Celgene.
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