The approval was based on findings from the phase 2 KarMMa trial and the phase 1 Study CRB-401 trial.
This content originally appeared on our sister site, OncLive.
Idecabtagene vicleucel (ide-cel; Abecma) has been approved in Japan for the treatment of adult patients with relapsed or refractory multiple myeloma, who have previously received at least 3 therapies, including an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody, and have progressed on their last therapy or relapsed following their last therapy.1
The regulatory decision was made based on data by from the phase 2 KarMMa trial (BB2121-MM-001; NCT03361748), and the phase 1 Study CRB-401 trial (NCT02658929).
Data from KarMMa showed that the CAR T-cell therapy, given at a target dose of 150, 300, or 450 x 106, elicited an overall response rate (ORR) of 73.4% (95% CI, 65.8%-81.1%) in 128 non-Japanese patients, which was determined to be statistically significant compared with the threshold of 50%. Among the 8 Japanese patients enrolled to the trial, the ORR with ide-cel was even higher, at 88.9% (95% CI, 51.8%-99.7%).
Findings from the dose-expansion portion of the CRB-401 trial showed that among 62 patients who received the product at a target dose of 50, 150, 450, or 800 x 106 (dose-escalation phase; n = 21) or target doses of 150 or 450 x 106 (dose-expansion phase; n = 41), the ORR was 74.2% (95% CI, 61.5%-84.5%). In the 38 patients who specifically received ide-cel at a target dose of 450 x 106, the ORR was 84.2% (95% CI, 68.7%-94.0%).
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“I am delighted that [ide-cel] has been approved as the first CAR T-cell therapy in Japan targeting BCMA. We hope that this cell therapy will bring new hope to patients suffering from relapsed or refractory multiple myeloma,” Tadao Ishida, MD, PhD, of the Japanese Red Cross Medical Center, and clinical trial investigator, stated in a press release.
The KarMMa trial enrolled patients with relapsed/refractory disease who had previously received at least 3 prior regimens with at least 2 consecutive cycles each, or a best response of progressive disease.2 Patients needed to have been previously exposed to an IMiD, a PI, and a CD28-directed monoclonal antibody; they also needed to have been refractory to the last therapy received.
Those manufacturing process began with leukapheresis, which was followed by bridging therapy at least 14 days prior to lymphodepletion, which was comprised of fludarabine at 30 mg/m2 and cyclophosphamide at 300 mg/m2 on days -5, -4, -3, and 0. Participants then received a single infusion of the CAR T-cell therapy.
The primary end point of the trial was ORR, and key secondary end points included complete response (CR) rate, safety, duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics, minimal residual disease, quality of life, and health economics and outcomes.
The median age of study participants was 61 years (range, 33-78) and 59% were male. Moreover, 53% had an ECOG performance status of 1, 70% had stage II disease, 35% had high-risk cytogenetics, 51% had high tumor burden, 85% had a tumor BCMA expression of 50% or higher, and 39% had extramedullary disease.
The median time since initial diagnosis was 6 years (range, 1-18), and the median number of prior anti-myeloma regimens received was 6 (range, 3-16). Ninety-four percent of patients previously underwent autologous stem cell transplant, 34% underwent more than 1 procedure, and 88% received bridging therapies for their disease. Notably, 94% of patients were refractory to CD38-directed monoclonal antibodies, 84% were triple-class refractory, and 26% were penta-refractory.
Data presented during the 18th International Myeloma Workshop showed that at a median follow-up of 24.8 months (range, 1.7-33.6), the ORR achieved with the CAR T-cell therapy was 73% among those who received 3 prior lines of therapy (n = 15); in those who received at least 4 prior lines of treatment (n = 113), the ORR was also 73%. In both subsets, 20% of patients achieved a partial response (PR). Among those who received at least 4 prior lines of therapy, 23% achieved a very good partial response (VGPR).
The median DOR with ide-cel was 8.0 months (95% CI, 3.3-11.4) in those who received 3 prior lines of therapy, and 10.9 months (95% CI, 9.2-13.5) in those who received at least 4 prior lines of treatment. The event-free DOR rates at 24 months in these subsets were 18.2% and 21.3%, respectively.
Notably, those who experienced a CR with ide-cel had a median DOR of 21.5 months (95% CI, 12.5–not evaluable [NE]), those who had a VGPR had a median DOR of 10.4 months (95% CI, 5.1-12.2), and those who experienced a PR had a median DOR of 4.5 months (95% CI, 2.9-6.7).
Among those who received 3 prior lines of treatment, the median PFS was 8.6 months (95% CI, 2.8-12.1); the median PFS in those who received at least 4 prior lines was 8.9 months (95% CI, 5.4-11.6). The over OS rate at 1 year was 78%; at 1.5 years and 2.0 years, respectively, these rates were 65% and 51%.
Notably, the median OS was noted to have exceeded 20 months across various high-risk patient subsets. In those with extramedullary disease, the median OS was 20.2 months (95% CI, 15.5-28.3) vs NE (95% CI, 21.3–NE) in those without. In those with triple-class refractory disease, the median OS was 21.7 months (95% CI, 18.2–NE) vs 31.2 months (95% CI, 19.9–NE) in those without.
Regarding safety, adverse reactions were reported in 134 out of 137 patients who received the CAR T-cell therapy in the KarMMa trial, this included 9 Japanese patients. Toxicities included cytokine release syndrome (CRS; 84.7%), neutropenia (59.9%), thrombocytopenia (45.3%), anemia (38.0%), leukopenia (27.7%), fatigue (16.1%), lymphopenia (14.6%), hypogammaglobulinemia (11.7%), and pyrexia (10.2%).
On the CRB-401 trial, 55 of 62 patients who received the CAR T-cell therapy reported adverse reactions, which included CRS (75.8%), neutropenia (41.9%), thrombocytopenia (40.3%), anemia (38.7%), fatigue (32.3%), leukopenia (27.4%), nausea (14.5%), headache (14.5%), hypophosphatemia (12.9%), and upper respiratory tract infection (11.3%).
“To make full use of this new CAR T-cell therapy, the cooperation and collaboration of doctors and others who will be involved in its dispensation will be essential. It will also be important for doctors to work closely with companies involved,” Ishida added in the release. “We will work diligently to develop a robust treatment system incorporating the proper use of [ide-cel] so that we can contribute to the treatment of as many patients with multiple myeloma as possible.”
In May 2021, the FDA approved ide-cel as the first BCMA-directed CAR T-cell therapy for patients with relapsed or refractory multiple myeloma following 4 or more prior lines of therapy, including an IMiD, a PI, and a CD38-targeted monoclonal antibody.3 The decision was supported by earlier findings from KarMMa.