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The FDA has extended the Prescription Drug User Fee Act target date for the biologics license application seeking the approval of the CAR T-cell therapy ciltacabtagene autoleucel for use in adult patients with relapsed and/or refractory multiple myeloma.
The FDA has extended the Prescription Drug User Fee Act target date for the biologics license application (BLA) seeking the approval of the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) for use in adult patients with relapsed and/or refractory multiple myeloma.1
On October 28, 2021, Janssen was alerted of the extension to allow for adequate time to review recently submitted data associated with an updated analytical method following an information request issued by the regulatory agency. Shortly after, on November 1, 2021, Janssen and Legend Biotech Corporation met with the FDA, and no additional clinical data were requested.
The BLA for cilta-cel was based on findings from, the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which showed that when the product was administered at the recommended phase 2 dose of 0.75 x 106 CAR-positive viable T cells per kg, it resulted in an overall response rate (ORR) of 97.0% (95% CI, 91.2%-99.4%) among 97 patients.2,3 The stringent complete response (sCR) rate was 67% and the time to first response was 1 month (IQR, 0.9-1.0).
Moreover, responses were found to deepen over time, and the median duration of response (DOR) was not yet reached at a median follow-up of 12.4 months (IQR, 10.6-15.2). Moreover, the median progression-free survival (PFS) with the product was also not yet reached (95% CI, 16.8–not estimable). The PFS rate at 12 months was 77% (95% CI, 66.0%-84.3%) and the overall survival (OS) rate was 89% (95% CI, 80.2%-93.5%).
The new decision date for the application is February 28, 2022.
“We are working closely with Janssen and the FDA to facilitate an efficient and thorough review of the BLA for cilta-cel,” Ying Huang, PhD, chief executive officer and chief financial officer at Legend Biotech Corporation, stated in a press release. “We remain confident that cilta-cel has shown great promise in patients with relapsed and refractory multiple myeloma, and we are focused on making this therapy available to them in the United States as soon as possible.”
The single-arm, open-label, phase 1b/2 trial enrolled patients with multiple myeloma who were at least 18 years of age, had measurable disease at screening, and an ECOG performance status of 0 or 1. Patients needed to have previously received 3 or more prior lines of therapy or become double refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and have received a PI, IMiD, and an anti-CD38 antibody, with documented progressive disease.
If patients previously received treatment with a CAR T-cell– or BCMA-targeted therapy, they were excluded.
Patients’ blood was apheresed in accordance with institutional standards. Between apheresis and CAR T-cell infusion, patients were permitted to receive bridging therapy if clinically indicated. After the successful manufacturing of cilta-cel, patients underwent lymphodepletion with cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2, both administered daily for 3 days. Five to 7 days following the initiation of lymphodepletion, patients were administered a single infusion at a target dose of 0.75 x 106 CAR-positive viable T cells/kg (range, 0.5 x 106-1.0 x 106).
The primary end point of the phase 1b portion of trial was to examine the incidence and severity of adverse effects (AEs). The primary end point of the phase 2 portion was ORR. Secondary end points in both phases included sCR, complete response (CR), very good partial response (VGPR), DOR, rate of minimal residual disease negativity, PFS, and OS. Investigators also evaluated pharmacokinetic and pharmacodynamic markers.
A total of 113 patients were enrolled to the trial and all underwent apheresis. Fourteen percent of patients did not receive the CAR T-cell therapy because of progressive disease (n = 2), study withdrawal (n = 2), or death (n = 8). A total of 101 patients underwent lymphodepletion; of these patients, 4 discontinued.
A total of 97 patients received cilta-cel; 29 of these patients received the product in the phase 1b portion and 68 did so in the phase 2 portion. Twenty-four patients in the phase 1b portion were still receiving treatment, as were 59 patients in the phase 2 portion.
The median age of patients was 61.0 years (IQR, 56.0-68.0), and 59% of patients were male. Moreover, most patients were White and non-Hispanic or non-Latino. Additionally, 24% of patients had a high-risk cytogenetic profile based on the presence of del(17p), t(14;16), or t(4;14), and 13% had extramedullary plasmacytomas at screening.
The median time from diagnosis was 5.9 years (IQR, 4.4-8.4), and patients received a median of 6 prior therapies (IQR, 4.0-8.0). Eighty-four percent of patients had been exposed to 5 drugs. Moreover, 84% were refractory to pomalidomide (Pomalyst), 65% to carfilzomib (Kyprolis), and 99% to anti-CD38 antibody treatment. Eighty-eight percent of patients were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to their last lane of therapy received.
Additional data showed that among those who achieved a CR or better, the 12-month PFS rate was 85% (95% CI, 72.0%-91.8%). In those who achieved a VGPR, this rate was 62% (95% CI, 42.1%-76.9%). Moreover, response rates were noted to be similar across the prespecified subsets analyzed.
Regarding safety, all patients experienced toxicities, including grade 3 or 4 effects. The most common AEs reported were hematologic in nature; grade 3 or 4 hematologic toxicities included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%).
Those who had grade 3 or 4 cytopenic events following day 1 of CAR T-cell infusion recovered to grade 2 or less by day 30 for lymphopenia (88%), neutropenia (70%), and thrombocytopenia (59%).