A biologics license application has been submitted to the FDA for idecabtagene vicleucel for the treatment of adult patients with relapsed and refractory multiple myeloma.
A biologics license application (BLA) has been submitted to the FDA for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of adult patients with relapsed and refractory multiple myeloma, according to Bristol Myers Squibb and bluebird bio, Inc., the co-developers of the BCMA-directed CAR T-cell therapy.1
This new submission includes further information on the Chemistry, Manufacturing, and Controls module to address outstanding regulatory requests issued by the agency in May 2020 following the original BLA submission in March 2020.
The new submission is based on topline data from the pivotal phase 2 KarMMa trial (NCT03361748), which were presented during the 2020 ASCO Virtual Scientific Program and showed that the therapy elicited deep and durable responses in heavily pretreated patients with highly refractory disease.2
Notably, both primary and key secondary end points of the trial had been met. The overall response rate (ORR) reported with the CAR T-cell therapy was 73% (95% CI, 65.8-81.1; P <.0001), which included a 33% complete response (CR) rate (95% CI, 24.7-40.9; P < .0001), a 20% very good partial response rate, and a 21% partial response rate. The overall CR rate included 26% of those who achieved a CR/stringent CR (sCR) and minimal residual disease (MRD) negativity, and 7% of patients who had a CR/sCR but who did not have MRD data available. The median duration of response (DOR) with ide-cel was 10.7 months.
“Ide-cel demonstrated frequent, deep, and durable responses in heavily pretreated, highly relapsed/refractory patients with myeloma,” lead study author Nikhil C. Munshi, MD, of Dana-Farber Cancer Institute and Harvard Medical School, said during his presentation. “Overall, ide-cel provides an attractive option for the treatment of patients with triple-class exposed relapsed/refractory myeloma.”
The trial enrolled a total of 128 patients with relapsed/refractory disease who had received at least 3 previous treatments, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.
The median age of participants was 61 months and 35% of patients had high-risk cytogenetics. Approximately half, or 51%, had high tumor burden, 39% had extramedullary disease, and 85% had ≥50% BRCA expression in their tumors. Fifty-three percent of patients had an ECOG performance status of 1, while 45% were 0. Moreover, R-ISS disease stage was I, II, or III, in 11%, 70%, and 16% of patients, respectively. Notably, participants had previous received a median of 6 (range, 3-16) prior regimens for their disease.
The majority of participants, or 94%, had underwent 1 prior autologous stem cell transplant, and 34% of patients had undergone more than 1 procedure. Additionally, 88% of participants reported to have received bridging therapies during CAR T-cell manufacturing, but only 4% had responded to the treatment they were given. Ninety-four percent of patients were refractory to anti-CD38 antibodies, while 84% were triple refractory.
In the trial, 4 patients received CAR+ T cell doses of 150 x 106, 70 patients received a 300 x 106 dose, and 54 patients received the 450 x 106 dose. The median follow-up for the three dosing cohorts was 18 months, 15.8 months, and 12.4 months, respectively. Overall, the median follow-up was 13.3 months.
The primary end point of the trial was ORR, and key secondary end points included CR, DOR, progression-free survival (PFS), overall survival (OS), and quality of life.
Notably, durable responses were observed across all dose cohorts, although ide-cel proved to be most effective when given at the target dose of 450 x 106 CAR+ T cells. For patients who received the therapy at that dose, the ORR was 82%, which included a 39% CR rate. The median DOR was 11.3 months and the median PFS was 12.1 months.
Clinically meaningful efficacy in terms of ORR were reported across subgroups, irrespective of age, risk categorization, tumor burden, BCMA expression level, extramedullary disease, triple-refractory status, penta-refractory status, and bridging therapy.
The median PFS was 8.8 months with ide-cel. However, PFS benefit was found to increase as the target dose increased. Specifically, at the 450 x 106 CAR+ T-cell dose, the median PFS was 12.1 months (95% CI, 8.8-12.3). The median PFS also increased by depth of response with a median of 20.2 months (95% CI, 12.3—not evaluable [NE]) among those who experienced a CR/sCR.
Although the survival data were still immature at the time of the presentation, the median OS was 19.4 months (95% CI, 18.2–NE) among all patients who received the therapy. The 1-year OS rate with ide-cel was 78%.
With regard to safety, the frequency of cytokine release syndrome (CRS) was found to increase with the dose; however, these effects were considered to be mostly low grade. Eighty-four percent of patients experienced ≥1 CRS event, with 78% of cases being grade 1/2. Five cases of grade 3 CRS were reported, 1 case of grade 4, and 1 case of grade 5. The median time to onset of CRS was 1 day and the median duration of the effect was 5 days.
Moreover, 18% of patients experienced ≥1 neurotoxicity event. In total, 19 cases of grade 1/2 neurotoxicity were reported, and there were 4 grade 3 cases. No grade 4 or 5 cases were observed. The median time to onset of neurotoxicity was 2 days with a median duration of 3 days.
Ninety-one percent of patients experienced any-grade neutropenia (89% grade ≥3), and more than half, or 63%, (52% grade ≥3) reported any-grade thrombocytopenia.
Five deaths were reported within 8 weeks of ide-cel infusion; 2 followed disease progression and 3 were due to adverse effects (AEs), namely CRS, aspergillus pneumonia, and gastrointestinal hemorrhage. One other AE-related death, related to cytomegalovirus, occurred within 6 months; this was in the absence of myeloma progression.
The CAR T-cell therapy has previously received a breakthrough therapy designation from the FDA for relapsed and refractory multiple myeloma. The agent has also received a PRIME designation by the European Medicines Agency (EMA) for the same population; its Marketing Authorization Application has also been validated by the EMA.