FDA Grants Priority Review to Idecabtagene Vicleucel for Multiple Myeloma

The FDA has granted a priority review designation to a biologics license application (BLA) for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of adult patients with multiple myeloma who have received at least 3 previous therapies, including a proteasome inhibitor (PI), an immunomodulatory (IMiD) agent, and an anti-CD38 antibody, according to an announcement from Bristol Myers Squibb.¹

The BLA is based on data from the pivotal phase 2 KarMMa trial (NCT03361748), which showed that the BCMA-targeting CAR T-cell product elicited a response in nearly three-fourths of heavily pretreated patients with relapsed/refractory multiple myeloma treated on the trial.

Results presented during the 2020 ASCO Virtual Scientific Program overall response rate (ORR) with ide-cel was 73%, which included a complete response (CR) rate of 33%.² The median duration of response (DOR) with the product was 10.7 months and the median progression-free survival (PFS) was 8.8 months (95% CI, 5.6-11.6).

Under the Prescription Drug User Fee Act, the FDA must make a decision on the BLA by March 27, 2021.

“Today’s priority review milestone recognizes the potential of this first anti-BCMA CAR T cell therapy to address a critical unmet need of patients with multiple myeloma,” Stanley Frankel, MD, senior vice president of Cellular Therapy Development at Bristol Myers Squibb, stated in a press release. “We are pleased by the significant progress that is being made in partnership with patients and the multiple myeloma community to bring ide-cel to adults with relapsed and refractory multiple myeloma who are triple-class exposed and may benefit from an important new therapeutic option.”

In March 2020, Bristol Myers Squibb and bluebird bio, Inc., the codevelopers of ide-cel, submitted the BLA to the FDA for the CAR T-cell therapy to be used as a treatment for adult patients with multiple myeloma who received at least 3 previous treatments, including an IMiD, a PI, and an anti0CD38 antibody.

In May 2020, however, the FDA issued a Refusal to File letter to the companies regarding the BLA. Following initial review, the regulatory agency concluded that additional data were needed regarding the Chemistry, Manufacturing, and Control module of the BLA.³ The FDA did not request any further clinical or nonclinical data. In July 2020, the companies submitted a new BLA for ide-cel, which included additional information to address the requests issued by the agency.

KarMMA included a total of 128 patients with relapsed/refractory multiple myeloma who had received at least 3 previous therapies, including an IMiD, a PI, and an anti-CD39 antibody. The median age of the participants was 61 years, and 35% of patients had high-risk cytogenetics. About half of patients, or 51%, had high tumor burden, while 39% had extramedullary disease and 85% had 50% or higher tumor BCMA expression. Forty-five percent of participants had an ECOG performance status of 0, 53% had a status of 1, and 2% had a status of 2. R-ISS stage disease was I in 11% of patients, II in 70% of patients, and III in 16%. Overall, participants had received a median of 6 previous treatments (range, 3-16).

The majority of patients, or 94%, had undergone 1 previous autologous stem cell transplant; 34% had undergone more than 1 of these procedures. Moreover, 88% of participants had been given bridging therapies during CAR T-cell manufacturing, but only 4% responded to that treatment. Ninety-four percent of patients proved to be refractory to anti-CD38 antibodies, and the majority, or 84%, were determined to be triple refractory.

In the trial, participants were given at the following CAR T cell doses: 150 x 106 (n = 4), 200 x 106 (n = 70), or 450 x 106 (n = 54). The median follow-up was 18 months for the first dosing cohort, 15.8 months in the second, and 12.4 months in the third. Across the entire study population, the median follow-up was 13.3 months. The primary end point of the trial was ORR, and key secondary end points were comprised of CR, DOR, PFS, overall survival (OS), and quality of life.

In the whole study population, the ORR with ide-cel was 73% (95% CI, 65.8-81.1; P <.0001); this included a CR rate of 33% (95% CI, 24.7-40.9; P <.0001), a very good PR rate of 20%, and a PR rate of 21%. Of those who achieved a CR, 26% experienced a CR/stringent CR (sCR) and had minimal residual disease (MRD) negativity, and 7% achieved a CR/sCR who did not have MRD information available. The median time to the first response was 1 month, while the median time to CR was 2.8 months.

Clinical benefit in terms of response was reported across all subgroups analysed, regardless of age, risk categorization, tumor burden, BCMA expression, extramedullary disease, triple-refractory status, penta-refractory status, and bridging therapy.

As the target dose increased, PFS benefit was also found to increase. The median PFS in those who received the highest dose of 450 x 106 was 12.1 months (95% CI, 8.8-12.3). Median PFS was also increased by depth of response with a median of 20.2 months (95% CI, 12.3–not evaluable [NE]) in those who experienced a CR/sCR.

Although the survival data were immature at the time of the presentation, the median OS was reported to be 19.4 months (95% CI, 18.2-NE), with a 78% 1-year OS rate.

With regard to safety, 18% of patients experienced 1 or more neurotoxic effects. Nineteen cases of grade 1 or 2 neurotoxicity were reported, along with 4 cases of grade 3 neurotoxicity. No grade 4 or 5 effects were reported. The median time to the onset of neurotoxicity was 2 days and patients experienced the toxicity for a median duration of 3 days. Two percent of these patients were given tocilizumab (Actemra) to manage the effect, while 8% were given corticosteroids.

Cytopenia was another significant adverse effect reported with the CAR T-cell product. Ninety-one percent of patients experienced neutropenia, 89% of which were grade 3 in severity, and 63% reported thrombocytopenia. The median time to recovery for these patients was 2 months and 3 months, respectively.

Five deaths were reported within 8 weeks of the infusion of ide-cel; 2 of these were post disease progression, and 3 were attributed to AEs: cytokine release syndrome, aspergillus pneumonia, and gastrointestinal hemorrhage. An additional toxicity-related death occurred within 6 months of infusion, which was due to cytomegalovirus pneumonia.

Previously, ide-cel was granted a breakthrough therapy designation by the FDA, as well as a PRIority Medicines designation. The Marketing Authorization Application for the CAR T-cell product was also validated by the European Medicines Agency for relapsed and refractory multiple myeloma. Regulatory submissions for ide-cell in additional markets outside of the United States and the European Union are planned, according to Bristol Myers Squibb.

References

1. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T Cell therapy idecabtagene vicleucel (ide-cel; bb2121). News release. Bristol Myers Squibb and bluebird bio, Inc. September 22, 2020. Accessed September 22, 2020. https://bit.ly/2G0K3Iq.
2. Munshi NC, Anderson LD, Shah N, et al. Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): initial KarMMa. J Clin Oncol. 2020;38(suppl 15):8503. doi:10.1200/JCO.2020.38.15_suppl.8503
3. Bristol Myers Squibb and bluebird bio provide regulatory update on idecabtagene vicleucel (ide-cel, bb2121) for the treatment of patients with multiple myeloma. News release. Bristol Myers Squibb and bluebird bio, Inc. May 13, 2020. Accessed September 21, 2020. https://bit.ly/3bA5n1T.