FDA Approval Sought for Idecabtagene Vicleucel in 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 multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, according to Bristol Myers Squibb and bluebird bio, Inc., the co-developers of the BCMA-directed CAR T-cell immunotherapy.¹

The BLA is supported by data from the phase II KarMMA trial (NCT03361748), in which idecabtagene vicleucel induced an overall response rate (ORR) of 73.4% in patients with relapsed/refractory multiple myeloma, meeting the primary endpoint of the trial.

Topline results from the trial showed that across the target dose levels of 150 to 450 x 10⁶ CAR T cells, the complete response (CR) rate was 31.3%, the median duration of response (DOR) was 10.6 months, and the median progression-free survival (PFS) was 8.6 months. Additional findings will be presented at an upcoming medical meeting.

Ide-cel is a BCMA-targeting CAR T cell therapy, which is expressed on the surface of normal and malignant plasma cells. In November 2017, the FDA granted breakthrough therapy designation to ide-cel based on the preliminary data from the phase I CRB-401 trial.

In updated findings of the phase I CRB-401 trial, ide-cel induced a median PFS of 11.8 months and a median DOR of 10.8 months in heavily pretreated patients with relapsed/refractory disease.² Additionally, the ORR was 95.5%, the CR or stringent CR rate was 50%, and 36.4% of patients had a very good partial response. In contrast, patients treated with an inactive dose (50 x 106) had an ORR of 33.3% and a 1.9-month median duration of response.

In the open-label, single-arm, multicenter, phase II KarMMa trial, investigators evaluated the efficacy and safety of ide-cel in patients with relapsed/refractory multiple myeloma in North America and Europe. A total 140 patients were enrolled, and 128 patients were treated with the agent across the target dose levels: 150 x 106 CAR T cells (n = 4), 300 x 106 CAR T cells (n = 70), and 450 x 106 CAR T cells (n = 54).

All patients who received treatment had received ≥3 prior therapies, including an immunomodulatory agent, proteasome inhibitor, and a CD38-directed antibody; all patients were refractory to their last regimen. A total 94% of patients were refractory to a CD38-directed antibody while 84% of patients were refractory to all 3 classes of agents.

The primary endpoint was ORR as assessed by an independent review committee according to International Myeloma Working Group criteria, and the key secondary endpoint was CR rate; additional secondary endpoints overall survival, minimal residual disease, and also DOR and PFS across the target dose levels and at each of the 3 target doses.

At a median follow-up of 11.3 months, results showed that for patients treated at the 150 x 10⁶ CAR T-cell dose, the ORR was 50.0% with a 25% CR rate; the median DOR and PFS were not reported due to the small number of evaluable patients. In the 300 x 10⁶ CAR T-cell cohort, the ORR was 68.6%, along with a 28.6% CR rate; the median DOR was 9.9 months, and the median PFS was 5.8 months. Finally, at the 450 x 10⁶ dose, the ORR was 81.5%, the CR rate was 35.2%, and the median DOR and PFS were both 11.3 months.

Regarding safety, the results were consistent with what was observed in the phase I CRB-401 trial. Grade ≥3 cytokine release syndrome (CRS) occurred in 5.5% of patients, and 1 death occurred due to a CRS event; grade ≥3 neurotoxicity events occurred in 3.1% of patients; no grade 4 events were reported. Additionally, grade ≥3 CRS and neurotoxicity events were reported in <6% of each target dose. All-grade CRS and neurotoxicity events occurred in 83.6% and 18% of patients, respectively.

References

1. Bristol Myers Squibb and bluebird bio Announce Submission of Biologics License Application (BLA) for Anti-BCMA CAR T Cell Therapy Idecabtagene Vicleucel (Ide-cel, bb2121) to FDA. Published March 31, 2020. https://bit.ly/2UtAxm6. Accessed March 31, 2020.
2. Raje NS, Berdega JG, Lin BY, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007). doi: 10.1200/JCO.2018.36.15_suppl.8007.