FDA: Idecabtagene Vicleucel Myeloma BLA Needs Further Details

The FDA has issued a Refusal to File letter to Bristol Myers Squibb and bluebird bio, Inc., regarding their Biologics License Application (BLA) for the BCMA-directed CAR T-cell therapy decabtagene vicleucel (ide-cel; bb2121) for patients with heavily pretreated relapsed/refractory multiple myeloma.¹

In its initial review, the agency concluded that additional information was needed for the Chemistry, Manufacturing and Control module of the BLA. The FDA did not ask for any further clinical or nonclinical data according to the companies, which plan to resubmit the application by the end of July of this year.

The BLA, which was submitted in March 2020,2 is specifically 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. The application is supported by data from the phase 2 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 end point 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 1 CRB-401 trial.

In updated findings of the phase 1 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.3 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 2 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 end point was ORR as assessed by an independent review committee according to International Myeloma Working Group criteria, and the key secondary end point was CR rate; additional secondary end points 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 1 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 Provide Regulatory Update on Idecabtagene Vicleucel (ide-cel, bb2121) for the Treatment of Patients with Multiple Myeloma. Published May 13, 2020. https://bit.ly/3bA5n1T. Accessed May 13, 2020.
2. 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.
3. 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.