Cilta-Cel FDA Rolling Submission Completed for Multiple Myeloma

The rolling submission of a biologics license application to support the approval of the investigational BCMA-directed CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) for the treatment of patients with relapsed/refractory multiple myeloma has been completed.¹

Results from the phase 1/2 CARTITUDE-1 trial (NCT03548207), presented during the 2020 ASH Annual Meeting, demonstrated that cilta-cel resulted in a high response rate with an acceptable toxicity profile in this patient population.²

The CAR T-cell therapy elicited an objective response rate (ORR) of 96.9%, when delivered at the recommended phase 2 dose; this included a 67.0% stringent complete response (sCR) rate, a 25.8% very good partial response (VGPR) rate, and a 4.1% partial response rate.

The phase 1b/2 trial evaluated the safety and efficacy of cilta-cel in patients with progressive disease defined by the International Myeloma Working Group criteria who had received at least 3 prior therapies which included a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted treatment; patients also could have been double refractory. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1.

Patients who underwent screening and were enrolled to the study then underwent apheresis and bridging therapy, if needed. Once that was completed, participants were given lymphodepleting chemotherapy which contained cyclophosphamide at 300 mg/m² and fludarabine at 30 mg/m² on days -5 to -3 prior to CAR T-cell administration. The target dose of cilta-cel was 0.75 x 10⁶ viable CAR-positive T cells/kg; the median dose administered was 0.71 x 10⁶ (range, 0.51-0.95 x 10⁶).

The primary end points of the phase 1b portion of the trial was safety and to determine the recommended phase 2 dose. The primary objective of the second phase of CARTITUDE-1 was efficacy per ORR.

Earlier data from the first phase of the trial showed that all 29 participants responded to treatment with cilta-cel and this had comprised a VGPR or higher rate of 97%.³

The data presented at ASH looked at all patients who received cilta-cel in both phases of the trial (n = 97). Eighty-six percent of patients were still on the trial at the time of the presentation. The median time for product manufacturing was 29 days. Notably, none of the participants discontinued the study due to a manufacturing failure.

Additional findings showed that 72.2% of patients were still responsive to the CAR T-cell product at the time of data cutoff. The median time to first response with cilta-cel was 1 month. Among 57 evaluable patients, the minimal residual disease negativity rate at 10^-5 was 93.0%, and this represented 54.6% of the total study population.

The median progression-free survival (PFS) had not yet been reached in cilta-cel responders. The PFS rate at 1 year was 76.6%; this rate was even higher, at 84.5%, in those who achieved a sCR. In those who had a VGPR, the 1-year PFS rate was 68.0%. The median overall survival (OS) had not yet been reached either; the OS rate at 1 year was 88.5%.

Additional data from CARTITUDE-1 presented during the Virtual 47th Annual Meeting of the EBMT showed that 57.9% of patients (n = 33) achieved MRD negativity and sCR and 86.0% experienced MRD negativity and a VGPR or better. The median time to MRD 10^-5 negativity was 1 month (range, 0.8-7.7). Of the participants who had 6 months of individual follow-up, most had cilta-cel CAR+ T cells below the level of quantification in their peripheral blood.

The most commonly experienced adverse effects that were grade 3 or 4 in severity and were reported by 99.0% of patients included neutropenia (94.8%), anemia (68.0%), leukopenia (60.8%), and thrombocytopenia (59.8%). Additionally, 57.7% of patients reported any-grade infections, with the most common grade 3 or 4 infections of pneumonia (8.2%) and sepsis (4.1%).

The majority of patients, or 94.8%, had any-grade cytokine release syndrome (CRS), but only 4.1% of these effects were determined to be grade 3 or 4 in severity. About 69.0% of patients needed to receive treatment with tocilizumab (Actemra), while 21.6% required corticosteroids. Almost 99% of patients had their CRS resolve within 2 weeks of onset.

References

1. Form 20-F Legend Biotech Corp: Annual and transition report of foreign private issuers [sections 13 or 15(d)]. Accessed April 6, 2021. https://bit.ly/3fLKJ4h
2. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell Maturation Antigen-directed chimeric antigen receptor T cell therapy, in relapsed/refractory multiple myeloma. Blood. 2020;136(suppl 1):22-25. doi:10.1182/blood-2020-136307
3. Berdeja JG, Madduri D, Usmani SZ, et al. Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8505. doi:10.1200/JCO.2020.38.15_suppl.8505
4. Madduri D, Berdeja JG, Usmani SZ, et al. CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen–directed chimeric antigen receptor t cell therapy, in relapsed/refractory multiple myeloma. Presented at: 47th Annual Meeting of the European Society for Blood and Marrow Transplantation; March 14-17, 2021; Virtual. Accessed March 17, 2021.