A marketing authorization application has been submitted to the European Medicines Agency for the approval of the CAR T-cell therapy ciltacabtagene autoleucel in the treatment of patients with relapsed and/or refractory multiple myeloma.
A marketing authorization application has been submitted to the European Medicines Agency (EMA) for the approval of the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) in the treatment of patients with relapsed and/or refractory multiple myeloma.1
The application is supported by data yielded from the phase 1b/2 CARTITUDE-1 trial (NCT03548207), which showed that the therapy elicited a high objective response rate (ORR) of 96.9%, when given at the recommended phase 2 dose in this patient population.2 Among responders, the stringent complete response (sCR) rate with cilta-cel was 67.0%, the very good partial response (VGPR) rate was 25.8%, and the partial response rate was 4.1%.
The EMA’s Committee for Medicinal Products for Human Use gave the green light to an accelerated assessment for the application.
“Today’s submission is a testimony to the promising results we have seen from the CARTITUDE-1 study showing the efficacy and safety of cilta-cel for treating patients with multiple myeloma who are heavily pretreated and in need of treatment options,” Ying Huang, PhD, chief executive office and chief financial officer of Legend Biotech, stated in a press release. “We are proud of our collaboration with Janssen and look forward to bringing this personalized treatment to patients in the European Union following the accelerated assessment.”
In the ongoing, multicenter, open-label phase 1/2 trial, investigators are examining the safety and efficacy of the CAR T-cell product in adults with relapsed and/or refractory multiple myeloma.
To be eligible for enrollment, patients had to have disease progression defined by International Myeloma Working Group criteria and have previously received at least 3 therapies that included a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted agent. Additionally, patients had to have an ECOG performance status of 0 to 1. Notably, patients could be double refractory.
Study participants underwent apheresis and bridging therapy, if required. Once completed, they were administered lymphodepleting chemotherapy, which comprised 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine on days -5 to -3 before CAR T-cell administration. The target dose of cilta-cel was determined to be 0.75 x 106 viable CAR-positive T cells/kg and the median dose given was 0.71 x 106 (range, 0.51-0.95 x 106).
The co-primary objectives of the phase 1b portion of CARTITUDE-1 was safety and to identify the recommended phase 2 dose of cilta-cel. In the second phase of the trial, the primary objective was efficacy in the form of ORR.
Previous findings from the first phase of the trial indicated that all 29 patients who received cilta-cel responded to the treatment. Among these patients, the VGPR or higher rate with the CAR T-cell product was reported to be 97.0%.3
Additional cilta-cel data presented during the 2020 ASH Annual Meeting indicated that 97 patients received the product across both phases of the trial and 86% were still on trial at the time of the presentation. The median manufacturing time for cilta-cel was 29 days and no one withdrew from the study because of a manufacturing failure.
The median progression-free survival (PFS) with the CAR T-cell product had not yet been reached, while the 1-year PFS rate was estimated to be 76.6%; this rate was even higher, at 84.5%, in those who had experienced a sCR. Among the participants who achieved a VGPR, the 1-year PFS rate with cilta-cel was 68.0%. The median overall survival (OS) had not yet been reached, and the 1-year OS rate was 88.5%.
Results from CARTITUDE-1 subsequently presented at the Virtual 47th Annual Meeting of the EBMT indicated that 57.9% of patients (n = 33) were found to have minimal residual disease negativity and sCR, while 86.0% achieved MRD negativity and a VGPR or better.4 The median time to MRD 10-5 negativity was 1 month (range, 0.8-7.7). The majority of the patients who had 6 months of individual follow-up had cilta-cel CAR+ T cells in their peripheral blood that were below the level of quantification.
The most frequent grade 3 or 4 toxicities reported in patients who received the CAR T-cell therapy included neutropenia (94.8%), anemia (68.0%), leukopenia (60.8%), and thrombocytopenia (59.8%). Moreover, 57.7% of patients experienced any-grade infections. The most common grade 3 or 4 infections included pneumonia (8.2%) and sepsis (4.1%).
Most of the patients on the trial, or 94.8%, experienced any grade of cytokine release syndrome; however, only 4.1% of these events were considered to be grade 3 or 4. Almost 70% of patients required tocilizumab (Actemra) and 21.6% needed corticosteroids. About 99% of participants had their CRS resolve within 2 weeks of onset.
“Today’s submission to the EMA epitomizes how we strive to make a meaningful impact in the multiple myeloma landscape through advancing innovative treatments for patients,” Saskia De Haes, vice president, EMEA Regulatory Affairs at Janssen R&D BE, stated in a press release.5 “We look forward to working in partnership with health authorities, as part of the accelerated assessment process, to support these patients by ensuring timely access to the latest therapeutic options.”
In April 2021, the rolling submission of a biologics license application to the FDA to support the approval of cilta-cel in the treatment of patients with relapsed/refractory multiple myeloma was completed. The application was supported by data from CARTITUDE-1.