A single low-dose infusion of ciltacabtagene autoleucel (cilta-cel), an autologous chimeric antigen receptor (CAR) T-cell therapy, was safe and associated with early, deep, and durable responses in patients with heavily pretreated multiple myeloma (MM), according to preliminary data from the phase Ib/II CARTITUDE-1 trial. Deepu Madduri, MD, from Mount Sinai Medical Center in New York, presented the updated phase Ib data alongside the initial phase II data from the CARTITUDE-1 trial during the 2020 ASH Annual Meeting.
The CARTITUDE-1 trial included adult patients with MM who had received three or more prior regimens or were double-refractory to an immunomodulatory drug and proteasome inhibitor. Cilta-cel, also known as LCAR-B38M and JNJ-68284528, includes a bioengineered T-cell receptor construct with a CD3ζ signaling domain, a 4-1BB costimulatory domain, and 2 B-cell maturation antigen (BCMA) binding domains.
After apheresis and collection of cells to create the CAR T-cell product, and bridging therapy if needed, patients were administered a three-day lymphodepletion course of therapy with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2. Patients then received a single infusion of cilta-cel at a target dose of 0.75×106 cells/kg (range = 0.5-1.0×106 cells/kg).
During the first phase of the trial, investigators looked for any new safety signals and established a phase II dose, then evaluated the therapy's efficacy at this dose.
At the cutoff date of September 1, 2020, a total of 97 of the 113 enrolled patients had received the study treatment: 29 patients in phase Ib and 68 in phase II. The median age of this cohort was 61 years (range = 43-78). This was an especially heavily pretreated population, Dr. Madduri noted, with patients receiving a median of six lines of therapy (range = 3-18) prior to enrollment.
The most commonly reported hematologic adverse events (AEs) across the study population included neutropenia (96%), anemia (81%), and thrombocytopenia (79%). "In general, most patients resolved their hematologic toxicities fairly quickly, without the complication of too many infections," Dr. Madduri said.
Nonhematologic AEs of special interest included cytokine release syndrome (CRS) and neurotoxicity – both of which are commonly associated with CAR T-cell therapies. CRS occurred in 92 patients (95%), with a median time to CRS onset of 7 days and a median duration of 4 days (range = 1-27). Most cases were grade 1/2 (95%), and CRS resolved within 14 days of onset in all but one case. Approximately 21% of patients experienced neurotoxicity, with 10% experiencing grade ≥3 events.
There were 14 deaths during the study: five were due to progressive disease, three to AEs unrelated to treatment, and six to treatment-related AEs (including sepsis, CRS, lung abscess, respiratory failure, and neurotoxicity).
In terms of efficacy, 97% of patients responded to treatment. This included:
- stringent complete response: 67%
- very good partial response: 26%
- partial response: 4%
"We saw how heavily pretreated these patients were, and to see a one-time treatment give these kinds of response rates is quite exceptional," Dr. Madduri said. Furthermore, "72% of these patients are still maintaining their response at the time of data cutoff."
In addition, of 57 patients evaluable for measurable residual disease (MRD), 93% achieved MRD-negativity.
At a median duration of follow-up of 12.4 months, the median progression-free survival (PFS) had not been reached, with a 12-month PFS rate of 77%. Looking at PFS according to response, the 12-month PFS rate in those who experienced a stringent complete response or a very good partial response was 85% and 68%, respectively.
These preliminary efficacy results represent one of the highest response rates for a CAR T-cell therapy candidate in MM, the authors concluded, but the findings need to be confirmed in larger trials with larger patient populations. Dr. Madduri said ongoing studies are evaluating cilta-cel as an earlier line of therapy and with outpatient administration.
Study authors report relationships with Janssen, which sponsored the trial.
Reference
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. Abstract #177. Presented at the 2020 American Society of Hematology Annual Meeting, December 5, 2020.
