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.
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.