Confirmed safety and efficacy of ciltacabtagene autoleucel with extended follow-up in the CARTITUDE-1 trial
The CARTITUDE-1 trial includes adult patients with multiple myeloma who had received three or more prior regimens or were double-refractory to an immunomodulatory drug and proteasome inhibitor. In these heavily pretreated patients, a single infusion of ciltacabtagene autoleucel yielded early, deep and durable responses, with no new safety signals with longer follow-up.
CARTITUDE-1 is a phase Ib/II study evaluating ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor (CAR) T-cell therapy with two B-cell maturation antigen (BCMA)-targeting single-domain antibodies, in patients with heavily pretreated relapsed/refractory multiple myeloma (R/R MM). At a median follow-up of 12.4 months after cilta-cel treatment, an overall response rate (ORR) of 97% was reported with a stringent complete response (sCR) in 67% of patients. The overall 12-month progression-free survival (PFS) and overall survival (OS) rates were 77% and 89%, respectively. At EHA 2021, Prof. Usmani presented updated results from CARTITUDE-1 in patients with longer follow-up (median 18 months).
CARTITUDE-1 study design
All enrolled patients (N=97) had measurable disease and received at least three prior therapies or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). Prior treatment with a PI, an IMiD and anti-CD38 directed therapy was mandatory. Bridging chemotherapy, if necessary, was allowed following the screening and apheresis process. Next, cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over three days (day -5 to -3) were used as the conditioning regimen. A single infusion of cilta-cel at the targeted dose of 0.75 x 106 (range: 0.5-1.0 x 106) CAR+ viable T cells/kg was administered five to seven days after the start of the conditioning regimen (day 1). As of September 1st 2020, a total of 97 patients with a median of six prior lines of therapy received cilta-cel. The median turnaround time for cilta-cel was 29 days. Most patients (87.6%) were triple-class refractory while 42.3% was even penta-drug refractory. Almost all patients (99.0%) were refractory to their last line of therapy
Updated safety and efficacy data
The ORR per independent review committee (primary endpoint) was 97.9%, with 80.4% of patients obtaining a stringent complete response. The median time to first response was 1 month (range, 0.9–10.7) with a median time to the best response of 2.6 months. Importantly, responses to cilta-cel were durable with a median duration of response of 21.8 months. Responses were comparable (range, 95%-100%) across different subgroups, irrespective of the number of prior treatment lines, refractoriness, the presence of extramedullary plasmacytomas, and the cytogenetic risk of patients. In total, 91.8% of minimal residual disease (MRD)-evaluable patients and 57.7% of all patients achieved MRD negativity at the 10-5 threshold. Median time to MRD 10-5 negativity was one month. Median PFS was not reached for patients with sCR and was reported at 22.8 months for all patients. The 18-month PFS rate in all patients was 66.0% increasing to 75.9% among patients with a sCR. The 18-month OS rate in all patients was 80.9%.
There were no new safety signals in CARTITUDE-1 with longer follow-up. In total, 21 patients died during the study: ten due to progressive disease, six due to treatment-related adverse events (AEs) as assessed by the study investigator, and five due to AEs unrelated to treatment. Cytokine release syndrome occurred in 92 out of 97 patients but remained low grade in the vast majority of patients (94.6% grade 1-2). The median time to the onset of CRS was seven days and it resolved in almost all patients (98.9%) within fourteen days. No new incidence of neurotoxicity was observed with longer follow-up and no additional movement and neurocognitive treatment-emergent adverse events (TEAEs) occurred. Overall, movement and neurocognitive TEAEs occurred in five of 97 patients. Risk factors (two or more) include high tumour burden, grade ≥2 CRS, ICANS, and high CAR-T cell expansion and persistence. Patient management strategies have been implemented in the CARTITUDE program to prevent and reduce the intensity of neurotoxicity. These management strategies include the use of enhanced bridging therapy to reduce the tumour burden, early and aggressive treatment of CRS and ICANS, handwriting assessments, and extended monitoring. With those strategies, more than 100 additional patients have been dosed in the CARTITUDE-1 program proving the success of these strategies in preventing or reducing the risk for these AEs.
Conclusion
At a longer median follow-up of 18 months, a single dose of cilta-cel led to early, deep and durable responses in heavily pretreated patients with RRMM. Cilta-cel has a manageable safety profile, consistent with its mechanism of action, and no new safety signals were observed with longer follow-up. Cilta-cel is being investigated in the ongoing phase II CARTITIDE-2 and phase III CARTITUDE-4 studies in earlier-line settings.
Reference
Usmani S, Berdeja J, Madduri D, et al. Updated CARTITUDE-1 results of ciltacabtagene autoleucel, a B-cell Maturation antigen–directed chimeric antigen receptor T cell therapy, In relapsed/refractory multiple myeloma. Presented at EHA 2021; abstract EP964.
