CARTITUDE is a phase 1b/2 study initiated with the aim of establishing the safety (phase 1b) and efficacy (phase 2) of JNJ-4528, a structurally differentiated CAR T-cell therapy with 2 B-cell maturation antigen (BCMA)-targeting single-domain antibodies designed to confer avidity. Here, updated data from the phase 1b portion of the trial are presented.
Patients with multiple myeloma who had measurable disease, had either received ≥3 prior regimens or were refractory to both a proteasome inhibitor and an immunomodulatory drug, and had received an anti-CD38 antibody were enrolled in this study. Bridging therapy followed apheresis if needed. Patients were administered a lymphodepleting regimen of cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 over 3 days, then a single infusion of JNJ-4528 was given (median dose of 0.73 x 106 CAR+ viable T-cells/kg [range, 0.5-0.9]).
Of the 29-patient study population, 100% experienced neutropenia, 93% experienced cytokine release syndrome (CRS), and 86% experienced thrombocytopenia, and these were the most frequent adverse events. In terms of adverse events grade ≥3, neutropenia was the most common (100%) followed by thrombocytopenia (69%) and leukopenia (66%). Among the 27 patients who experienced CRS, most were low-grade events, although 1 grade 3 event and 1 grade 5 event occurred. Median time to onset of CRS was 7 days (range, 2-12 days). The median duration of CRS was 4 days (range, 2-64 days). In terms of treatment-related neurotoxicity, 1 patient had grade 3 and 3 patients had grade 1 or 2. Incidence of grade 3 or 4 infections was low.
The overall response rate with JNJ-4528 was 100%. A total of 22 (86%) patients achieved stringent complete response, 6 (10%) achieved very good partial response, and 1 (3%) achieved partial response. Two months (range, 1-9 months) was the median time to complete response. The 6-month progression-free survival was 93%, and the longest ongoing response was 15 months. At median follow-up (11.5 months; range, 3-17 months), 22 of the 29 patients enrolled were progression-free and alive. Three deaths were reported (CRS, 1; acute myeloid leukemia, 1; progressive disease, 1). The 9-month progression-free survival rate was 86% (95% confidence interval, 67-95).
Bone marrow samples from baseline and at least 1 postbaseline time point were available from 26 patients. As such, minimal residual disease (MRD) was assessed using next-generation sequencing. Most patients showed MRD-negative responses beyond day 28. Of the 16 patients in complete response who were evaluable for MRD assessment, 13 (81%) were MRD negative at 10-5 or 10-6, and 11 (69%) were MRD negative at 10-6.
JNJ-4528 CAR+ T-cell expansion reached its peak between days 10 and 14, and at 6-month follow-up, they were below the level of quantification in peripheral blood in 22/28 patients. This suggests that deepening of response over time was not correlated with CAR T-cell persistence. Rather, responses were early, deep, and durable with a low dose of CAR T-cells in heavily pretreated patients. The safety profile of JNJ-4528 is consistent with a prior study and is generally manageable.
Reference
Abstract and Poster EP926. EHA 2020. June 12, 2020. Treatment of relapsed/refractory multiple myeloma with JNJ-4528, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy: update of phase 1b results from CARTITUDE-1.