First CARTITUDE-2 Data Promising for Cilta-Cel in Earlier Myeloma Setting

Mounzer E. Agha, MD

A single infusion of ciltacabtagene autoleucel (cilta-cel) elicited a response in nearly all patients with relapsed/refractory multiple myeloma previously treated with 1 to 3 prior treatments. Moreover, the stringent complete response (sCR) rate with the CAR T-cell therapy was 75%, according to the first report of data from cohort A of the phase 2 CARTITUDE-2 (NCT04133636) study presented virtually during the 2021 ASCO Annual Meeting.

The overall response rate (ORR) with a target dose of cilta-cel at 0.75 x 10^6/kg was 95% (95% CI, 75%-100%). The very good partial response rate or better, which includes sCR, was 85% (95% CI, 62%-97%). However, at the time of the January 2021 data cutoff, the median follow-up was just 5.8 months and a median duration of response had not yet been reached. The median time to first response with cilta-cel was 1 month (range, 0.7–3.3) and the median time to best response was 1.9 months (0.9–5.1).

“Early and deep responses were observed with a single infusion of cilta-cel in lenalidomide refractory patients with multiple myeloma who received 1 to 3 prior lines of therapy,” study author Mounzer E. Agha, MD, director, Mario Lemieux Center for Blood Cancers, clinical director of Hematopoietic Stem Cell Transplantation, UPMC Hillman Cancer Center, said during a recorded presentation of the data. “The safety profile was manageable, including in the one patient that was treated in the outpatient setting. There were no cases of movement and neurocognitive adverse events (AEs).”

Cilta-cel, formerly JNJ-68284528, is a second-generation CAR T-cell therapy with 2 BCMA-targeting, single-domain antibodies designed to confer avidity. Previous data that were published from the phase 1b/2 CARTITUDE-1 trial demonstrated that single infusion of cilta-cel was associated with deep and durable response among heavily pretreated patients with relapsed/refractory disease. Based on these findings, a biologics license application for cilta-cel in patients with myeloma treated with ≥3 prior regimens is currently being evaluated at the FDA under priority review, with a Prescription Drug User Fee Act target action date of November 29, 2021.

The primary objective of this cohort of the phase 2 CARTITUDE-2 trial was to assess minimal residual disease (MRD) negativity at 10^-5 threshold among patients who were refractory to lenalidomide or relapsed after one to three prior lines of therapy. Additional secondary outcomes included ORR, duration of response (DOR), time and duration of MRD negativity, and incidence and severity of adverse events (AEs).

Patients received the targeted dose of cilta-cel 5 to 7 days after the beginning of lymphodepletion (daily cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for 3 days). A total of 20 patients (median age, 60 years; 65% male) received the single-infusion CAR T-cell therapy. One of the patients was treated in an outpatient setting. Twelve of the patients had received fewer than 3 lines of therapy, and the remaining 8 received 3 prior lines of therapy.

All the patients had been previously treated with a proteasome inhibitor (PI), an immunomodulatory drug (IMiD) and dexamethasone. Almost all (95%) of the patients were exposed to alkylating agents and 65% received daratumumab (Darzalex).

All patients (n = 4) with MRD-evaluable samples were MRD negative at the January 2021 cutoff and more samples are being evaluated.

In terms of safety, hematologic AEs that occurred in 20% or more of the patients included neutropenia (95%), thrombocytopenia (80%), anemia (65%), lymphopenia (60%) and leukopenia (55%). Moreover, cytokine release syndrome occurred in 85% of patients, of which 10% were considered grade 3 or 4.

Cytokine release syndrome (CRS) of any grade occurred in 85% of patients treated with cilta-cel. Neurotoxicity was seen in 20% of patients. These AEs were mostly low grade, and grade 3/4 events were relatively rate. Grade 3/4 CRS was experienced by 10% of patients and none had grade 3/4 neurotoxicity. The median time to CRS onset was 7 days with a median duration of 3.5 days, with complete recovery in 94% of patients at the data-cutoff. The median time to neurotoxicity onset was 8 days and median duration was 2 days.

Agha noted that one death occurred 100 days after the infusion of cilta-cel due to COVID-19 infection and was assessed as treatment-related by the investigators.

The CAR T-cell therapy is being evaluated in other cohorts of the CARTITUDE-2 in earlier line settings, as well as in the phase 3 CARTITUDE-4 study in patients with one to three prior lines of therapy.

Reference

Agha ME, Cohen AD, Madduri D, et al. CARTITUDE-2: Efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) after one to three prior lines of therapy. J Clin Oncol. 2021;39(suppl 15): abstract 8013.