YTB323 (Rapcabtagene Autoleucel) in R/R DLBCL After ≥2 Lines of Prior Therapy

Despite novel treatment options, many patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) do not achieve sustained remission or do not have timely access to therapies. YTB323 (rapcabtagene autoleucel) is an autologous CD19-directed, 4-1BB chimeric antigen receptor T-cell (CAR-T) therapy rapidly manufactured by the T-Charge™ platform, which preserves T-cell stemness. Efficacy, safety, dose exposure, and biomarker analyses for YTB323 in adults with R/R DLBCL in the ongoing phase 1, multicenter, dose-escalation study (NCT03960840) were presented at the 64th American Society of Hematology Annual Meeting and Exposition.

Eligible patients had R/R DLBCL after ≥2 prior lines of therapy (LOTs), measurable disease at enrollment, and Eastern Cooperative Oncology Group performance score of 0-1. Bridging therapy was allowed at the treating investigator’s discretion, followed by lymphodepleting chemotherapy. Patients received single-dose YTB323 at targeted dose level (DL) 1 (2.5 × 10⁶ CAR⁺ T-cells), DL2 (12.5 × 10⁶ CAR⁺ T-cells), DL3 (25 × 10⁶ CAR⁺ T-cells), or DL4 (40 × 10⁶ CAR⁺ T-cells). Primary end points characterized safety and dose-limiting toxicities to determine a recommended dose. Secondary end points included cellular kinetics, overall response rate (ORR), and duration of response (DOR).

As of September 15, 2022, with a median (range) follow-up of 13 (4.4-34.3) months (mo), 47 patients with R/R DLBCL received YTB323: 4 at DL1, 30 at DL2, 7 at DL3, and 6 at DL4. Median age was 65 years, 72% received 2 prior LOTs, and 30% had prior autologous stem-cell transplant. Median (range) time since most recent relapse or progression was 2.8 (1.4-11.1) mo. Complete response (CR) rate at DL2 was 73%. CR rate at DL2, excluding patients in CR before YTB323 (due to either a late effect of prior treatment or bridging chemotherapy), was 70%. Responses at DL2 were durable, with CR rates of 60% (18/30) at 3 mo and 62% (16/26) at 6 mo. Median DOR at DL2 was 16 mo (95% confidence interval [CI], 10.4-not estimable), and ORR at DL2 was 83% (95% CI, 65.3-94.4). Of 47 patients evaluable for safety, 100% reported ≥1 adverse event (AE) of any grade and 96% had ≥1 grade ≥3 AE. Cytokine release syndrome (CRS) was experienced by 16 patients (34%): 1 at DL1, 11 at DL2, 2 at DL3, and 2 at DL4. Two DL2 patients (7%) experienced grade 3/4 CRS. CRS was managed with tocilizumab, corticosteroids, and vasopressors in 8 (73%), 4 (36%), and 2 (18%) patients at DL2, respectively, whereas 1 DL3 patient (50%) received tocilizumab. Median (range) time to CRS onset was 8 (1-17) days, and resolution was 6 (2-25) days. Five patients (11%) had immune effector cell–associated neurotoxicity syndrome (ICANS) events: 3 at DL2 and 2 at DL4. Two DL2 patients (7%) experienced grade 3/4 ICANS. Median (range) time to onset and resolution of ICANS was 16 (10-28) days and 16 (11-24) days, respectively. ICANS management included utilization of dexamethasone, methylprednisolone, and anakinra (an interleukin-1 receptor antagonist) in 2 (67%), 1 (33%), and 1 (33%) patient at DL2, respectively, and 1 (50%) patient at DL4 received dexamethasone.

YTB323 kinetics measured by qPCR showed robust expansion at DL2 with no further increases at higher doses. scRNAseq clonal analysis showed the YTB323 manufacturing process preserves T-cell stemness by retaining the composition of cell populations from apheresis to the final product through short manufacturing time.

YTB323 is a potent new CD19-directed CAR-T therapy that preserves T-cell stemness through its rapid manufacturing process, translating into durable efficacy and a favorable safety profile. DL2 (12.5 × 10⁶ CAR⁺ T-cells) was established as the recommended dose for phase 2/3 studies based on the CR rate, favorable safety profile, and cellular kinetics.

Source

Barba P, Kwon M, Briones J, et al. YTB323 (rapcabtagene autoleucel) demonstrates durable efficacy and a manageable safety profile in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL): phase I study update. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA. Oral presentation 439.