Rapcabtagene Autoleucel (YTB323) in Patients (Pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL): Phase II Trial Clinical Update

Introduction: Rapcabtagene autoleucel is a CD19-directed CAR-T cell therapy that utilizes the T-Charge™ platform to preserve T-cell stemness by rapidly manufacturing product (<2 days). Here we report an interim descriptive analysis of the ongoing phase 2 trial (NCT03960840).

Methods: Eligible pts received a single dose of rapcabtagene autoleucel (12.5x10⁶ cells). Bridging therapy before infusion was permitted. The primary endpoint was CRR (BOR of CR). Secondary endpoints included cellular kinetics, ORR, PFS, and DOR.

Results: As of February 1, 2024, 63 pts had received rapcabtagene autoleucel with a median follow-up (FU) of 16.4 mo (range 0.1-44.1). At study entry, median age was 64 y (range 26-81), 46% of pts were ≥65 y. Pts received a median of 2 (range 2-6) prior lines of therapy. 59% of pts were refractory to the last line. 30% of pts received a prior HSCT. Before infusion, 43% of pts had elevated LDH (>ULN), 38% had an IPI score ≥3, and 25% had double/triple hit MYC/BCL2/BCL6 rearrangements. 28 pts (44%) received lower-dose lymphodepletion (LD) (fludarabine/cyclophosphamide [flu/cy] 25/250 mg/m² for 3 d), median FU 32.8 mo, and 33 pts (52%) received higher-dose LD (flu/cy 30/500 mg/m² for 3 d), median FU 5.4 mo. 2 pts (3%) received bendamustine (90 mg/m²) LD. Among the 60 pts infused who had ≥1 mo FU, ORR was 88% and CRR was 65%. CRR at 3, 6, and 12 mo were 55% (30/55), 57% (25/44), and 47% (18/38), respectively. Median DOR was 15.2 mo (5.1-NE); in pts with a BOR of CR, the median DOR was not reached (10.4-NE) and the 12-mo DOR was 69%. Median PFS was 11.9 mo; among pts in CR at 3 mo, the median PFS was not reached. PFS rates at 12 mo were 48% for all pts and 79% for pts in CR at 3 mo.

High CR rates at 3 mo were observed across most pt subgroups including high-risk populations; 64% for pts age ≥65 y, 53% for pts with ≥3 prior therapies, 46% for pts with an IPI ≥3; a lower CR rate of 29% was reported for pts with elevated LDH before infusion. CR rates at 3 and 6 mo for pts who received lower-dose LD were 61% and 61%. For pts who received higher-dose LD, CR rates at 3 and 6 mo were 44% and 47%. Notable differences in demographic and baseline characteristics between the lower- and higher-dose LD pt cohorts included elevated LDH before infusion (36% vs 49%), IPI score ≥3 (43% vs 30%), and proportion of pts ≥65 y (57% vs 36%), respectively. Additionally, 57% and 61% of pts who received lower- and higher-dose LD were refractory to the last line of therapy.

Among the 63 infused pts, AEs were reported in 98% (gr ≥3, 84%) including infections (all gr, 49%; gr ≥3 27%), CRS (all gr, 43%; gr ≥3 6%), and ICANS (all gr, 6%; gr ≥3, 3%). Gr ≥3 infections were reported in 27% (17/63), 15% (8/55), and 19% (6/32) of pts any time, between 12 w and 1 y, and >1 y post infusion, respectively. Median time to any gr CRS onset was 8 d (range, 1-20); ICANS was 13 d (range, 10-28). Gr ≥3 cytopenias included neutropenia (62%), anemia (33%), thrombocytopenia (25%), and lymphopenia (16%). Probability of resolution by 3 mo for neutropenia and anemia was 100%; for thrombocytopenia and lymphopenia 3 and 6 mo resolution was 92%/100% and 65%/74%, respectively. Pts who received higher- vs lower-dose LD experienced higher rates of gr ≥3 CRS (12% vs 4%), neutropenia (64% vs 57%), and febrile neutropenia (9% vs 0%) but similar rates of gr ≥3 infections (12% vs 11%) and ICANS (3% vs 4%). As of data cutoff, 12 deaths had occurred, all unrelated to rapcabtagene autoleucel; 6 due to disease progression and 6 due to AEs. 4 deaths reported were non-relapse mortalities; 2 deaths due to AEs were reported post progression.

Cellular kinetics showed robust in vivo expansion by qPCR with a median C_max of 41,800 copies/µg DNA. Median C_max was 47,100 copies/µg DNA for pts who received higher-dose LD and 36,900 copies/µg DNA for pts who received lower-dose LD.

Conclusions: At the 12.5x10⁶ CAR+ cell dose, rapcabtagene autoleucel showed promising efficacy and a favorable safety profile. Although pt numbers were limited, risk-benefit analysis supports use of the lower-dose LD regimen before infusion; continued assessment of long-term efficacy and safety outcomes is needed.