Rapcabtagene Autoleucel (YTB323) in Patients (Pts) with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL): Phase II Trial Clinical Update
Authors: Riedell Peter A. , Kwon Mi , Flinn Ian W. , Dickinson Michael J. , Solano Carlos , Jaeger Ulrich , Briones Javier , Kato Koji , Fleming Shaun , Bachy Emmanuel , Rambaldi Alessandro , Shune Leyla O. , Shah Nirav N. , Blaise Didier , Frigault Matthew J. , Ramakrishnan Aravind , Yang Anne , Pearson David , Zia Aiesha , Segura Eduardo , Masood Aisha , Barba Pere 
Published: December 2024

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 (&lt;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 (&gt;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 &gt;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 Cmax of 41,800 copies/µg DNA. Median Cmax 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.