Real world comparison of commercial CAR T-cell constructs for the treatment of LBCL

Abstract Background: Anti-CD19 chimeric antigen receptor T-cell therapy (CART) is an effective therapy for relapsed or refractory (R/R) large B-cell lymphoma (LBCL) with 3 FDA approved CART constructs: axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), & lisocabtagene maraleucel (liso-cel). Clinical trials report variability in manufacturing, efficacy, & treatment related toxicities, but limited data exists directly comparing these treatments. Here we report the largest real-world comparison of all 3 CART constructs for the treatment of R/R LBCL. Methods: Patients (pts) >18yr treated with CART for R/R LBCL were identified across 15 academic institutions. Wilcoxon rank-sum test, Kruskal-Wallis, & pooled t-test were utilized (p<.05) to determine the statistical significance of differences between variables. Time-to-event curves were estimated from time of CART infusion using Kaplan-Meier, & Cox regression was performed to determine the impact of variables on survival. Results: 925 pts were identified: axi-cel (61%), tisa-cel (19%), liso-cel (20%). There was no difference in disease stage, histology, presence of c-MYC/BCL-2 gene rearrangement (DHL), primary refractory disease (PRD), or pre-infusion performance status among pts for each construct. Pts treated with liso-cel were older (median age 68, range 19-85) compared to axi-cel (60, 21-86) & tisa-cel (64, 22-89; p=0.001) & received more bridging therapy liso-cel (61%) compared to axi-cel (50%, p=0.01). Axi-cel had the lowest incidence of out of specification (OOS) product (2.5%) vs tisa-cel (16.6%) & liso-cel (12.6%; p=0.001) but did not account for recent changes in defined OOS criteria for liso-cel. Time from apheresis to CART infusion (vein-to-vein) was shorter with axi-cel (28 days (d), range 9-250) vs tisa-cel (40d, 12-180) & liso-cel (40d, 24-393; p=0.001). There was a higher incidence of CRS (78%) with axi-cel compared to tisa-cel (53%, p=0.001) & liso-cel (52%, p=0.001). Liso-cel was associated with the lowest incidence of grade 3-4 CRS (n=1, 0.5%) vs axi-cel (n=61, 11%) & tisa-cel (n=17, 10%, p=0.001). Axi-cel also had a higher incidence of ICANS (50%) vs tisa-cel (29%) & liso-cel (22%, p=0.02) with tisa-cel having the lowest incidence of grade 3-4 ICANS (n=12, 6.8%) vs axi-cel (n=116, 20%) & liso-cel (n=22, 12%, p=0.011). There was no difference in 30-day mortality post-CART: axi-cel (2.1%), tisa-cel (2.8%), & liso-cel (1.6%, p=0.73). At a median follow up of 469d (IQR 941), there was no difference in incidence of microbiologically confirmed infection, hypogammaglobulinemia, secondary malignancy, or administration of IVIG across the 3 CART constructs. Tisa-cel was associated with a lower CR rate (41%) vs axi-cel (51%) & liso-cel (57%; p=0.002) & this difference persisted when examined in the 3L+ only (p=0.001). Tisa-cel was also associated with inferior median progression free survival (mPFS) at 147d (95% CI 105-218) vs axi-cel 582d (95% CI 339-1352) & liso-cel 332d (95% CI 184-926; p=0.001) & with inferior median overall survival (mOS) at 550d (95% CI 423-723) vs axi-cel 1154d (95% CI 866-1853) & liso-cel 722 d (95% CI 524-1630; p=0.001). Results were similar when stratified by 3L+. There was no significant difference in CR rate between axi-cel or liso-cel overall (p=0.62) or when stratified by 2L or 3L+ therapy. There was also no significant difference in mPFS or mOS between axi-cel & liso-cel overall (p=0.29 & 0.50, respectively) or when stratified by lines of therapy. In a multivariate analysis, after adjusting for pt age, LDH, PRD, use of bridging therapy, line of therapy, & vein-to-vein time, axi-cel had higher OS when compared to pts treated with tisa-cel (HR 1.46, 95% CI 1.14-1.86, p=0.003) but comparable OS to liso-cel (HR 1.08, 95% CI 0.82-1.42, p=0.602). Additionally, multivariate analysis demonstrated a higher PFS in pts treated with axi-cel compared to tisa-cel (HR 1.6, 95% CI 1.25-2.04, p=0.001) but this was not statistically significant when compared to liso-cel (HR 1.2, 95% CI 0.93-1.55, p=0.17). Conclusions: In the largest, real-world comparison study of FDA approved CART constructs for R/R LBCL, tisa-cel was associated with inferior response rates & survival outcomes. Despite differences in manufacturing, treatment timelines, & toxicity profiles, there was no statistically significant difference in response rates or survival outcomes with axi-cel compared to liso-cel, in contrast to previously published reports.