Background: Elderly pts with R/R LBCL are at risk of inferior outcomes, increased toxicity, and inability to tolerate second-line (2L) SOC treatment (Tx) (Di M, et al. Oncologist. 2021). Further 2L SOC Tx is often associated with poor health-related quality of life (QoL) (Lin V, et al. J Clin Oncol. 2020;38:e20070). In the pivotal Phase 3 ZUMA-7 study, we assessed outcomes, including PROs, of 2L axi-cel (an autologous anti-CD19 CAR T-cell therapy) versus SOC in elderly pts with R/R LBCL. Methods: Pts aged ≥65 y were assessed in a planned subgroup analysis. Pts with ECOG PS 0-1 and R/R LBCL ≤12 mo after 1L chemoimmunotherapy (CIT) were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based CIT; pts with partial or complete response [CR] proceeded to HDT-ASCT). PRO instruments, including the EORTC QLQ-C30 (Global Health [GH] and Physical Functioning [PF]) and the EQ-5D-5L VAS, were administered at timepoints including baseline (BL; prior to Tx), Day (D) 50, D100, D150, and Month (M) 9, then every 3 mo up to 24 mo or time of event-free survival event (EFS), whichever occurred first. The QoL analysis set included all pts who had a BL PRO and ≥1 completed measure at D50, D100, or D150. A clinically meaningful change was defined as 10 points for each EORTC QLQ-C30 score, 7 points for EQ-5D-5L VAS score. Results: As of 03/18/2021, 51 and 58 elderly pts were randomized to the axi-cel and SOC arms, respectively, with median ages (range) of 70 y (65-80) and 69 y (65-81). At BL, more axi-cel versus SOC pts had high-risk features, including 2L age-adjusted IPI 2-3 (53% vs 31%) and elevated LDH (61% vs 41%). EFS was superior with axi-cel versus SOC (HR, 0.276, P< 0.0001), with higher CR rates (75% vs 33%). Grade ≥3 Tx-emergent adverse events (AEs) occurred in 94% and 82% of axi-cel and SOC pts, respectively, and Grade 5 Tx-related AEs occurred in 0 and 1 pt. In the QoL analysis set comprising 46 axi-cel and 42 SOC pts, there were statistically significant and clinically meaningful differences in mean change of scores from BL at D100 favoring axi-cel for EORTC QLQ-C30 GH (P<0.0001) and PF (P=0.0019) and EQ-5D-5L VAS (P<0.0001). For all 3 domains, scores also favored (P<0.05) axi-cel over SOC at D150. The mean estimated scores numerically returned to or exceeded BL scores earlier in the axi-cel arm (by D150) but never equaled or exceed BL scores by M15 in the SOC arm. Conclusions: Axi-cel demonstrated superiority over 2L SOC in pts ≥65 y with significantly improved EFS and a manageable safety profile. Compared with SOC, axi-cel also showed meaningful improvement in QoL over SOC, measured by multiple validated PRO instruments, with suggested faster recovery to pre-Tx QoL. The superior clinical outcomes and pt experience with axi-cel over SOC should help inform Tx choices in 2L R/R LBCL for pts ≥65 y. Clinical trial information: NCT03391466.