Background: The Phase 3 randomized ZUMA-7 trial in 2L R/R LBCL showed axi-cel superiority to SOC (salvage chemotherapy and HDT-ASCT) in event-free survival (EFS; hazard ratio [HR], 0.398; P<.0001; Locke et al. N Eng J Med. 2021). We report results of exploratory analyses of tumor characteristics, including preTx tumor burden (TB), tissue hypoxia-related lactate dehydrogenase (LDH) level, and tumor microenvironment (TME). Methods: TB was calculated as the sum of product diameters of ≤6 reference lesions (Locke et al. Blood Adv. 2020). Serum LDH was assessed. PreTx tumor samples were assessed for RNA expression by the NanoString IO 360™ panel and prespecified immune contexture indexes related to T-cell involvement (Immunosign 15 [IS15] and 21 [IS21]; Galon et al. ASCO 2020. #3022). ZUMA-1 data were used for comparison to 3L R/R LBCL. CD19 protein expression was assessed by immunohistochemistry (H-score). Associations between biomarkers and clinical outcomes were assessed using descriptive statistics (P<.05 was significant). Results: Axi-cel EFS was superior to SOC for both high and low TB (HR, 0.29 and 0.49, respectively; P<.001 for both) and elevated and nonelevated LDH (HR, 0.32 and 0.5, respectively; P<.001 for both). EFS in axi-cel pts was not associated with preTx TB (HR, 1.01 [95% CI, 0.88-1.16]; P=.89) or LDH (HR, 0.98 [95% CI, 0.74-1.29]; P=.86), but was worse in SOC pts with higher preTx TB (HR, 1.17 [95% CI, 1.03-1.32]; P=.01) or higher LDH (HR, 1.29 [95% CI, 1.02-1.63], P =.03). PreTx TB was lower in SOC pts with ongoing response vs nonresponders and pts who relapsed (P=.07), but not in axi-cel pts (P=.99). Non-germinal center B-cell (GCB) cell-of-origin subtypes is a poor prognostic factor for EFS in SOC (EFS was significantly worse in SOC pts with non-GCB vs GCB; HR, 1.82 [95% CI, 1.12-2.96]; P=.02) but not in axi-cel. In IO360 analysis, gene expression of B-cell lineage antigens (CD19, CD20, BCMA) and markers highly expressed by tumor cells (CD45RA, IRF8, BTLA) positively associated with objective and durable responses to axi-cel. While axi-cel remained superior to SOC with high ( > median) or low CD19 expression level, the probability of an ongoing response increased with a higher CD19 H-score. PreTx TME IS15 and IS21 scores were generally higher in 2L vs 3L. Conclusions: Axi-cel was superior to SOC in all subgroup analyses, including higher TB and LDH. Durable responses with axi-cel were greatest in tumors with prominent B-cell features, but were superior to SOC regardless of these features. Axi-cel intervention in 2L is supported by durable response rates not impacted by high TB, as seen in 3L axi-cel or 2L SOC. Higher preTx immune involvement in 2L vs 3L tumors suggests high TB may be overcome with axi-cel in patients with a more favorable immune contexture. Clinical trial information: NCT03391466.