Exploring the prognostic and predictive value of IL-1β, TROP2, and B7-H3 in EGFR-mutated (EGFRm) NSCLC: Insights for personalized treatment strategies.

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e20680 Background: IL-1β is a pro-inflammatory cytokine linked to tumor progression and immune modulation, making it a valuable prognostic marker in NSCLC. However, IL-1β inhibition shows inconsistent outcomes in combination therapy, as seen in the CANOPY trials. High IL-1β expression is linked to resistance to EGFR inhibitors (EGFRi). TROP2 promotes EGFRi resistance by enhancing cell survival, while B7-H3 fosters resistance through immune evasion. Understanding the interplay between IL-1β, TROP2, and B7-H3 may refine biomarker-guided therapeutic strategies in EGFRm NSCLC. Methods: Among 36,089 NSCLC tumors that underwent next-gen sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ), 4,719 EGFRm were identified. Tumors were stratified by overall cohort IL-1β, B7-H3 and TROP2 expression quartiles (Q1: low, Q4: high). Overall survival (OS) was estimated from either tissue collection or EGFRi initiation to last contact from insurance claims data using Cox proportional hazards for hazard ratio (HR) and log-rank tests for p -values. EGFRi included Osimertinib, Erlotinib, Afatinib and Gefitinib. Results: In EGFRm NSCLC patients, low IL-1β (Q1) improved OS compared to high IL-1β (Q4) (n = 981 vs 516; 37.6 vs 26.6 months (m); HR 0.78, p = 0.002). IL-1β Q1 showed superior OS over IL-1β Q4 in low B7-H3 subgroups (n = 501 vs 60; 49.7 vs 26.1 m; HR 0.63, p = 0.012), but not in high B7-H3 (n = 52 vs 187; 28.8 vs 25.8 m; HR 1.05, p = 0.84). OS from EGFRi initiation was longer in IL-1β Q1 compared to IL-1β Q4 (n= 398 vs 251; 44.5 v. 36.8 m; HR 0.80, p = 0.07), with further increase in OS in B7-H3 Q1/IL-1β Q1 over B7-H3 Q1/IL-1β Q4 (n = 216 vs 33; 47.0 vs 32.4 m; HR 0.59, p = 0.035). No significant OS difference was seen in B7-H3 Q4/IL-1β Q1 and B7-H3 Q4/IL-1β Q4 subgroups (n = 20 vs 89; 28.1 vs 38.4 m; HR 1.10, p = 0.81) Low TROP2 (Q1) showed OS benefit over high TROP2 (Q4) (n = 557 vs 741; 31.9 vs 24.4 m; HR 0.83, p = 0.03), with a similar trend in IL-1β Q1 subgroups (TROP2 Q1 vs Q4 n = 278 vs 140; 34.6 vs 28.8 m; HR 0.76, p = 0.087). Among EGFRi-treated patients, low TROP2 (Q1) was associated with longer OS from EGFRi initiation over high TROP2 (Q4) (n = 263 vs 352; 42.6 vs 33.3 m; HR 0.72, p = 0.007), as well as in IL-1β Q1 subgroups (TROP2 Q1 vs Q4 n = 130 vs 56; 50.1 vs 40.9 m; HR 0.6, p = 0.042), while the opposite trend was observed in IL-1β Q4 subgroups (TROP2 Q1 vs Q4 n = 29 vs 90; 28.3 vs 45.4 m; HR 1.56, p = 0.13). Conclusions: IL-1β, combined with B7-H3 or TROP2, may serve as critical biomarkers for survival outcome in EGFRm NSCLC. Low IL-1β and B7-H3 expression correlate with improved survival, highlighting their potential to guide targeted therapies. These findings suggest the potential value of targeting IL-1β, alongside actionable biomarkers like B7H3 and TROP2, to enhance EGFRi efficacy and improve outcomes, enabling personalized treatment approaches for EGFRm NSCLC.

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