3130 Background: Most metastatic non-small cell lung cancer (NSCLC) patients are tumor mutational burden (TMB)-low (0.05); APOBEC-positive patients were younger (median 64 vs 69 years, p=0.002). The APOBEC-positive group demonstrated significantly improved OS (median 33.7 vs 17.4 months; HR=0.60; 95% CI, 0.42–0.85; p=0.004). The survival benefit was absent in ICI-untreated patients (HR=0.98; 95% CI, 0.76–1.26; p=0.85). Formal interaction testing confirmed that the APOBEC benefit was specific to ICI-treated patients (interaction HR=0.62; p=0.032). APOBEC-positive tumors demonstrated higher DCR at 180 days (21.4% vs 7.6%; OR=3.32; p=0.006). In multivariate analysis adjusting for PD-L1 and age, APOBEC remained independently predictive (HR=0.57; 95% CI, 0.40–0.81; p=0.002). In the validation cohort, APOBEC independently predicted superior PFS (HR=0.23; 95% CI, 0.05–0.94; p=0.020) after adjusting for PD-L1, with numerically higher ORR (55.6% vs 25.4%, p=0.068). Conclusions: APOBEC mutational signatures represent a robust, independently validated predictive biomarker for ICI response in TMB-low metastatic NSCLC. Unlike prior studies linking APOBEC predominantly to TMB-high tumors, we demonstrate clinical utility specifically in the TMB-low population, where predictive biomarkers are most needed. This biomarker could expand immunotherapy access for NSCLC patients.
Yaacov et al. (Wed,) studied this question.
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