Genomic profiling of non-small cell lung cancer with rare aberrations in EGFR codon L858 and the survival outcome under real-world first-line EGFR tyrosine kinase inhibitor treatment compared to classic EGFRL858R.

8596 Background: Rare genomic aberrations in EGFR codon L858 causing L858R (rare EGFR L858R ) or non-L858R mutations have been reported, besides the predominant c.2573T>G genomic mutation leading to classic EGFR L858R . However, molecular features, survival benefit under EGFR tyrosine kinase inhibitors (TKIs), and resistance mechanisms of these rare mutations lack comprehensive investigation in non-small cell lung cancer (NSCLC). Methods: We retrospectively included 489 NSCLCs with treatment-naive tumor tissues/plasma biopsies harboring rare EGFR L858R (N=124), EGFR L858Q/M (N=17), or classic EGFR L858R mutations (N=348). Mutational landscapes, tumor mutation burden (TMB), and chromosome instability (CIN) scores, were investigated using tissue samples subject to a targeted next-generation sequencing panel covering 437 cancer-related genes. Advanced NSCLCs receiving EGFR TKIs as first-line therapy were sub-grouped to study survival benefit and resistance mechanisms. Results: NSCLCs with rare EGFR L858R had less-frequently mutated TP53 (59% vs. 72%, P=0.04) and lower CIN scores (0.29 vs. 0.23, P=0.02) than those with classic EGFR L858R , while age, sex, stage at diagnosis, histology subtype, and TMB were comparable. We also detected the cooccurrence of EGFR L858Q/M with EGFR L861Q ( P<0.01), particularly in patients carrying EGFR L858M (100%). Compared to 233 advanced NSCLCs harboring classic EGFR L858R , 58 patients with rare EGFR L858R exhibited superior first-line progression-free survival (PFS) [median: 13.0 vs. 10.0 months, hazard ratio (HR): 0. 57, 95% confidence interval (CI): 0.41–0.80], with a similar association observed in approximately 80% of included patients who received first-generation EGFR TKIs (median: 12.0 vs. 10.0 months, HR: 0.64, 95% CI: 0.45–0.92). After controlling for age, sex, histological subtype, EGFR TKI category, and anti-vascular therapy, rare EGFR L858R remained associated with improved PFS (adjusted HR: 0.55, 95% CI: 0.39–0.77). Patients with EGFR L858Q/M also had better PFS than those with classic EGFR L858R (adjusted HR: 0.26, 95% CI: 0.10–0.67). Of note, NSCLCs with combined EGFR L858M and EGFR L861Q appeared to have lower progression risks when receiving afatinib than using gefitinib/icotinib as first-line therapy. Furthermore, matched samples at baseline and progression revealed similar resistance mechanisms between NSCLCs with rare and classic EGFR L858R . Conclusions: NSCLCs carrying rare genomic aberrations in EGFR codon L858 were likely to get more survival benefits from first-line EGFR TKI treatment than those with classic EGFR L858R , giving scientific evidence supporting the clinical application of EGFR TKIs in these patients.