Genomic profiling of non-small cell lung cancer with rare aberrations in <i>EGFR</i> codon L858 and the survival outcome under real-world first-line EGFR tyrosine kinase inhibitor treatment compared to classic <i>EGFR</i><sup>L858R</sup>.
Authors: Hengyuan Li, Jingying Zhang, Zhi Feng, Wei Wu, Xiaotian Zhao, Minyi Zhu, Yao Xiao, Jiaohui Pang, Qiuxiang Ou, Junfei Zhu, Hao Qu, Minchi Yuan, Guojie Xia, Youyou Shao, Meng Liu, Peng Lin
Journal: Journal of Clinical Oncology (2024)

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&gt;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&lt;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.