Co-Occurring Potentially Actionable Oncogenic Drivers in Non-Small Cell Lung Cancer

BACKGROUND: Several oncogenic drivers in non-small cell lung cancer (NSCLC) are considered actionable with available or promising targeted therapies. Although targetable drivers rarely overlap with each other, there were a minority of patients harboring co-occurring actionable oncogenic targets, whose clinical characteristics and prognosis are not yet clear. METHODS: A total of 3,077 patients with NSCLC who underwent molecular analysis by NGS were included, and their demographic and clinical data were retrospectively collected. RESULTS: Our study found that the frequency of NSCLC patients harboring co-occurring potentially actionable alterations was approximately 1.5% (46/3077); after excluding patients with EGFR-undetermined mutations, the incidence was 1.3% (40/3077); 80% (37/46) harbored both EGFR mutations and other potentially actionable drivers such as MET amplification (21.6%; 8/37) and alterations in ERBB2 including mutations (27%; 10/37) and amplification (21.6%; 8/37); other combinations of potentially actionable drivers including alterations in ERBB2, KRAS, MET, ALK, and RET were also identified. Additionally, de novo MET/ERBB2 amplification in patients harboring EGFR-mutant NSCLC treated with first-generation EGFR tyrosine kinase inhibitors (TKIs) was associated with shorter PFS (p < 0.05). The efficacy of TKIs in NSCLC patients harboring other co-occurring potentially actionable drivers varied across different molecular subtypes. CONCLUSIONS: Approximately 1.5% of NSCLCs harbored co-occurring potentially actionable oncogenic drivers, commonly involving EGFR mutations. Co-occurring actionable targets may impact the efficacy of TKIs; therefore, future clinical trials in these patients should be anticipated to tailor the combination or sequential treatment strategies.