Abstract
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC)1–3. Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations4–6. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown1,3,7–10. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure–function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure–function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
Highlights
Patients with classical Epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletions (Ex19del)) show marked improvements in clinical outcomes when treated with first, second- or third-generation tyrosine kinase inhibitors (TKIs)[4,5,6,11]
When treated with an EGFR TKI, patients with atypical EGFR mutations had a shorter TTF compared with patients with classical EGFR mutations (Fig. 1d, hazard ratio (HR) = 1.8, P < 0.0001), even when patients with exon 20 insertions (Ex20ins) were excluded from the analysis (Fig. 1e, HR = 1.6, P < 0.0001) or when patients were stratified by mutation exon location (Fig. 1e, Extended Data Fig. 1c)
When patients were stratified by TKI treatment, those with classical EGFR mutations had a longer TTF than those with atypical EGFR mutations when treated with first-generation (HR = 1.9, P = 0.0005) or third-generation TKIs (HR = 3.0, P < 0.0001) (Extended Data Fig. 1d, e)
Summary
The diversity and higher than previously appreciated prevalence of atypical EGFR mutations shown here highlights the necessity of comprehensive next-generation sequencing (NGS) for patients with NSCLC. 3. Klughammer, B. et al Examining treatment outcomes with erlotinib in patients with advanced non-small cell lung cancer whose tumors harbor uncommon EGFR mutations. C. et al Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. Uncommon epidermal growth factor receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance. B. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. H. et al Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09). L. et al Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. S. et al Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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