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Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC

Abstract

Early clinical studies of tyrosine kinase inhibitors (TKIs) that target the EGFR in patients with advanced non-small-cell lung cancer (NSCLC) showed that some patients experienced rapid, durable, complete or partial responses. These data were the basis for attempts to identify specific subgroups of patients who would further benefit from these agents. The discovery of somatic mutations in EGFR that correlated with sensitivity to TKIs identified a plausible explanation for these observations. Clinical and pathological factors such as female sex, never having smoked, Asian origin and adenocarcinoma histology correlate with the presence of EGFR mutations and objective responses to TKIs in patients with NSCLC. Recent studies in metastatic colorectal cancer highlighted that somatic mutations in KRAS represent a negative predictor of response to anti-EGFR monoclonal antibodies; KRAS mutations also represent an important mechanism of resistance to TKIs in NSCLC. Many large clinical studies are currently investigating the predictive and prognostic value of EGFR mutational status and other candidate biomarkers. We summarize the literature and present an overview of the field of anti-EGFR therapy in NSCLC, focusing on the influence of somatic EGFR mutations on selection of patients for TKI therapy and the influence of EGFR pathway regulation.

Key Points

  • In non-small-cell lung cancer (NSCLC), somatic EGFR mutations (deletions in exon 19, L858R in exon 21) are most common in Asian patients and those with adenocarcinoma histology, nonsmokers and women

  • Deletions in exon 19 and L858R are associated with response of NSCLC to gefitinib or erlotinib monotherapy whereas the T790M point mutation in exon 20 (and other exon 20 mutations) confer resistance to erlotinib and gefitinib

  • The prognostic and predictive significance of somatic EGFR mutations, and effects of mutations in EGFR, KRAS and other genes on survival outcomes in response to EGFR inhibitors, remain unclear

  • Somatic EGFR mutations are currently favored over clinical and pathological factors for deciding which patients should receive treatment with tyrosine kinase inhibitors (TKIs)

  • In patients with advanced or relapsed NSCLC, monotherapy with TKIs offers an alternative to chemotherapy

  • KRAS mutations are mutually exclusive from EGFR mutations, and represent a candidate biomarker of nonresponsiveness to TKIs

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Figure 1: Heterodimerization, ligand binding and signaling in the EGFR and ERBB family.
Figure 2: Schematic view of EGFR tyrosine kinase bound to gefitinib.
Figure 3: Incidence of somatic EGFR mutations.

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Linardou, H., Dahabreh, I., Bafaloukos, D. et al. Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol 6, 352–366 (2009). https://doi.org/10.1038/nrclinonc.2009.62

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