Abstract
Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance.
Highlights
At least 85% of lung cancers are histologically classified as non-small-cell lung cancer (NSCLC), often requiring systemic therapy for advanced disease [1]
Exploration of biomarkers in IPASS found that gefitinib significantly prolonged PFS in cases where tumors had high epidermal growth factor receptor (EGFR) gene copy number and an EGFR mutation, but not when high EGFR gene copy number was unaccompanied by an EGFR mutation; in the latter subset, PFS was significantly shorter with gefitinib versus carboplatin/paclitaxel
Personalized therapy is a clinical reality in NSCLC—an era that began with the reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib for EGFR mutation-positive disease
Summary
At least 85% of lung cancers are histologically classified as non-small-cell lung cancer (NSCLC), often requiring systemic therapy for advanced disease [1]. EGFR, epidermal growth factor receptor; TKIs, tyrosine kinase inhibitors; NSCLC, non-small-c ell lung cancer; RR, response rate; PFS, progression-free survival; OS, overall survival; AEs, adverse events; HR, hazard ratio; CI, confidence interval; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NR, not reported.
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