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World Cancer 2019: Efficacy of first and second generation-EGFR-TKIs in NSCLC patients with uncommon EGFR mutations: A literature-based pooled analysis

  Yiyin Zhang

The approval of tyrosine kinase inhibitors (TKIs) to selectively target tumors with activating epidermal protein receptor (EGFR) mutations marked a revolutionary milestone within the management of non–small-cell carcinoma (NSCLC) and signaled the dawn of the precision medicine. Approximately 25% of patients with NSCLC who were never- or ex-light smokers were found to own activating EGFR mutations, and this number will be up to 50% to 60% in Asian non-smoker patients whose tumors have adenocarcinoma histology. There are multiple generations of EGFR TKIs approved for clinical use. First-generation EGFR TKIs, gefitinib and erlotinib, inhibit EGFR by competitive binding with ATP and demonstrate remarkable improvements in progression-free survival (PFS) over platinum doublet chemotherapy. Subsequent generations of TKIs were designed to beat treatment resistance. Second-generation TKIs, afatinib and dacomitinib, irreversibly inhibit all 4 ERBB receptors including EGFR. As such, they're more impregnable inhibitors of EGFR, but at the price of increased toxicity. Osimeritinib, the sole available third-generation TKI, is specifically designed to focus on the T790M resistance mutation that emerges with EGFR TKI treatment but also shows activity against tumors harboring the exon 19 deletion and exon 21 L858R point mutations.