Can acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors be overcome by different small-molecule tyrosine kinase inhibitors?

摘要

The introduction of inhibitors of the epidermal growth factor receptor (EGFR) pathway marked a new chapter in the treatment of lung cancer patients. Before 1990, no systemic therapy was proven to prolong survival in patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer death in the US. Meta-analyses of studies of systemic chemotherapy (primarily platinum-based doublets) conducted in the 1980s and 1990s demonstrated that chemotherapy improved survival in stage II to IV NSCLC. The EGFR has been known to be overexpressed in the majority of NSCLC rumors for many years. Phase I and II trials of the small-molecule EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib as well as the anti-EGFR monoclonal antibody cetux-imab demonstrated that objective responses occurred in 10% to 15% of patients with advanced NSCLC and other solid tumors. Dose-limiting toxicities included skin rash, other cutaneous toxicities, diarrhea, and other GI toxicities. Allergic reactions occurred in some patients receiving cetuximab, and rare patients receiving EGFR TKIs were reported to develop interstitial lung disease.