Advanced non-small-cell lung cancer with epidermal growth factor receptor mutations: current evidence and future perspectives

Abstract

The identification of activating mutations in the tyrosine kinase domain of the EGF receptor (EGFR) predictive of response to tyrosine kinase inhibitors (TKIs) led to a therapeutic revolution in the treatment of patients with metastatic non-small-cell lung cancer (NSCLC). To date, eight randomized clinical trials have demonstrated that first-line treatment with TKIs in advanced NSCLC patients harboring activating EGFR mutations is associated with significant improvement in response rate, progression-free survival, quality of life and tolerability, compared with platinum-based chemotherapy. These results prompted the EGFR TKIs as the current standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations. However, there are several questions that need to be addressed, including the best choice among different EGFR TKIs, the treatment of resistant disease and of patients with specific clinical conditions. Ongoing and future, well-designed trials should answer all these questions.

Tyrosine Kinase Inhibitors in EGFR-Mutated Large-Cell Neuroendocrine Carcinoma of the Lung A Case Report

“…Eight important studies were conducted to evaluate the efficacy and tolerability of TKIs on advanced NSCLC in comparison with standard platinum-based chemotherapy [1]. Not surprisingly, the use of TKIs was correlated with a higher response rate, a longer progression-free survival and a better quality of life in patients with advanced NSCLC activating EGFR mutation.…”

“…Not surprisingly, the use of TKIs was correlated with a higher response rate, a longer progression-free survival and a better quality of life in patients with advanced NSCLC activating EGFR mutation. The IRESSA Pan-Asia Study (IPASS), which enrolled 1,217 patients, was the largest trial in which patients were randomized to receive gefitinib or standard chemotherapy, and in the group of TKIs therapy the primary endpoints were reached obtaining a statistically significantly higher response rate, a longer progression-free survival and better symptom control [1]. Similar results were reported by First-SIGNAL and by West Japan Thoracic Oncology Group (WJTOG 3405) studies [1].…”

Afatinib: An overview of its clinical development in non-small-cell lung cancer and other tumors

“…Nausea and vomiting were infrequent. Elevated levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST), frequently observed with gefitinib (55-75% patients, with grade  3 in 14-26% cases) and less frequently with erlotinib (6-37% patients, with grade  3 in 2-4% cases), were rarely described with afatinib: no liver dysfunction was reported with afatinib in LuxLung 3 trial, and only a mild-moderate increase of ALT was observed in 20% patients treated with afatinib in Lux-Lung 6 trial [33]. Interstitial lung disease (ILD), the most serious adverse event associated with gefitinib therapy in 2-5% patients treated in NEJ002 and WJTOG3405 trial, was rare with afatinib and it was reported in <1% patients.…”

The Role of microRNAs in the Regulation of Apoptosis in Lung Cancer and Its Application in Cancer Treatment

“…Studies have shown that these mutations preferentially bind to first generation EGFR-TKIs, gefitinib and erlotinib [119, 120]. First generation EGFR-TKIs function by selectively targeting the receptor via a competitive, reversible binding at the tyrosine kinase domain, thus leading to the inhibition of ATP binding and subsequent signal transduction and downstream functions [121]. However, acquired resistance to EGFR-TKIs in the metastatic setting is unavoidable.…”