Advanced NSCLC With EGFR Mutations

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Advanced NSCLC With EGFR Mutations

Abstract and Introduction

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.

Introduction


Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Platinum-based chemotherapy has been for many years the standard treatment for all fit patients with metastatic disease, but it is associated with a small survival benefit and substantial toxicity. In the last few years, the identification in a subgroup of NSCLC patients of mutations in the tyrosine kinase domain of the EGF receptor (EGFR), that are highly predictive of response to EGFR tyrosine kinase inhibitors (TKIs), has profoundly changed this scenario, leading to a substantial diagnostic and therapeutic change for patients with metastatic NSCLC.

EGFR is a 170-kDa plasma membrane glycoprotein, composed of an extracellular ligand binding domain, a transmembrane domain and an intracellular tyrosine kinase domain and belongs to a family of four different tyrosine kinase receptors (EGFR (ErbB1), HER2/neu (ErbB2), HER3 (ErbB3), HER4 (ErbB4)). Dimerization of EGFR occurs after binding of a ligand, such as EGF, with activation of the intrinsic tyrosine kinase activity and tyrosine autophosphorylation, which may result in cancer cell proliferation, apoptosis blocking, invasion, metastasis and tumor-induced neovascularization. Therefore, EGFR plays a central role in the process of cell growth and tumor progression and its overexpression occurs in many human epithelial tumors, including NSCLC. On these bases, EGFR has been considered an attractive target for novel biological anticancer agents and several strategies have been developed to target EGFR, including small-molecule TKIs, such as gefitinib and erlotinib, and monoclonal antibodies, such as cetuximab.

EGFR mutant NSCLC was first identified in 2004 as a distinct molecular subset of lung cancer, following sequencing of the EGFR gene from patients with NSCLC responding to gefitinib or erlotinib. Interestingly, EGFR mutations were found strongly associated with some clinical and pathological features, being more frequent in female patients, adenocarcinoma subtype, non-smokers or former smokers and patients from Eastern Asia. The most frequent EGFR mutations are small in-frame deletions in exon 19 (nearly 50%) that affect the conserved sequence LREA (delE746-A750) and a single point mutation in exon 21 (nearly 40%) that substitutes an arginine for a leucine at codon 858 (L858R). These mutations are responsible of constitutive activation of the tyrosine kinase domain of the EGFR, which is normally maintained, in the absence of ligand stimulation, in an auto-inhibited conformation. Therefore, kinase domain mutations of EGFR, referred as 'activating mutations', identify a specific subtype of lung cancer, whose growth is dependent on EGFR pathway activation, which represents the leading pathway in inducing cellular transformation in these selected patients ('oncogenic addiction'). It has been also demonstrated that activating EGFR mutations may led to increased affinity of TKIs for the mutant receptor compared with the wild-type one. To date, eight randomized clinical trials in selected patients (two including clinically selected patients and six prospectively dedicated to EGFR-mutant patients) have consistently demonstrated the efficacy of TKIs as first-line therapy of EGFR mutated NSCLC (Table 1).

This review summarizes the available evidences coming from the randomized trials that support the use of TKIs as the standard first-line treatment of patients with advanced NSCLC harboring EGFR mutations. Moreover, it discusses several issues associated with the use of first-generation (gefitinib, erlotinib) and second-generation (afatinib, dacomitinib) TKIs and with the treatment of resistant disease.

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