Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Abstract

Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A) 1 , which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B). 2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed 1,3,4 , but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype. 5-7 The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyrosine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4). 5 Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signalling cascades. 5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/ RAF/MEK and PI3K/AKT pathways, among others. 5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients. 5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signalling. 8 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C). 9 Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, anti-tumor activity (Table 1A) and safety. 10 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance. 11 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation. 12 Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progressionfree survival (PFS) relative to those treated with first-generation EGFR-TKIs. 13, 14 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the EGFR T790M mutation who had disease progression with first-and second-generation EGFR-TKIs. 15 Although the treatment landscape of advanced NSCLC has dramatically ch...

A személyre szabott terápia legújabb lehetőségei a molekuláris onkológiában

“…Első esetben, amikor a ligandum bekötődését kell legátolni, akkor EGFR-hez szelektíven kapcsolódó ellenanyag-terápiát alkalmaznak (1. táblázat). Ha az EGFR kináz aktivitását kell a mutáció miatt blokkolni, akkor pedig szintetikus kis molekulák a hatékonyak, melyek szelektíven képesek a mutált EGFR funkcióját legátolni (Meisel-Hochmair 2020).…”

Molecular Diagnostic and Precision Medicine in Non-Small Cell Lung Cancer. An Update on the Treatment of the Most Important Actionable Oncogenic Driver Alterations

“…A comprehensive review on EGFR-mutated NSCLC highlighting the current state-of-the-art treatment and unsolved questions has been recently published in this journal. 35…”