Elsevier

Cancer Treatment Reviews

Volume 38, Issue 5, August 2012, Pages 416-430
Cancer Treatment Reviews

Antitumour Treatment
EGFR-mutated oncogene-addicted non-small cell lung cancer: Current trends and future prospects

https://doi.org/10.1016/j.ctrv.2011.10.003Get rights and content

Abstract

Non-small cell lung cancer (NSCLC) tumours with certain mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase have been termed ‘oncogene addicted’ to reflect their dependence on EGFR-mediated pro-survival signalling and their high susceptibility to apoptosis induced by EGFR tyrosine kinase inhibitors (EGFR–TKIs, e.g. gefitinib and erlotinib). The most common mutations (L858R and exon 19 deletions) predict an improved clinical response to first-line oral EGFR–TKIs compared with standard platinum-based chemotherapy in patients with advanced NSCLC. Moreover, these mutations are also prognostic of a relatively indolent course of disease, regardless of treatment, as compared with classical NSCLC. Treatment strategies for oncogene-addicted NSCLC are therefore distinct from those for non-oncogene addicted NSCLC, and will depend on the specific genetic mutation present.

Introduction

Lung cancer causes a fifth of all cancer-related deaths.1 Non-small cell lung cancer (NSCLC) accounts for most cases of lung cancer and is usually diagnosed in advanced stages. Platinum-based chemotherapy, the recommended standard first-line systemic treatment for advanced NSCLC,2 has limited efficacy3 and significant toxicity. The identification of oncogenic mutations that contribute to the pathogenesis of NSCLC has recently led to novel approaches to diagnosis, classification and management of this disease. The epidermal growth factor receptor (EGFR) tyrosine kinase has been a particularly important target for new therapies. EGFR (also known as ErbB1 or human epidermal growth factor receptor [HER]1) belongs to the Erb family of transmembrane receptor tyrosine kinases.4 Two EGFR tyrosine kinase inhibitors (TKIs), erlotinib (Tarceva®; Roche)5 and gefitinib (Iressa®; AstraZeneca),6 are currently approved for the treatment of NSCLC. EGFR–TKIs bind reversibly to the EGFR tyrosine kinase, competing with the substrate, adenosine triphosphate (ATP), and thereby blocking the catalytic activity of the enzyme. First-line EGFR–TKI therapy when given as monotherapy or in combination with chemotherapy,7, 8, 9, 10, 11, 12 had disappointing efficacy in Phase III trials performed in populations of patients with NSCLC who were not selected according to any molecular analysis of EGFR. It is now known that the efficacy of EGFR–TKI is influenced by somatic mutations in EGFR. More fundamentally, there is accumulating evidence that EGFR-mutated NSCLC represents one of several ‘oncogene-addicted’ forms of NSCLC that differ from classical NSCLC in terms of the patient groups affected, the prognosis, and the optimal diagnostic and therapeutic approaches. Focusing on EGFR, this paper reviews these developments and discusses their important implications for molecular testing and screening, treatment selection and sequencing, and the evaluation of future treatments for NSCLC.

Section snippets

EGFR TKI in unselected NSCLC populations

Early Phase III trials showed little benefit of EGFR TKI when these agents were used as monotherapy after the failure of standard chemotherapy in patients with advanced NSCLC. In the BR.21 trial, erlotinib monotherapy significantly improved overall survival (OS) and progression-free survival (PFS) after the failure of standard chemotherapy, as compared with placebo.13 Gefitinib did not improve survival or other outcomes compared with placebo when used as second- or third-line therapy in the

EGFR abnormalities in NSCLC

EGFR is activated by the binding of various ligands of the extracellular growth factor (EGF) family of peptides.20 Upon ligand binding, the enzyme homo- or hetero-dimerizes with other EGFR units or other Erb receptor subtypes, e.g. ErbB2 (HER2). The intracellular domain undergoes autophosphorylation and increased kinase activity. These changes result in the transduction of oncogenic signals via downstream pathways that mediate cell survival, proliferation and invasion, including the

The role of EGFR–TKI in patients with EGFR mutation

Small studies in 2004 first showed that NSCLC tumours with activating EGFR mutations were more likely to respond to EGFR–TKIs.39, 40 Subsequent single-arm studies showed that EGFR mutations predicted survival or progression in patients treated with gefitinib.24, 35, 45, 46, 47, 48, 100, 101 A pooled analysis of five trials showed that the presence of EGFR mutations predicted these outcomes more accurately than did the clinical predictors of ethnicity, sex, histology and smoking status.102

Resistance to EGFR–TKI

The long-term efficacy of current EGFR–TKIs in patients with activating EGFR mutations is limited by the invariable development of resistance.

Molecular testing in practice and in research

The optimal therapy for individuals with NSCLC depends on the molecular ‘portrait’ of their tumour (Fig. 3). Accordingly, biopsy sampling should be performed to give adequate material for genetic testing.55 Advances in testing methods should soon facilitate the identification of mutations, allowing the simultaneous screening for multiple mutations and the use of less invasive sampling. The key biomarkers used in clinical decision-making or with a role in future trials of molecular targeted

Conclusions

Cancer management is moving away from organ-based disease definitions to molecular-based classifications. Treatment strategies for oncogene-addicted NSCLC are distinct from those for non-oncogene addicted NSCLC, and will depend on the specific genetic mutation (e.g. in EGFR, HER-2, EML4ALK, PIK3CA/Akt and FGFR1). EGFR mutations are now known to be both prognostic (i.e. associated with indolent course) and predictive of survival benefit from EGFR–TKI therapy. In the near future the routine care

Conflict of interest statement

J.C.S. has acted as a consultant for Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, glaxosmithkiline, Lilly, Merck-Serono, Merck Sharp & Dohme, Pfizer, Roche-Genentech, Servier and sanofi-aventis. T.S.M. has acted as a consultant for AstraZeneca, Roche, Eli Lilly, Pfizer, Taiho, BMS, Merck Serono and Boellinger Ingelheim, has received honoraria from AstraZeneca, Roche, Eli Lilly, Pfizer, Merck Serono, Boehringer-Ingelheim, and has received research funding from

Acknowledgement

Editorial assistance in the development of this paper, furnished by Prism Ideas Ltd. (Nantwich, Cheshire, UK) was supported by an unrestricted grant from Boehringer-Ingelheim.

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