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Next-generation EGFR/HER tyrosine kinase inhibitors for the treatment of patients with non-small-cell lung cancer harboring EGFR mutations: a review of the evidence

Authors Wang X, Goldstein D, Crowe P, Yang J

Received 17 May 2016

Accepted for publication 12 August 2016

Published 6 September 2016 Volume 2016:9 Pages 5461—5473


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ram Prasad

Peer reviewer comments 2

Editor who approved publication: Dr Faris Farassati

Xiaochun Wang,1,2 David Goldstein,3 Philip J Crowe,1,2 Jia-Lin Yang1,2

1Department of Surgery, 2Sarcoma and Nanooncology Group, Adult Cancer Program, Lowy Cancer Research Centre, 3Department of Medical Oncology, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

Tyrosine kinase inhibitors (TKIs) against human epidermal growth factor receptor (EGFR/HER) family have been introduced into the clinic to treat cancers, particularly non-small-cell lung cancer (NSCLC). There have been three generations of the EGFR/HER-TKIs. First-generation EGFR/HER-TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR TK domain, show a significant breakthrough treatment in selected NSCLC patients with activating EGFR mutations (actEGFRm) EGFRL858R and EGFRDel19, in terms of safety, efficacy, and quality of life. However, all those responders inevitably develop acquired resistance within 12 months, because of the EGFRT790M mutation, which prevents TKI binding to ATP-pocket of EGFR by steric hindrance. The second-generation EGFR/HER-TKIs were developed to prolong and maintain more potent response as well as overcome the resistance to the first-generation EGFR/HER-TKIs. They are different from the first-generation EGFR/HER-TKIs by covalently binding to the ATP-binding site, irreversibly blocking enzymatic activation, and targeting EGFR/HER family members, including EGFR, HER2, and HER4. Preclinically, these compounds inhibit the enzymatic activation for actEGFRm, EGFRT790M, and wtEGFR. The second-generation EGFR/HER-TKIs improve overall survival in cancer patients with actEGFRm in a modest way. However, they are not clinically active in overcoming EGFRT790M resistance, mainly because of dose-limiting toxicity due to simultaneous inhibition against wtEGFR. The third-generation EGFR/HER-TKIs selectively and irreversibly target EGFRT790M and actEGFRm while sparing wtEGFR. They yield promising efficacy in NSCLC patients with actEGFRm as well as EGFRT790M resistant to the first- and second-generation EGFR-TKIs. They also appear to have a lower incidence of toxicity due to the reduced inhibitory effect on wtEGFR. Currently, the first-generation EGFR/HER-TKIs gefitinib and erlotinib and second-generation EGFR/HER-TKI afatinib have been approved for use as the first-line treatment of metastatic NSCLC with actEGFRm. This review will summarize and evaluate a broad range of evidence of recent development of EGFR/HER-TKIs, with a focus on the second- and third-generation EGFR/HER-TKIs, in the treatment of patients with NSCLC harboring EGFR mutations.

Keywords: EGFR/HER, tyrosine kinase inhibitors, NSCLC, EGFR mutations, acquired resistance

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