Dacomitinib

EGFR tyrosine-kinase inhibitors (TKIs) have now been firmly established as the first-line treatment for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations, based on seven prospective randomized Phase III trials. However, despite significantly improved overall response rate and improved median progression-free survival when compared to platinum-doublet chemotherapy, EGFR-mutant NSCLC patients treated with EGFR TKIs invariably progress due to the emergence of acquired resistances, with the gatekeeper T790M mutation accounting for up to 60% of the resistance mechanisms. Second-generation irreversible EGFR TKIs were developed in part to inhibit the T790M mutation, in addition to the common activating EGFR mutations. Dacomitinib is one such second-generation EGFR TKI designed to inhibit both the wild-type (WT) EGFR and EGFR T790M. Afatinib is another second-generation EGR TKI that has been now been approved for the first-line treatment of EGFR-mutant NSCLC patients, while dacomitinib continues to undergo clinical evaluation.

BACKGROUND: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases.

INTRODUCTION: Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a dismal prognosis. With the emergence of monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR), several drugs were developed and tested in HNSCC. To date, the monoclonal antibody cetuximab is the only approved therapy for curative and recurrent/metastatic patients. Other EGFR-targeting drugs either failed in the clinical trials or are still in the early phases of drug development and research. Areas covered: In this article, previously published data and ongoing studies regarding dacomitinib, a second-generation irreversible TKI, for the treatment of HNSCC are presented and discussed. Expert opinion: The current body of evidence is not mature enough to indicate the use of dacomitinib for the treatment of HNSCC in curative or in recurrent/metastatic settings. Phase II data suggest the potential of improved outcome in selected recurrent/metastatic HNSCC based on several biomarkers, which need to be evaluated in randomized phase III trials.

BACKGROUND: Dacomitinib, an irreversible panHER inhibitor, shows significant preclinical antitumor activity in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). The aim of this study was to evaluate the clinical activity of dacomitinib and discover potential biomarkers in HER2-positive GC patients.