59IN - Strategies to Optimize EGFR Therapies

Abstract

ABSTRACT The epidermal growth factor receptor remains the best validated target for systemic therapy of squamous cell carcinoma of the head and neck (SCCHN), with the EGFR-directed monoclonal antibody cetuximab the only targeted therapy to impact overall survival in this disease. However, the augmentation of response when cetuximab is added to conventional chemotherapy for recurrent/metastatic disease is modest, as is the delay in time to progression; thus, de novo and acquired resistance to EGFR inhibition are significant problems. De novo resistance may result when downstream signaling intermediaries are altered, as with H-ras mutation or PTEN loss. To date, no signature of abnormality in the signaling stream has been shown to predict cetuximab resistance in SCCHN in a manner analogous to K-ras mutation as a predictor of cetuximab resistance in colorectal cancer. Combinations of cetuximab with PI3K, mTOR or Aurora kinase inhibitors are in clinical trial currently. Nuclear translocation of phosphorylated EGFR is documented in SCCHN and associated with worsened outcome. Once present in the nucleus, EGFR interacts with transcription factors and phosphorylates and stabilizes PCNA. Gefinitib and lapatinib appear to inhibit nuclear translocation. Nuclear translocation of EGFR and its intranuclear functions may represent targets more amenable to tyrosine kinase inhibitors than to cetuximab, and we are currently studying the combination of cetuximab and erlotinib together with standard chemotherapy for recurrent/metastatic disease. Acquired resistance may result from the upregulation of alternate HER family member receptor tyrosine kinases, and dual EGFR/HER2 or pan-HER inhibitors such as lapatinib and afatinib are under study. Afatinib is the first kinase inhibitor to show activity comparable to that of cetuximab. As an oral agent, it is more suited to prolonged administration than is cetuximab, and an international phase III trial of afatinib vs. placebo for patients with poor risk locally advanced head and neck cancer who have completed chemoradiation. MET is another receptor tyrosine kinase overexpressed in head and neck cancer, and associated with cetuximab resistance. Novel agents targeting MET include monoclonal antibodies and tyrosine kinase inhibitors. Disclosure Paid consultant to Bristol Myers Squibb in 2012. Unpaid Steering Committee member Boehringer Ingelheim, unpaid consultant Millenium Pharmaceuticals.