Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: It's Time to Get Back on Target

Abstract

A key signature of targeted cancer therapy is selectivity. This selectivity depends on identification of a target that is tightly associated with the malignant phenotype. Inhibition of the target must alter this phenotype and must not adversely affect normal tissues. An ability to measure the presence of the target is a requirement for clinical development, such that individuals with tumors that do not express the target are spared exposure to ineffective treatment. Inhibitors of the epidermal growth factor receptor (EGFR) illustrate some of the triumphs and pitfalls associated with the development of targeted cancer therapy. Murine epidermal growth factor was identified more than 40 years ago, and its human homolog and receptor were isolated 15 years later. 1-5 Subsequently, the receptor was shown to have intrinsic kinase activity. 5 During the 1980s and 1990s, several significant observations established EGFR as a potential therapeutic target. 6,7 First, studies demonstrated homology between EGFR and the proto-oncogene v-erbB. 8 Second, frequent expression of EGFR was found in a variety of epithelial malignancies, with expression conferring poor prognosis. Finally, inhibitory antibodies and small molecules were shown to block receptor phosphorylation, cellular proliferation, and xenograft growth. 9-12 Given the frequent expression of EGFR in colorectal cancer (approximately 70% to 75% by immunohistochemistry [IHC]), 13 this malignancy was identified as appropriate for the clinical development of EGFR inhibitors. Clinical activity has been demonstrated for the anti-EGFR monoclonal antibodies cetuximab 14-16 (a human-mouse chimera) and panitumumab 17 (a fully human antibody) in patients with metastatic colorectal cancer. Cetuximab is approved by the US Food and Drug Administration for use in patients with EGFRexpressing metastatic colorectal cancer. 18 Based on xenograft models that indicated potentiation of anti-EGFR monoclonal activity with cytotoxic chemotherapy, 11 the initial phase II trial of cetuximab in patients with metastatic colorectal cancer was a combination study of irinotecan plus cetuximab. 14 Subsequent clinical trials confirmed the hypothesis that irinotecan plus cetuximab in combination is superior to cetuximab monotherapy, with response rates of approximately 20%v 10%, respectively, in patients who previously showed resistance to irinotecan. 15,16 The most common toxicity associated with cetuximab is skin rash, and the presence and severity of rash have been consistently predictive of response and survival in patients with colorectal cancer. 14,16 This clinical observation has led to the exploration of skin as a surrogate pharmacodynamic marker of EGFR inhibition, and numerous studies have demonstrated the predicted downstream perturbations of EGFR signaling, such as phosphorylated EGFR, phosphorylated AKT, Ki67, and p27 in the skin of patients treated with antibody and small-molecule EGFR inhibitors. 19-21 Unfortunately, a clear association between signaling inhibition in skin and antitumor response has not been found.