Understanding Resistance to EGFR Inhibitors—Impact on Future Treatment Strategies

Deric L. Wheeler; Emily F. Dunn; Paul M. Harari

In This Article

EGFR Inhibitors

Monoclonal Antibodies

Cetuximab (C225, Erbitux® [Bristol-Myers Squibb, New York, NY]) is an immunoglobulin G1 chimeric mouse–human monoclonal antibody that specifically targets the extracellular domain of EGFR (Table 1). It has a mean half-life of approximately 112 h in humans (63–230 h).[15,16,54] Cetuximab functions by blocking endogenous ligand binding to the extracellular domain of EGFR and enhances receptor internalization and degradation. Cetuximab can also induce antibody-dependent cell-mediated cytotoxicity (Table 2).[55] Cetuximab has exhibited promising antitumor activity in clinical trials as monotherapy and when used in combination with chemotherapy and/or radiation, particularly in the settings of metastatic CRC[27,56–59] and HNSCC.[23,60,61] In 2004, the FDA approved cetuximab for use in combination with irinotecan for the treatment of patients with EGFR-expressing metastatic CRC refractory to irinotecan-based chemotherapy. In addition, cetuximab was approved for use as a single-agent in patients with metastatic CRC who cannot tolerate irinotecan-based therapies. In 2006, the FDA approved the use of cetuximab in combination with radiation for the treatment of locoregionally advanced HNSCC. In addition, cetuximab was approved as a single-agent for the treatment of patients with recurrent or metastatic HNSCC for whom platinum-based therapy had failed.

Panitumumab (ABX-EGF, Vectibix® [Amgen, Thousand Oaks, CA]) is a fully humanized immunoglobulin G2 monoclonal antibody with high affinity for EGFR and a mean half-life of approximately 7.5 days in humans (range 3.6–10.9 days; Table 1).[62] Panitumumab functions by blocking EGF and TGF-α binding to EGFR, and also leads to receptor internalization and degradation (Table 2).[63] Panitumumab has exhibited promising antitumor activity in several clinical trials, and in 2006 gained FDA approval for the treatment of patients with EGFR-expressing metastatic CRC with disease progression following chemotherapy regimens containing fluoropyrimidine, oxaliplatin, and irinotecan.[64–66]

Tyrosine Kinase Inhibitors

TKIs under active clinical investigation are mostly derived from quinazoline, and are low molecular weight synthetic molecules that block the magnesium-ATP-binding pocket of the intracellular tyrosine kinase domain (Table 1). Several drugs, such as gefitinib and erlotinib, are specific for EGFR, whereas others (lapatinib [GlaxoSmithKline, Brentford, UK], vandetanib [AstraZeneca, London, UK], and AEE788 [Novartis, Basel, Switzerland]) inhibit more than one receptor in addition to EGFR, such as HER2 and VEGFR2. TKIs block ligand-induced receptor autophosphorylation by binding to the tyrosine kinase domain and disrupting tyrosine kinase activity, thereby abrogating intracellular downstream signaling (Table 2). The FDA approved gefitinib through a new accelerated process in May 2003 as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies. As a condition of accelerated approval, the FDA required demonstration of a survival benefit in a subsequent clinical trial. After three large, prospective studies (INTACT 1, INTACT 2 and ISEL) showed no improvement in overall survival, the original FDA approval was modified in 2005, limiting the indication to cancer patients who, in the opinion of their treating physician, are currently benefiting or have previously benefited from gefitinib treatment. Erlotinib was originally approved in November 2004 as monotherapy for the treatment of NSCLC patients who did not respond to at least one prior chemotherapy. In November 2005, erlotinib was approved in combination with gemcitabine for advanced pancreatic cancer patients who have not received previous chemotherapy.