Commentary (Harari): Anti-EGFR Therapy Update
Commentary (Harari): Anti-EGFR Therapy Update
Since initial characterization over 40 years ago, strong preclinical and clinical data have clearly established the epidermal growth factor receptor (EGFR) as a worthy molecular target for intervention in cancer therapy. The receptor is expressed, overexpressed, or mutated in many human tumors, including head and neck, colorectal, pancreatic, non-small-cell lung, ovarian, esophageal, gastric, breast, prostate, bladder, and renal cancers. Experiments in several model systems have confirmed that EGFR signaling is involved in regulating several key biologic processes, including cell proliferation, epithelial development, organogenesis, apoptosis, angiogenesis, and differentiation. Furthermore, EGFR function has been shown to be altered and/or dysregulated in a variety of spontaneous tumors.
In the clinical setting, several studies indicate that EGFR expression may serve as a predictor of poor prognosis, particularly in patients with head and neck, ovarian, cervical, bladder, or esophageal tumors. Collectively, sufficient evidence exists to demonstrate that the EGFR contributes to the malignant phenotype of a broad spectrum of neoplasms, and to support the inhibition of EGFR signaling as a rational therapeutic strategy in the treatment of cancer.
Monoclonal Antibodies and Tyrosine Kinase Inhibitors
The development and administration of agents that effectively inhibit EGFR signaling has proven to be a feasible anticancer treatment strategy. To date, anti-EGFR therapies with either monoclonal antibodies or with small tyrosine kinase inhibitors (TKIs) remain the most clinically mature strategies available. Several other approaches have also been designed to target EGFR signaling, including bispecific antibodies that target the ligand-binding domain of EGFR, recombinant vaccines containing human EGF attached to an immunogenic recombinant bacterial protein, antisense oligonucleotides to block the translation of proteins from genes activated by EGFR, and dual TKIs targeting the kinases of both EGFR and HER2. However, these strategies are not as fully developed in clinical trials as monoclonal antibodies and TKIs.
Anti-EGFR monoclonal antibodies and TKIs have distinct mechanisms for inhibiting EGFR activity. Monoclonal antibodies recognize epitopes in the extracellular domain of EGFR, preventing binding of the receptor's natural ligands and simultaneously reducing EGFR exposure on the cell surface. In contrast, TKIs block binding of adenosine triphosphate to the catalytic site of the EGFR TK domain, thus preventing receptor autophosphorylation and activation of downstream signaling. In addition to their distinct mechanisms of action, both classes of agents demonstrate differing pharmacokinetics and pharmacodynamics. Activity and toxicity profiles for both classes of agents are helping to define which tumor types and patients are most effectively treated with either class of drug.
Currently, three EGFR-targeted agents are clinically available: the monoclonal antibody cetuximab (Erbitux) and small-molecule TKIs gefitinib (Iressa) and erlotinib (Tarceva). Cetuximab is currently indicated in combination with irinotecan (Camptosar) for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are refractory to irinotecan, or as a single agent for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients intolerant to irinotecan. Gefitinib and erlotinib are indicated for patients who have previously treated non-small-cell lung cancer. Indications for all three EGFR inhibitors are likely to expand in the near future as outcome data mature from a series of major clinical trials across several different tumor types.
Toxicities Associated With Anti-EGFR Agents
Although clinical studies have shown that treatment with anti-EGFR agents is generally safe and well tolerated, and does not substantially exacerbate toxicities commonly associated with chemotherapy or radiation therapy, anti-EGFR agents are associated with several specific toxicities. For example, EGFR inhibitors are linked to dermatologic toxicities that manifest as acneiform rash, nail disorders, or hair abnormalities that often require specific management strategies. In addition, monoclonal antibodies have demonstrated the potential to induce hypersensitivity reactions. Tyrosine kinase inhibitors can induce diarrhea that may limit their incorporation into certain chemotherapeutic regimens at fully effective doses.
In order to optimize the clinical outcomes of patients receiving anti-EGFR cancer therapies, several important aspects remain the subject of continued study. These include reliable methods to establish EGFR signaling footprints in individual tumors, the respective role of different EGFR inhibitors for various anatomic tumor types, the optimal selection of patients (tumors) most likely to respond to EGFR inhibition strategies, preferred timing and dosing as single-agent therapy or in combination with other agents, and potential beneficial interactions with other treatment modalities.