Combination chemotherapy has been extensively studied in NSCLC. In order to improve upon overall response rate and survival , investigators have begun to study drugs that are mechanistically different and complementary to cytotoxic chemotherapy.

One promising approach is to use drugs that target the epidermal growth factor receptor (EGFR). Drugs that target EGFR block the effects of this receptor, inhibiting growth and proliferation of cells. They also enhance apoptosis.

EGFR regulates growth for many cell types. Most NSCLC express EGFR and its natural ligand, transforming growth factor alpha. Overexpression of EGFR is common in squamous cell carcinomas and late stage NSCLC. Overexpression of EGFR has also been seen in adenocarcinomas , large cell carcinomas and some early stage lung cancers

Investigators have looked at several EGFR inhibitors in phase I studies of NSCLC. These include cetuximab (C225, Erbitux), erlotinib (OSI-774, Tarceva) and gefitinib (ZD1839, Iressa). Phase II studies of erlotinib and gefitinib have been completed.

There have also been phase I combination studies of gefitinib with paclitaxel plus carboplatin, and gefitinib with gemcitabine plus cisplatin. Phase III trial results for gefitinib with chemotherapy was presented at the ASCO meeting.

Not all patients with tumors that express EGFR derive clinical benefit from these targeted agents. No one yet understands why only selected tumors respond. Researchers hope that with advances in technology they will be able to identify patients in whom EGFR is critical for regulating cancer growth.

Possible future investigations include the use of EGFR inhibitors in postoperative or other adjuvant settings. In addition, these agents might be used as initial therapy for patients who cannot receive chemotherapy due to comorbid disease or poor functional status.

Some intriguing preclinical investigations suggest a potential role for EGFR inhibitors as chemoprevention agents. In the United States, the lung cancer Specialized Programs of Research has proposed a trial to evaluate gefitinib as chemoprevention for individuals who are at high risk for NSCLC.