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The EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) have been included in standard treatments for advanced NSCLC. EGFR works through two different downstream signaling pathways, which are activated by the phosphorylation of the ATP-binding domain of the receptor: the MAPK cascade, which activates different genes linked to cell proliferation and survival; and the PI3K–AKT cascade, in which phosphorylated AKT inactivates proapoptotic proteins.

TKIs inhibit the phosphorylation and tyrosine kinase activity of the intracellular domain of EGFR through competitive binding to this site, thus preventing the activation of downstream signaling.

Tarceva (erlotinib), a small molecule (MW: 394 Da), has been approved for second- or third-line advanced NSCLC treatment thanks to the results reported in the BR.21 study (1), which found that, with respect to placebo, it prolonged overall survival (OS) in heavily pretreated patients.

Iressa (gefitinib), another small molecule (MW: 446 Da) that is very similar to Tarceva in terms of mechanism of action, was found to have significant anti-tumoral activity in patients with advanced NSCLC in two Phase II studies (IDEAL-1 and -2) (2,3), but its approval as a treatment for NSCLC was obtained following the IPASS trial (4), in which Iressa was compared with carboplatin–paclitaxel chemotherapy in previously untreated stage IV patients selected on the basis of clinical and histological features, such as female gender, nonsmoker history and adenocarcinoma histology.

In this trial, Iressa proved to be more effective than chemotherapy in prolonging progression-free survival (PFS) in the intention-to-treat population. In a subgroup of patients with activating EGFR mutations (exon 19 or exon 21), a 70% response rate was achieved, and the PFS and OS were longer than that following chemotherapy. Thanks to these encouraging findings, Iressa gained approval in the treatment of patients harboring EGFR mutations, also as first-line therapy.

EGFR TKIs are usually well tolerated, the main side effects being grade 1–2 diarrhea and skin rash. Only 1–2% of patients develop the potentially life-threatening adverse event of interstitial pneumonia (5,6).

1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al.; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353(2), 123–132(2005).

2. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized Phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (the IDEAL 1 trial) [corrected]. J. Clin. Oncol. 21(12), 2237–2246(2003).

3. Kris MG, Natale RB, Herbst RS et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290(16), 2149–2158(2003).

4. Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361(10), 947–957(2009).

5. Ando M, Okamoto I, Yamamoto N et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J. Clin. Oncol. 24(16), 2549–2556(2006).

6. Takano T, Ohe Y, Kusumoto M et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 45(1), 93–104(2004).