The current situation: erlotinib (Tarceva) and gefitinib (Iressa) in non-small cell lung cancer.

Correspondence: Robert L. Comis, M.D., Director, Drexel University College of Medicine, Clinical Trials Research Center, 1818 Market Street, Suite 1100, Philadelphia, PA 19013, USA. Telephone: 215-789-3609; Fax: 215-789-3655; e-mail: rcomis@ecogchair.org Received July 14, 2005; accepted for publication July 21, 2005. ©AlphaMed Press 1083-7159/2005/$12.00/0 Introduction Molecular targeted therapies, such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), provide a different mechanism of action from chemotherapy and can be much more specific in their approach to cancer treatment. The New Drug Application (NDA) for erlotinib (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com; Hoffman-La Roche, Basel, Switzerland, http://www.roche.com; Genentech, Inc., South San Francisco, CA, http://www.gene.com) use for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen was approved in the United States on November 18, 2004, as well as in Switzerland on March 22, 2005. The dossier is currently undergoing review with the European Medicines Agency (EMEA). These approvals were based on data from the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Study BR.21, a randomized, doubleblinded, placebo-controlled, phase III study of singleagent erlotinib at a dose of 150 mg daily in patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen [1]. Erlotinib is the only EGFR TKI therapy shown in a randomized phase III trial to provide a survival benefit to NSCLC patients (hazard ratio [HR] = 0.73). Changes/Advances in Treatment of NSCLC Since the Approval of Erlotinib

[1]  N. Thatcher,et al.  Pr4 ISEL: A Phase III survival study comparing gefitinib (IRESSA) plus best supportive care (BSC) with placebo plus BSC, in patients with advanced non-small-cell lung cancer (NSCLC) who had received one or two prior chemotherapy regimens , 2005 .

[2]  I. Wistuba,et al.  Phase I/II trial of bevacizumab plus erlotinib for patients with recurrent non-small cell lung cancer: Correlation of treatment response with mutations of the EGFR tyrosine kinase gene , 2005 .

[3]  R. Gray,et al.  Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599 , 2005 .

[4]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[6]  K. Papadopoulos,et al.  A pilot, pharmacokinetic (PK), and pharmacodynamic (PD) study to determine the feasibility of intrapatient dose escalation to tolerable rash and the activity of maximal doses of erlotinib (E) in previously treated patients with advanced non-small cell lung cancer (NSCLC) , 2005 .

[7]  J. Farndon,et al.  EPIDERMAL-GROWTH-FACTOR RECEPTOR STATUS AS PREDICTOR OF EARLY RECURRENCE OF AND DEATH FROM BREAST CANCER , 1987, The Lancet.

[8]  H. Kato,et al.  A comparison of epidermal growth factor receptor levels and other prognostic parameters in non-small cell lung cancer. , 1996, European journal of cancer.

[9]  B. Wiens,et al.  ABX-EGF monotherapy in patients (pts) with metastatic colorectal cancer (mCRC): An updated analysis , 2004 .

[10]  L. Schwartz,et al.  Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  A. Bezjak,et al.  A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial , 2004 .

[12]  Neal J Meropol,et al.  Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  L. Seymour,et al.  Tarceva™ (erlotinib) exposure/effects (EE) analysis from a Phase III study in advanced NSCLC: Effect of smoking on the PK of erlotinib , 2005 .

[14]  Takayuki Kosaka,et al.  Mutations of the Epidermal Growth Factor Receptor Gene in Lung Cancer , 2004, Cancer Research.

[15]  L. Seymour,et al.  Molecular analysis of the epidermal growth factor receptor (EGFR) gene and protein expression in patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial BR.21 , 2005 .

[16]  R. Pazdur,et al.  FDA drug approval summary: erlotinib (Tarceva) tablets. , 2005, The oncologist.

[17]  L. Seymour,et al.  Smoking history is more predictive of survival benefit from erlotinib for patients with non-small cell lung cancer (NSCLC) than EGFR expression , 2005 .

[18]  P. Catalano,et al.  High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200 , 2005 .

[19]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[20]  Armando Santoro,et al.  Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. , 2004, The New England journal of medicine.