This Article Full Text Full Text (PDF) eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maione, P. Articles by Ciardiello, F. Search for Related Content PubMed PubMed Citation Articles by Maione, P. Articles by Ciardiello, F.

Combining Targeted Therapies and Drugs with Multiple Targets in the Treatment of NSCLC

^a Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy; ^b Second University of Naples, Naples, Italy

Key Words. NSCLC • Multitargeted therapy • Erlotinib • Bevacizumab • ZD6474

Correspondence: Paolo Maione, M.D., Division of Medical Oncology, "S.G. Moscati" Hospital, Contrada Amoretta, 83100 Avellino, Italy. Telephone: 39-0825-203573; Fax: 39-0825-203556; e-mail: pmaione{at}libero.it.

The first generation of clinical trials of targeted agents in non-small cell lung cancer (NSCLC) treatment has concluded. To date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. Nevertheless, clinically meaningful advances have already been achieved. In chemotherapy-refractory advanced NSCLC patients, gefitinib and erlotinib, two epidermal growth factor receptor tyrosine kinase inhibitors, represent a further chance for tumor control and symptom palliation. In chemotherapy-naive, advanced, nonsquamous NSCLC patients, the combination of the anti–vascular endothelial growth factor monoclonal antibody bevacizumab with chemotherapy was demonstrated to produce better survival outcomes than with chemotherapy alone. The relative failure of first-generation targeted therapies in lung cancer may be a result of multilevel cross-stimulation among the targets of the new biological agents. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Preclinical evidence of the synergistic antitumor activity achievable by combining targeted agents that block multiple signaling pathways has recently been emerging. Clinical trials of multitargeted therapy may represent the second generation of studies in this field, and some of these are already ongoing. In a recent phase I/II trial, the combination of erlotinib and bevacizumab demonstrated very promising activity in the treatment of advanced NSCLC pretreated with chemotherapy. Whether the multitargeted approach is best performed using combinations of selective agents or agents that intrinsically target various targets is a matter of debate.

This article has been cited by other articles:

				A. L. Boehm, M. Sen, R. Seethala, W. E. Gooding, M. Freilino, S. M. Y. Wong, S. Wang, D. E. Johnson, and J. R. Grandis Combined Targeting of Epidermal Growth Factor Receptor, Signal Transducer and Activator of Transcription-3, and Bcl-XL Enhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck Mol. Pharmacol., June 1, 2008; 73(6): 1632 - 1642. [Abstract] [Full Text] [PDF]

				Y.-C. Wang, S. K. Kulp, D. Wang, C.-C. Yang, A. M. Sargeant, J.-H. Hung, Y. Kashida, M. Yamaguchi, G.-D. Chang, and C.-S. Chen Targeting Endoplasmic Reticulum Stress and Akt with OSU-03012 and Gefitinib or Erlotinib to Overcome Resistance to Epidermal Growth Factor Receptor Inhibitors Cancer Res., April 15, 2008; 68(8): 2820 - 2830. [Abstract] [Full Text] [PDF]

				J. Krol, R. E. Francis, A. Albergaria, A. Sunters, A. Polychronis, R. C. Coombes, and E. W.-F. Lam The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells Mol. Cancer Ther., December 1, 2007; 6(12): 3169 - 3179. [Abstract] [Full Text] [PDF]

				C. Gridelli, P. Maione, A. Rossi, and F. De Marinis The Role of Bevacizumab in the Treatment of Non-Small Cell Lung Cancer: Current Indications and Future Developments Oncologist, October 1, 2007; 12(10): 1183 - 1193. [Abstract] [Full Text] [PDF]

				A. Zundelevich, G. Elad-Sfadia, R. Haklai, and Y. Kloog Suppression of lung cancer tumor growth in a nude mouse model by the Ras inhibitor salirasib (farnesylthiosalicylic acid) Mol. Cancer Ther., June 1, 2007; 6(6): 1765 - 1773. [Abstract] [Full Text] [PDF]

				C. Gridelli, P. Maione, F. Del Gaizo, G. Colantuoni, C. Guerriero, C. Ferrara, D. Nicolella, D. Comunale, A. De Vita, and A. Rossi Sorafenib and Sunitinib in the Treatment of Advanced Non-Small Cell Lung Cancer Oncologist, February 1, 2007; 12(2): 191 - 200. [Abstract] [Full Text] [PDF]

				M. Ono and M. Kuwano Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs Clin. Cancer Res., December 15, 2006; 12(24): 7242 - 7251. [Abstract] [Full Text] [PDF]