Implications of key trials in advanced nonsmall cell lung cancer

• Published in: Cancer Vol. 116; no. 5; pp. 1155 - 1164
• Main Author: Bonomi, Philip D.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2010; Wiley-Blackwell
• Subjects: advanced NSCLC; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Cetuximab; Clinical Trials, Phase III as Topic; Drug Delivery Systems; first‐line treatment; Humans; Lung Neoplasms - drug therapy; Medical sciences; molecular markers; Patient Selection; Pneumology; targeted therapy; Treatment Outcome; Tumors; Tumors of the respiratory system and mediastinum; Antineoplastic agent; Genetic marker; Targeted therapy; Lung cancer; Selection; Monoclonal antibody; Molecular marker; non-small cell lung carcinoma; advanced NSCLC; Epidermal growth factor receptor; Bevacizumab; Cancerology; Bronchus disease; Clinical trial; Advanced stage; first-line treatment; Antiangiogenic agent; Cetuximab; Human; Lung disease; Respiratory disease; Malignant tumor; First line treatment; Vascular endothelium growth factor; patient selection; molecular markers; Cancer
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.24815

Many different targeted therapies with varying mechanisms of action have been added to standard first‐line chemotherapy doublets in an effort to improve survival of patients with advanced nonsmall cell lung cancer (NSCLC). Only 2 targeted therapies—bevacizumab and cetuximab—have been associated with superior survival in phase 3 first‐line studies. For both agents, the decision to enter phase 3 was based on results from randomized phase 2 trials, unlike other targeted therapies where the decision was made using either phase 1 or single study arm phase 2 results. There is also mounting evidence that patient selection will play a key role in the successful development of any targeted agent. Bevacizumab is indicated for patients with nonsquamous NSCLC who do not have certain comorbidities. Use of cetuximab is not restricted by safety factors, but may be focused on patients whose tumors are epidermal growth factor receptor (EGFR)‐dependent; whether EGFR expression or absence of KRAS mutations are appropriate markers is still under study. By including randomized phase 2 trials in the development pathway, and by improving patient selection for individual agents (enriching trials with patients most likely to respond), it may be possible to enhance the success rate of future phase 3 clinical trials and, in turn, define future clinical practice with improved patient outcomes. Cancer 2010. © 2010 American Cancer Society. Among the numerous targeted agents investigated in first‐line advanced nonsmall cell lung cancer (NSCLC), only bevacizumab and cetuximab have demonstrated overall survival improvements. The clinical development of these agents indicate that approaches based in randomized phase 2 trials before transitioning to phase 3 may have better chances of success. In addition, sound clinical development for any agent in NSCLC in the near future will almost certainly depend on reliable patient selection strategies.