Authors' objectives:

The objective of this Assessment is to evaluate tumor cell EGFR gene mutation analysis as a means to select (or deselect) patients with advanced non-small-cell lung cancer (NSCLC) for therapy with the small-molecule tyrosine kinase inhibitor (TKI) erlotinib (Tarceva®).

Gefitinib (Iressa®), also a TKI, received accelerated marketing approval from the U.S. Food and Drug Administration (FDA) in May 2003; whereas, erlotinib received approval through the new drug approval (NDA) process in November 2004. On the basis of unanticipated poor results with gefitinib in a postapproval phase III monotherapy trial (ISEL), the FDA revised its labeling in mid-2005. Gefitinib is no longer available for routine use in new patients in the U.S. However, given the close pharmacologic and pharmacodynamic similarities of gefitinib and erlotinib, both agents were considered in the evidence review.

Authors' recommendations: Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether use of EGFR mutation analysis to predict TKI sensitivity meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria. 1. The technology must have final approval from the appropriate governmental regulatory bodies. EGFR mutation analysis (PCR amplification and gene sequencing) is commercially available as a laboratory-developed test (Genzyme Genetics, Westborough, MA). Such tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing. 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes. Evidence compiled from nonconcurrent and retrospective studies is sufficient to conclude that a gain-of-function somatic mutation in one of exons 18-24 of tumor cell EGFR gene tyrosine kinase domain reasonably predicts ORR to gefitinib therapy in patients with advanced NSCLC, based on the sensitivity, specificity, PPV, and NPV of mutation presence compared to absence, suggesting this marker has clinical validity in this setting. Results from single-arm prospective phase II studies are sufficient to conclude that the presence of a gain-of-function somatic mutation in one of exons 18-24 of the EGFR gene TK domain is a strong predictor of ORR based on the PPV, supporting clinical validity. Evidence from the prospective gefitinib studies cannot be used to determine the NPV, nor correlations with OS, and thus does not permit conclusions concerning the clinical utility of tumor cell EGFR mutation analysis to predict the net health outcome relative to standard therapy. Furthermore, because gefitinib is not available for routine use in the U.S., conclusions about the clinical utility of mutation analysis in guiding its use have little practical value. Evidence is insufficient to permit conclusions about the clinical validity or utility of EGFR mutation testing to predict erlotinib sensitivity or guide therapy in patients with advanced NSCLC. There is no prospective evidence on the NPV of mutation analysis that could be used to justify withholding erlotinib therapy. 3. The technology must improve the net health outcome; and4. The technology must be as beneficial as any established alternatives. There is insufficient evidence to permit conclusions regarding the use of tumor cell EGFR mutation analysis results for managing advanced NSCLC treatment in the context of a standard of care in which erlotinib therapy would be offered to all endstage patients. 5. The improvement must be attainable outside the investigational settings. Whether or not the use of tumor cell EGFR mutation analysis for managing advanced NSCLC treatment improves health outcomes has not been demonstrated in the investigational setting. Based on the above, use of tumor cell EGFR mutation analysis to predict therapeutic sensitivity to erlotinib (Tarceva®) does not meet the TEC criteria.

Project Status: Completed

URL for project: http://www.bcbs.com/blueresources/tec/contact-tec.html

Year Published: 2007

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: BlueCross BlueShield Association

Contact Address: BlueCross BlueShield Association, Technology Evaluation Center, 225 North Michigan Ave, Chicago, Illinois, USA. Tel: 888 832 4321

Contact Name: tec@bcbsa.com

Contact Email: tec@bcbsa.com

Copyright: BlueCross BlueShield Association (BCBS)