TEC Assessment Index

Epidermal Growth Factor Receptor Mutations and Tyrosine Kinase Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer

Assessment Program
Volume 22, No. 6
November 2007

Executive Summary

Background

Traditional treatment options for advanced (stage IIIA/B, IV) non-small-cell lung cancer (NSCLC) depend on tumor stage and location at diagnosis. Outcomes are particularly poor, with often severe systemic toxicities in patients treated with current platinum-based chemotherapy. As a consequence, targeted therapies, including those specific to the epidermal growth factor receptor (EGFR), have been sought to improve outcomes and reduce systemic toxicities.

EGFR is a protein kinase involved in key cellular processes that include growth, differentiation, apoptosis, and morphogenesis. It is commonly overexpressed on the surface of cells in a variety of human epithelial cancers, including NSCLC. Genetic dysregulation in carcinogenesis has been associated with constitutive activation of EGFR TK and downstream signaling pathways. Anti-EGFR drugs, including the small-molecule tyrosine kinase inhibitors (TKI) gefitinib (Iressa®) and erlotinib (Tarceva®) inhibit EGFR activation. In the initial phase II and phase III monotherapy studies in patients with refractory NSCLC, gefitinib had no survival benefit, but improved intermediate outcomes; whereas, erlotinib produced a small, but statistically significant, improvement in survival compared to placebo. Subsequent phase III studies showed no benefit of adding gefitinib or erlotinib to standard chemotherapy regimens in first-line treatment of advanced NSCLC. However, subgroup analyses of several trials revealed consistent correlations between therapeutic response to TKI drugs and adenocarcinoma histology, female sex, never-smoking history, and East Asian ancestry.

These observations, in the context of earlier preclinical findings, led to the identification in 2004 of somatic gain-of-function mutations in the TK domain of the EGFR gene in tumor samples from patients who had objective response to TKI drugs. A corollary to identification of the TKI mechanism of action is that this also permits testing to predict response of individual patients’ tumors to these agents. The ultimate goal of EGFR mutation testing in this setting is to select individuals who have increased probability of obtaining clinical benefit from EGFR TKI therapy and, if sufficiently predictive, to exclude individuals from such therapy who are highly unlikely to benefit from treatment.

This Assessment uses a conceptual framework that examines the analytical validity, clinical validity, and clinical utility of EGFR mutation analysis as a predictor of clinical response to either drug. As defined by the U.S. National Human Genome Research Institute, National Institutes of Health (http://www.genome.gov/10002404), the analytical validity of a genetic test defines its ability to accurately and reliably measure the genotype of interest. The clinical validity of a genetic test defines its ability to detect or predict the presence or absence of the phenotype, which in the case of this Assessment is defined as response to treatment. The clinical utility of a genetic test refers to the likelihood that using the pretreatment test results to help make management decisions will lead to an improved outcome.

Objective

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.

Search Strategy

A MEDLINE® search (via PubMed) was performed through May 2007 to obtain references to original reports on TKI therapy and mutation analysis in NSCLC, using keywords or phrases “EGFR,” “epidermal growth factor receptor,” “tyrosine kinase inhibitor,” “gefitinib,” “erlotinib,” and “mutation.” The electronic search was limited to English-language studies of human subjects. Review articles and meta-analyses provided background information. The bibliographies of retrieved articles were consulted to identify references that may have been overlooked by the electronic search. The “related articles” function was used in conjunction with key articles to identify other papers that may have been missed by the search process. Manufacturers and other vendor websites were consulted for information on commercial laboratory assays.

Selection Criteria

Original full-length, peer-reviewed studies were selected for inclusion if they provided sufficient information to calculate the analytic performance of EGFR mutations in terms of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and related those to clinical outcomes (e.g., objective response rate [ORR], overall survival [OS], progression-free survival [PFS]) with TKI therapy for advanced NSCLC.

Main Results

In 23 nonconcurrent or retrospective studies, investigators analyzed tumor samples from patients with advanced NSCLC who already had entered a TKI protocol or compassionate-use program (n=1,471 patients analyzed). The data for gefitinib consistently suggested that the presence of an EGFR gene mutation in tumors is associated with improved response, reflected in a median ORR of 72% in patients with mutations and 11% in patients with the wild-type gene. Calculation of the analytic performance of EGFR mutations as a predictor of ORR to gefitinib yields median values for sensitivity, specificity, PPV, and NPV of 75%, 91%, 72%, and 89%, respectively. Median ORR values for erlotinib were 34% and 12%, with sensitivity, specificity, PPV and NPV of 32%, 87%, 34%, and 88%, based on two reports. The presence of EGFR mutations generally correlated with longer PFS and OS, compared to results in tumors with wild-type EGFR, but the relationship between EGFR mutations and ORR is not absolute. A proportion of patients with wild-type EGFR did respond (median ORR=11%) and some with mutations did not respond (median ORR=28%).

Six subsequent peer-reviewed reports of phase II, nonrandomized studies presented results of first-line or greater TKI monotherapy in 397 patients with EGFR mutation-positive advanced NSCLC. EGFR mutations were found in 144 (36%) individual tumor samples ranging from 24% to 64% among the studies. An ORR of 81% is based on compiled mutation data from 112 patients who entered phase II treatment protocols using gefitinib. Individual study response rates ranged from 75% to 90%, with median PFS ranging from 8 months to more than 15 months and a median PPV of 82%. Comparable data on erlotinib alone are unavailable.

Discussion

The nonconcurrent and retrospective analyses of tumor cell EGFR gene TK domain mutations consistently suggest an association between the presence (or absence) of a mutation and therapeutic response (or nonresponse) to TKI drugs, primarily gefitinib. The magnitude and consistency of the PPVs for EGFR mutation analysis among 6 prospective, single-arm phase II studies supports the conclusion that this test has clinical validity as a predictor of NSCLC response to gefitinib. However, no prospective data are available on the use of EGFR mutation analysis to reliably identify nonresponders (i.e., a high NPV) to gefitinib, such that mutation-negative patients could be excluded from therapy when it is otherwise likely to be prescribed. Therefore, the clinical utility of mutation analysis remains unproven for gefitinib. A scarcity of clinical data precludes conclusions on the clinical validity or utility of EGFR mutation analysis to predict response of advanced NSCLC to erlotinib.

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; and
4. 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.

TEC Assessment Index

KEYWORDS: adenocarcinoma; adverse effects; analysis; analytic validity; biomarkers; cancer; candidate; chemotherapy; chronic myelogenous leukemia; CLIA; clinical utility; clinical validity; EGAPP; EGFR; epidermal growth factor receptor; erlotinib; gain-of-function; gefitinib; gene testing; genetic variation; genetics; genomics; germline; IDEAL; Iressa; ISEL; lung cancer; MAb; microarray; molecular; monoclonal antibody; monotherapy; mutation; neoplasms; non-small-cell; NSCLC; oncogene; oncology; PCR; personalized medicine; pharmacodynamics; pharmacogenetics; pharmacogenomics; pharmacokinetics; phase II; phase III; polymorphism; predictive; pretreatment; side effects; small cell; small molecule; small molecule inhibitors; somatic; sorafenib; Tarceva; target; targeted; TK; TKI; toxicity; transcriptional; tyrosine kinase inhibitor; wild type;