Epidermal Growth Factor Receptor Mutations and Tyrosine Kinase Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer
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 generally poor, and patients treated with current platinum-based chemotherapy often experience severe systemic toxicities. 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 tyrosine kinase and downstream signaling pathways. Anti-EGFR drugs, including the small-molecule tyrosine kinase inhibitors (TKI) gefitinib (Iressa®, AstraZeneca; not commercially available for new patients in the U.S.) and erlotinib (Tarceva®, Genentech BioOncology) 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. Subgroup analyses of several trials revealed consistent correlations between therapeutic response to TKI drugs and adenocarcinoma histology, female sex, neversmoking 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 tyrosine kinase domain of the EGFR gene—small deletions in exon 19 and point mutations in exon 21 (L858R)—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 distinguish patients who would benefit from EGFR TKI therapy from those who would not. In the U.S., the impact of EGFR mutation testing on erlotinib response is the particular focus of interest.
A Technology Evaluation Center (TEC) Assessment on this topic was first published in November 2007 (Vol. 22, No. 6). This Assessment used a conceptual framework that examined 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 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. The 2007 Assessment concluded that there was insufficient evidence to permit conclusions about the clinical validity or utility of EGFR mutation testing to predict erlotinib sensitivity or to guide treatment in patients with advanced NSCLC.
Since that analysis there have been numerous new clinical studies evaluating the relationship between EGFR mutations and TKI responses, as well as a large number of additional reviews, editorials, and perspectives on this subject. This current Assessment evaluates new information available on this subject and updates the analysis using the same conceptual framework applied in 2007.
There are now over a dozen studies linking response to erlotinib to EGFR mutation status. Most of these studies are either nonconcurrent-prospective designs or one-arm prospective enrichment studies (i.e., evaluating response to erlotinib in test-positive or –negative patients only). While the statistical interpretations are variable, the studies are quite uniform in suggesting patients with EGFR mutation-positive tumors are likely to respond favorably to erlotinib, while patients with wild-type tumors are not. In addition, patients with EGFR mutation-positive tumors appear to show better tumor response to erlotinib than to standard chemotherapy. Taken together, these findings indicate that patients with EGFR mutation-positive tumors are ideal candidates for erlotinib treatment and have a high likelihood of responding favorably to this therapy. Patients with wild-type tumors are unlikely to respond to erlotinib therapy and should be considered candidates for alternative therapies without delay.
Objective
The objective of this Assessment is to evaluate EGFR testing as a predictor of tumor response to the small-molecule TKI erlotinib (Tarceva®). This would allow for targeted and optimized selection of patients for TKI therapy based on the EGFR genetic profile of the tumor being treated.
Search Strategy
A MEDLINE® search (via PubMed) was performed from May 2007 to December 2010 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,” “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 objective radiologic response rate, progression-free survival or in some cases, time to progression and/or the overall survival with erlotinib therapy for advanced NSCLC.
Main Results
Thirteen publications provide data on EGFR mutations in tumor samples obtained from NSCLC patients in erlotinib treatment studies. Nine of these were nonconcurrent-prospective studies of patients treated with erlotinib and then studied for the presence or absence of mutations. Four were prospective one-arm enrichment studies of patients with mutation-positive (3 studies) or wild-type (1 study) tumors that were treated with erlotinib.
A total of 630 patients were studied in the 9 nonconcurrent-prospective studies comparing erlotinib results in patients with EGFR mutation-positive versus wild-type tumors. The median objective radiologic response rates in patients with EGFR mutation-positive tumors was 45% compared to 5% in wild-type patients, median progression-free survival in patients with EGFR mutation-positive tumors was 12.5 months compared to 2.5 months in wild-type patients, and median overall survival rate in patients with EGFR mutation-positive tumors was 21 months compared to 8.1 months in wild-type patients. According to the U.S. Food and Drug Administration (FDA) drug label, second-line treatment with erlotinib in untested patients results in a progression free survival of 2.8 months and an overall survival of 12 months.
In the 3 prospective studies of patients with EGFR mutation-positive tumors (n=465) treated with erlotinib, objective radiologic response rates ranged from 40 to 70%, progression-free survival times from 8 to 14 months, and overall survival times from 16 to 29 months. This performance was distinctly different than that observed in similarly treated patients with wild-type tumors who, in a small independent single-arm enrichment trial (n=30), exhibited an objective radiologic response of 3.3%, a progression-free survival of 2.1 months, and an overall survival of 9.2 months.
In the largest study, EGFR mutation status was measured in 2,105 patients and erlotinib administered to 217 patients with EGFR mutation-positive advanced NSCLC. In this EGFR mutation-positive, erlotinib-treated group, the objective radiologic response rate was 70%, median progression-free survival 14 months, and median overall survival 27 months. Adverse events were most commonly mild rashes and diarrhea. Only about 11% of patients experienced grade 3 (severe) toxic effects. The authors concluded that using historic benchmarks of response to chemotherapy (estimates of objective radiologic response of 30%, progression-free response of 5 months, and overall survival of 12 months) targeted use of erlotinib appeared to produce an improvement in net health outcome.
EGFR testing appears to identify a mutation-positive subset that is particularly sensitive to erlotinib treatment. These patients show superior response when compared to erlotinib treatment in patients with wild-type tumors. They also show superior response when compared to the use of standard chemotherapy in patients with mutation-positive tumors. Patients whose tumors are EGFR mutation positive thus appear to be ideal candidates for erlotinib treatment. Patients with wild-type tumors are much less likely to respond to erlotinib and are better served by exploring other therapeutic options.
One important final observation is that patients with EGFR mutation-positive tumors and who are treated with either erlotinib or with standard chemotherapy appear to exhibit better outcomes than patients with wild-type tumors with the same treatments. This suggests part of the predictive behavior of mutational testing is attributed to an underlying prognostic signal. Based on the information gathered so far, it is impossible to determine the relative magnitude of prognostic versus predictive effect observed as a result of testing.
Discussion
The studies of tumor-cell EGFR gene tyrosine kinase domain mutations consistently demonstrate an association between the presence (or absence) of a mutation and therapeutic response (or nonresponse) to erlotinib. Patients with EGFR mutation-positive tumors are also likely to show better response when treated with erlotinib than with standard chemotherapy and to exhibit an improved prognosis, regardless of therapy.
While to date there have been no prospective, randomized clinical trials specifically looking at how EGFR-directed therapy affects patient outcomes, there is strong evidence that response to erlotinib can be predicted based on EGFR mutation status. In evaluating patients with NSCLC, a serious disease with a poor overall prognosis, use of EGFR mutation testing appears to be a valuable tool in assisting physicians in making optimal treatment choices and improving their ability to identify patients likely to benefit or not benefit from erlotinib treatment.
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 response to erlotinib (Tarceva®) 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 is commercially available at both academic medical centers and commercial laboratories. The tests available are being offered as laboratory-developed tests, and at the current time, the FDA is not actively regulating these as a matter of enforcement discretion. The laboratories performing these tests must meet quality standards as prescribed under the Clinical Laboratory Improvement Amendments (CLIA).
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
Evidence compiled from nonconcurrent-prospective studies and one-arm prospective enrichment studies is sufficient to conclude that a gain-of-function somatic mutation in the tumor-cell EGFR gene tyrosine kinase domain identifies a population subset (patients with mutation-positive tumors) with advanced NSCLC who exhibit improved objective radiologic response, progression-free survival, and overall survival when treated with erlotinib compared to the same treatment in patients with wild-type tumors or to standard chemotherapy in patients with EGFR mutation-positive tumors.
Data are strongest for demonstrating differences in objective radiologic response, is less consistent, but strong, for progression-free survival, and is less consistent, but strong, for overall survival. Radiologic response is not generally viewed by itself as a meaningful endpoint, since its ability to predict standard and more established outcomes such as progression free survival, overall survival, or quality of life is not reliable. However, there is a published meta-analysis suggesting objective radiologic response is strongly associated with median overall survival in patients with NSCLC treated with TKIs. There is also growing discussion that overall survival may be a compromised endpoint for NSCLC due to the fact that NSCLC is a particularly aggressive disease with an increasing number of treatment choices, many specifically available for cross-over use in patients demonstrating resistance to earlier therapies. These cross-over therapies are likely to make evaluation of overall survival a challenging, and perhaps impossible, study endpoint.
3. The technology must improve the net health outcome.
Recent prospective and retrospective studies have shown convincing evidence that EGFR mutations can identify disease likely to respond to erlotinib. There is growing evidence that this information affects the net health outcome by identifying patients who are likely to exhibit good outcomes with this treatment with minimal toxicity. Recent reports suggest EGFR mutations also identify patients more likely to respond to erlotinib than to standard chemotherapy. In these patients, use of erlotinib therapy may be much more effective than alternative drug choices.
There is also growing information demonstrating that EGFR status can help physicians identify wild-type tumors in patients who are unlikely to respond to erlotinib. In these patients, alternative treatment choices should be considered. It is therefore prudent for physicians to evaluate patients with wild-type tumors carefully, considering the unique patient-specific variables and preferences at hand, to discuss these with the patient, and to use this information to make patient-informed, collaborative personalized treatment choices.
4. The technology must be as beneficial as any established alternatives.
Alternatives—in particular, use of empiric therapy—appear to be less reliable at estimating likely objective response and progression-free and overall survival than testing using EGFR mutation analysis to select patients for erlotinib therapy. The role for use of clinical risk features (female sex, adenocarcinoma histology, nonsmoking history, or Asian heritage) requires further study to determine how this information might help in making accurate testing or treatment choices.
5. The improvement must be attainable outside the investigational settings.
EGFR mutation testing is now widely available commercially, and studies have indicated that it is possible to utilize testing for improved decision making at multiple clinical sites. Testing is recognized to be of value in centers of oncology excellence, and the only impediment is the need for increased access to testing (an ongoing process) and introduction of more wide-scale use of tests with rapid turnaround time.
Based on the available evidence, use of tumor-cell EGFR mutation analysis to predict response to erlotinib (Tarceva®) in patients with advanced non-small-cell lung cancer meets the TEC criteria.
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