Epidermal growth factor receptor mutations in patients with non-small cell lung cancer

A year has passed since mutations of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) were discovered in patients with non-small cell lung cancer (NSCLC) who had dramatic clinical responses to treatment with gefitinib. Additional laboratory and clinical studies have provided further insight into the biological impact of EGFR mutations in cell culture experiments and in patients with NSCLC. In vitro characterizations of NSCLC cell lines and host cell lines transfected with these mutant and wild-type EGFR show that most cell lines with mutated EGFR are growth-inhibited by 10- to 100-fold lower concentrations of gefitinib and erlotinib compared with wild-type EGFR. NSCLC lines with mutations of the EGFR treated with concentrations of gefitinib and erlotinib that are achievable in the plasma undergo apoptosis rather than growth arrest. Retrospective studies of patients with NSCLC-treated gefitinib have reported a close association between EGFR mutations, increased chance of clinical response and longer survival. This review will provide information on the impact of EGFR mutations on gefitinib and erlotinib treatment by in vitro experiments, the outcome of NSCLC patients with these mutations when treated with gefitinib and erlotinib, and the subsets of patients with NSCLC in whom these mutations arise.     

“Who Should Receive Epidermal Growth Factor Receptor Inhibitors for Non-Small Cell Lung Cancer and When?”

Opinion statement Inhibition of the epidermal growth factor receptor (EGFR) pathway in non-small cell lung cancer (NSCLC) is an exciting and rapidly evolving field. Erlotinib and gefitinib, two tyrosine kinase inhibitors (TKIs) of EGFR, have demonstrated activity in advanced NSCLC in the second- and third-line settings. Subset analyses of phase II and phase III clinical trials lead to the recognition that these two agents had more activity in certain subsets of NSCLC patients including never smokers, people of Asian descent and patients with EGFR FISH-positive or mutation-positive tumors. In particular, never smokers had statistically significant improvements in survival with either erlotinib or gefitinib therapy. Patients with EGFR FISH- or mutation-positive tumors had improved response rates to TKI therapy while those with KRAS mutant tumors did not derive any benefit. In the BR.21 trial treatment with erlotinib resulted in statistically significant improvements in overall survival and quality of life. Thus, while the question of who should receive EGFR TKI therapy is still not completely answered, all patients should be considered for erlotinib therapy in the second- or third-line setting. In daily clinical practice, there is currently no data to support the use of EGFR mutation or FISH status in this decision making process. Prospective trials are ongoing to determine which patient and tumor characteristics are predictive of a clinical benefit from TKI therapy.     

The use of first-generation tyrosine kinase inhibitors in patients with NSCLC and somatic EGFR mutations

Initial studies with the first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib in patients with non-small cell lung cancer (NSCLC) showed that, although most did not have an objective radiographic response, a minority of patients had dramatic and durable clinical and radiographic responses. The discovery of EGFR mutations in tumours from patients with NSCLC and the association of these mutations with clinical response to gefitinib and erlotinib provided an opportunity to tailor treatment to the mutation profile of the tumour. A number of retrospective reviews and prospective trials have established that gefitinib or erlotinib therapy leads to radiographic responses in approximately 75-80% of patients with NSCLC with EGFR mutations. Although a variety of mutations in EGFR have been identified, the two most common somatic activating EGFR mutations are the LREA deletions in exon 19 and the L858R substitution in exon 21. Together, these mutations make up 85-90% of EGFR mutations. At least two retrospective reviews have indicated a difference in the outcome of patients with different EGFR mutations: after treatment with gefitinib or erlotinib, patients with exon 19 deletions have an increased survival compared with those patients whose tumours have an L858R substitution. These findings remain to be confirmed in prospective studies. Improved understanding of the association of EGFR mutations with clinical outcome may improve the ability of physicians to match treatment to mutation status for patients with NSCLC.     

KRAS-mutated non-small cell lung cancer cells are responsive to either co-treatment with erlotinib or gefitinib and histone deacetylase inhibitors or single treatment with lapatinib

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib provide significant clinical benefit for non-small cell lung cancer (NSCLC) patients whose tumors bear EGFR mutations/amplifications. However, anti-EGFR therapy is largely ineffective in NSCLC with activating KRAS mutations. In this study, we investigated the treatment efficacy of erlotinib and gefitinib in combination with the histone deacetylase inhibitors (HDACi) vorinostat and sodium butyrate in the KRAS-mutated NSCLC cell line A549. For comparison, we tested the combination of HDACi with the dual tyrosine kinase inhibitor lapatinib. A549 cells proved to be resistant to erlotinib and gefitinib, but could be sensitized by cotreatment with HDACi, as assessed by flow cytometric analyses of cell death and mitochondrial depolarization. In contrast, A549 cells were a priori responsive to lapatinib treatment, but responsiveness to lapatinib could not be enhanced by HDACi cotreatment. These divergent effects of the different combination regimens may be explained by dissimilar types of cell death induced by the treatments: The use of the pan-caspase inhibitor z-VAD-fmk in the cell death and mitochondrial depolarization assays as well as fluorescence microscopy analyses indicated that erlotinib or gefitinib combined with HDACi elicited apoptosis, whereas lapatinib treatment induced a non-apoptotic type of cell death. Our study suggests that both HDACi/EGFR inhibitor-combination treatment and lapatinib-single treatment may be effective options for the therapy of NSCLC with KRAS mutations.     

Overcoming molecular mechanisms of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have provided substantial benefits to patients with advanced non-small cell lung cancer (NSCLC). However resistance to these agents has emerged as a significant clinical issue; most patients who initially respond to treatment eventually experience relapse. The mechanisms underlying gefitinib and erlotinib resistance are multifactorial and several have been described. Clearly there is a need for novel and more effective therapies that can overcome resistance to the currently available TKIs. Several agents are in clinical development, including irreversible EGFR TKIs, inhibitors of the MET pathway, and others. In this review we discuss the various underlying mechanisms of gefitinib and erlotinib resistance and highlight the agents currently in clinical development that may have potential for overcoming this resistance.     

EGFR mutation testing in NSCLC: Patterns of care and outcomes in Western Australia

Aims:   This study evaluated the EGFR mutation status, administration of gefitinib or erlotinib and outcomes of patients assessed for EGFR mutations since the commencement of testing in Western Australia.
Methods:   A retrospective study identified patients with NSCLC who undergone EGFR mutation testing in the Department of Anatomical Pathology, Royal Perth Hospital, Western Australia from March 2005 until May 2007. Patient characteristics, cancer history, treatment, outcomes and survival were collected from the medical records and pathology reports.
Results:   Tumor samples from 64 patients were sequenced for mutations in exons 18–21 EGFR and, of these, 53 patients with NSCLC were included in the analysis. The mean age at diagnosis was 61 years (range 19–80) and most of the tumor samples tested were from female patients (76%). Overall 36% of patients tested were mutation-positive with 95% of mutations occurring in exons 19 or 21. A total of 63% of mutation-positive and 18% of mutation-negative patients were treated with gefitinib or erlotinib. Of these, 83% of patients whose tumors had an EGFR mutation had a favorable response following treatment, compared to 17% of mutation-negative patients. The duration of treatment was longer in mutation-positive patients (mean 30 weeks vs 9 weeks).
Conclusion:   EGFR mutation testing is not routinely performed in NSCLC in Western Australia. Referral for testing is at the discretion of the treating physician, accounting for the high proportion of women and adenocarcinoma histology. Selection of mutation-positive tumors for treatment with gefitinib or erlotinib is associated with good responses to treatment. This study supports the use of gefitinib or erlotinib in routine clinical practice in patients with NSCLC carrying an EGFR mutation.     

Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer

Epidermal growth factor receptor (EGFR) related therapies - mainly tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, but also monoclonal antibodies targeting EGFR, for example, cetuximab - have been investigated in numerous settings in non-small cell lung cancer (NSCLC) and in different combinations. The overall clinical benefit of EGFR TKI therapy is roughly 10-30%, with higher benefit in nonsmoker Asiatic women with EGFR-mutated adenocarcinoma. Currently, there are several biomarkers that are able to direct and predict the yield of EGFR-related therapies in NSCLC. These include EGFR mutation status, EGFR protein expression, EGFR gene copy number and a serum proteomic marker (Veristrat?, Biodesix; CO). The usage of such biomarkers is important from many aspects. First, it helps clinicians to make the right treatment decisions and second, it leads to a wiser usage of financial resources. This review will focus on EGFR-related biomarkers for their prognostic power and their ability to predict clinical benefit from EGFR-related therapy.     

Gefitinib therapy for non-small cell lung cancer

Opinion statement Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.     

Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non-small-cell lung cancer: a meta-analysis of 13 randomized trials

Advanced non-small-cell lung cancer (NSCLC) harboring activating mutations of epidermal growth factor receptor (EGFR) are particularly sensitive to tyrosine kinase inhibitors (TKIs), namely erlotinib and gefitinib. The purpose of this meta-analysis was to evaluate the benefit of EGFR TKIs in EGFR-mutated NSCLCs. Eligible studies included published randomized controlled trials in which erlotinib or gefitinib (alone or with chemotherapy) were compared with standard therapy in 1260 patients with EGFR-mutated NSCLCs who were included in 13 trials. The mutational status was obtained through a retrospective or prospective analysis. Relative risk (RR) was calculated for response rate, and hazard ratios (HRs) were calculated for progression-free and overall survival. EGFR TKIs increase the chance of obtaining an objective response almost 2-fold when compared with chemotherapy (RR, 2.06; 2p < .00001). The response rate was 70% vs. 33.2% in first-line trials. In 3 second-line trials, response rates were 47.4% vs. 28.5%, with a benefit similar to first-line trials (RR, 1.79; 2p = .04). EGFR TKIs reduced the hazard of progression by 70% in all trials (HR, 0.30; 2p < .00001) and by 65% in first-line trials only (HR, 0.35; 2p < .00001). Overall, however, they do not improve survival (HR, 0.96; 2p = .71). NSCLCs harboring EGFR mutations derive greater benefit from erlotinib or gefitinib than from chemotherapy. All patients affected by NSCLC with an EGFR-positive mutation test result must be offered the opportunity to be treated with an EGFR TKI upfront or during the natural course of the disease if not previously exposed.     

Molekular zielgerichtete Therapie des nichtkleinzelligen Lungenkarzinoms

Chemotherapy remains the standard first-line treatment for advanced non-small cell lung cancer (NSCLC). In the second or third-line setting, however, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has proven its benefit in a randomized trial. FDA approval of gefitinib was withdrawn after the negative results of the ISEL study. Recent identification of mutations in the ATP binding pocket of EGFR is the first step towards proper patient selection for therapy with gefitinib. Predictive potential for erlotinib application has been seen with EGFR gene amplification. Monoclonal antibodies against EGFR are evaluated in NSCLC. Use of the anti-angiogenic monoclonal VEGF antibody bevacizumab showed a survival benefit in a selected group of NSCLC patients in combination with standard chemotherapy in a phase III study. Confirmatory studies are awaited before the addition of bevacizumab to standard chemotherapy can be generally recommended. Multi-kinase inhibitors such as sorafenib show great promise for systemic treatment of solid cancers, including NSCLC.     

Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors

The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy and a number of EGFR-targeted agents have been developed. Those most advanced in development are the EGFR tyrosine kinase inhibitors gefitinib ('Iressa', ZD1839) and erlotinib ('Tarceva', OSI-774), and the monoclonal antibody cetuximab ('Erbitux', IMC-C225). This review provides a clinical overview of these agents, highlighting their antitumour activities in different tumour types. Epidermal growth factor receptor-targeted agents are generally well tolerated and are not typically associated with the severe adverse events often seen with cytotoxic chemotherapy. Gefitinib is the agent with the most extensive clinical experience, particularly in non-small-cell lung cancer (NSCLC). Recently, gefitinib became the first-approved EGFR-targeted agent, for use in patients with previously treated advanced NSCLC in Japan, the USA and other countries. Further studies are required to explore the full potential of these novel agents either as monotherapy or combination therapy.     

Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions.

PURPOSE: Gefitinib and erlotinib are small molecules that selectively inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. When these drugs were introduced into the clinic, the specific targets affected in human tumors were unknown. In April 2004, two groups reported that mutations in the tyrosine kinase domain of EGFR are strongly associated with gefitinib sensitivity in patients with non-small-cell lung cancer (NSCLC). We subsequently extended these findings and showed that such mutations are also associated with sensitivity to erlotinib. Here, we present current knowledge about EGFR mutations in the context of clinical trials involving gefitinib and erlotinib in NSCLC. DESIGN: This article reviews the rationale for targeting EGFR, the development of gefitinib and erlotinib, the discovery of EGFR mutations, and subsequent studies to define the incidence, spectrum, and functions of EGFR mutations. RESULTS: The discovery of EGFR mutations promises to alter the ways in which we consider and treat NSCLC. CONCLUSION: This information can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC.     

Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib.

PURPOSE: Somatic mutations in the epidermal growth factor receptor (EGFR) have been detected in patients with non-small cell lung cancer (NSCLC) and are associated with sensitivity to treatment with gefitinib or erlotinib. Our study explored the relationship between the two most common types of somatic EGFR mutations, exon 19 deletions and the L858R point mutation, and outcomes of patients following treatment with gefitinib or erlotinib. EXPERIMENTAL DESIGN: Tumor specimens obtained before treatment with gefitinib or erlotinib were analyzed for EGFR mutations. Patients with exon 19 deletion or L858R mutations were identified. The response rate, time to progression, and overall survival were determined for the two groups. RESULTS: We identified 36 patients with NSCLC and an EGFR mutation who were treated with gefitinib or erlotinib. Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis. A difference in response rate for patients treated with gefitinib compared with erlotinib was also noted [18 of 23 (78%) versus 3 of 9 (33%); P = 0.04]. No obvious difference in time to progression or overall survival was noted between gefitinib- and erlotinib-treated patients. CONCLUSIONS: Patients with NSCLC and EGFR exon 19 deletions have a longer survival following treatment with gefitinib or erlotinib compared with those with the L858R mutation. Pooling of greater numbers of patients and completion of prospective trials are needed to further define the predictive and prognostic roles of different EGFR mutations with respect to treatment with gefitinib, erlotinib, and other EGFR inhibitors.     

Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: Comparative pharmacokinetics and drug–drug interactions

The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50–60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls – afatinib and dacomitinib – covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug–drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.     

Where next for gefitinib in patients with lung cancer?

Gefitinib belongs to the small-molecule class of epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors. It was given conditional approval by the US Food and Drug Administration (FDA) in 2003 for treatment of advanced, chemorefractory non-small-cell lung cancer (NSCLC), but was relabelled for restricted use for patients that were already receiving and benefiting from it after the negative result of the phase III Iressa Survival Evaluation in Advanced Lung Cancer (ISEL) trial. By contrast, erlotinib, another EGFR tyrosine-kinase inhibitor, showed an overall survival benefit compared with placebo and best supportive care in the National Cancer Institute of Canada's BR21 trial, and now has full FDA approval for treatment of patients with NSCLC who have progressed after treatment with chemotherapy. Although the ISEL trial result was negative overall, preplanned subgroup analyses showed a significant overall survival benefit for gefitinib treatment in never-smokers and in patients of Asian origin. Here, we review the clinical experience with gefitinib and, in light of the licensing of erlotinib, address the lessons learned, the ongoing trials, and whether scope remains for clinical development of gefitinib in selected patients.     

Epidermal growth factor receptor tyrosine kinase inhibitors in elderly or poor performance status patients with advanced non-small cell lung cancer

Elderly and poor performance status advanced non-small cell lung cancer (NSCLC) patients often tolerate chemotherapy poorly. Special approaches are needed for these patient populations. Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), erlotinib and gefitinib, are active agents in the treatment of advanced NSCLC. Several phase II trials have been conducted utilizing EGFR TKIs in elderly or poor performance status patients with advanced NSCLC. This review will summarize the results of erlotinib or gefitinib in these subsets of patients with advanced NSCLC.     

Incidence of T790M in Patients With NSCLC Progressed to Gefitinib,Erlotinib, and Afatinib: A Study on Circulating Cell-free DNA

BackgroundInsights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non–small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib.Patients and MethodsThe present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay.ResultsA total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001).ConclusionsAlthough gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.     

Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: Focus on epidermal growth factor receptor mutation testing and mutation-positive patients

Activation of the epidermal growth factor receptor (EGFR) pathway has been implicated in tumorigenesis in non-small cell lung cancer (NSCLC), the most common type of lung cancer. As a result, EGFR has become a key focus for the development of personalized therapy, with several molecular biomarkers having been investigated as potential predictors of response with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC (e.g., EGFR expression, EGFR gene copy gain, and EGFR mutations). Of these, activating mutations in EGFR have thus far given the most consistent results based on the available evidence from preclinical studies and clinical trials. In an attempt to identify patients who are most likely to benefit from treatment with EGFR TKIs, EGFR mutation testing is being increasingly utilized in clinical practice. Currently in the United States, no EGFR TKI or accompanying mutational test is approved for the identification and first-line treatment of patients with advanced NSCLC. However, the first-generation EGFR TKIs, erlotinib and gefitinib, as well as investigational ErbB family TKIs and EGFR mutation testing methods are being evaluated in this setting. This review will discuss EGFR mutation testing as a biomarker of response to EGFR TKIs and the evolution of EGFR mutational analysis in NSCLC. Completed and ongoing clinical trials evaluating currently available or investigational EGFR TKIs as first-line therapy in molecularly and clinically selected patients with NSCLC, with a focus on trials in patients whose tumors have EGFR mutations, will also be reviewed.     

Gefitinib and epidermal growth factor receptor gene mutation

Epidermal growth factor receptor (EGFR) gene mutations are frequent in lung cancer of Asian ethnicity, female gender, non-smokers,and of adenocarcinoma histology. About 80% of the patients with EGFR mutations respond to EGFR tyrosine kinase inhibitor (TKI) including gefitinib and erlotinib, while only 10% of those without EGFR mutations do so. Therefore, EGFR mutation is being recognized as one of the most reliable predictive factors in gefitinib treatment. Another important issue in clinical practice is fatal interstitial lung disease (ILD) in patients with gefitinib treatment, especially for Asian patients. A nested case-control study recently conducted in Japan identified some risk factors which cause ILD. About half of the acquired resistance to gefitinib that almost always occurs during the course of gefitinib administration is reportedly caused by secondary mutation at codon 79 0 (T 79 0 M). EGFR-TKIs are not universally effective for lung cancer,but these drugs are effective in patients who have particular characteristics. Therefore, patients who would benefit from gefitinib therapy should be included in clinical trials. Based on this concept, phaseIII clinical trials comparing gefitinib monotherapy with standard platinum-based chemotherapy in lung cancer patients with EGFR mutations are ongoing.