Gefitinib in non-small cell lung cancer

Gefitinib (Iressa^TM), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received ≤ 2 (IDEAL1) or ≥ 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were ~ 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.     

Gefitinib for non-small-cell lung cancer treatment

INTRODUCTION: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures. AREAS COVERED: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC. EXPERT OPINION: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

A review of the benefit-risk profile of gefitinib in Asian patients with advanced non-small-cell lung cancer

BACKGROUND: Improvements in first-line therapy of advanced non-small-cell lung cancer (NSCLC) have increased the need for effective second-line treatment options. In a Phase II trial of the anticancer drug gefitinib (IRESSA), greater efficacy was observed in Japanese compared with non-Japanese patients. Furthermore, results from a placebo-controlled Phase III trial (IRESSA Survival Evaluation in Lung cancer [ISEL]) showed that treatment with gefitinib was not associated with a statistically significant improvement in survival in either the overall or adenocarcinoma co-primary populations, although there was marked heterogeneity in survival outcomes between patient groups, with patients of Asian origin achieving a significant survival benefit with gefitinib compared with placebo. OBJECTIVE: To review the benefit:risk profile of gefitinib in Asian patients with advanced NSCLC. RESEARCH DESIGN AND METHODS: We identified and reviewed 31 reports (each with >or= 25 patients) of clinical experience with gefitinib 250 mg/day in Asia involving a total of > 2000 patients with refractory NSCLC in Japan, China, Korea and Taiwan by searching EMBASE and Medline databases for publications between 1 January 2003 and 1 July 2005. RESULTS AND DISCUSSION: In the majority of these reports, objective response rates of > 25% and disease control rates of > 60% have been described. Treatment with gefitinib resulted in a median time to progression of > 3 months and a median survival time of > 6 months in most studies. These 31 reports also demonstrated the efficacy of gefitinib in patients with secondary brain metastases, those with poor performance status (PS) and in patients receiving the drug as first-line treatment. Female gender, adenocarcinoma histology, non-smoking history, good PS and the presence of multiple lung metastases are associated with improved responsiveness to gefitinib. Reflecting the results of previous clinical trials, the reports indicate that gefitinib is generally well tolerated by Asian patients. The incidence of interstitial lung disease appears to be higher in Japanese than non-Japanese patients, although the reasons for this are not clear. Recent findings regarding cellular and genetic factors that may underlie the increased responsiveness to gefitinib among Asian patients are discussed.     

Gefitinib for non-small-cell lung cancer treatment

Introduction: Gefitinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that demonstrated efficacy in patients with advanced non-small cell lung cancer (NSCLC) across therapy lines. In the first-line setting, recent randomized Phase III trials comparing EGFR-TKIs versus platinum-based doublets demonstrated that in patients harboring an activating EGFR mutation, gefitinib is superior to chemotherapy in terms of response rate, progression-free survival, toxicity profile and quality of life, with a marginal positive effect on survival. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures.

Areas covered: All published data on gefitinib in lung cancer were analyzed using PubMed. The aim of this review is to summarize activity and safety data from major clinical trials of gefitinib in patients with advanced NSCLC.

Expert opinion: EGFR-TKIs including gefitinib are the best option we can offer today in patients with EGFR mutation, regardless of treatment line. Administration of gefitinib to patients with advanced NSCLC is usually well-tolerated and it also appears to be feasible in special populations characterized by a significantly poorer risk:benefit ratio with standard chemotherapy, like elderly patients and patients with poor performance status.     

Optimal management of patients with non-small cell lung cancer and epidermal growth factor receptor mutations

In recent years, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, which have promising activity and a favourable toxicity profile, have been used in the management of advanced non-small cell lung cancer (NSCLC). The knowledge that EGFR-activating mutations confer sensitivity to EGFR TKIs has led to the design and analysis of phase II and III studies of gefitinib or erlotinib treatment in various clinical scenarios. We review the important NSCLC clinical trials of the efficacy of EGFR TKIs in the context of EGFR-activating mutations. In all phase II single-arm studies or phase III randomized comparative studies, EGFR TKIs as monotherapy were superior to combination chemotherapy in terms of response rate and progression-free survival in patients with activating EGFR mutations. EGFR TKIs have contributed to the superior overall survival time in NSCLC patients with EGFR mutations compared with those patients without EGFR mutations. The results of these studies have led to a paradigm shift in the treatment of patients with advanced NSCLC. NSCLC with EGFR mutations constitutes a new entity requiring different personalized treatment strategies.     

A review of the benefit–risk profile of gefitinib in Asian patients with advanced non‐small‐cell lung cancer

ABSTRACT

Background: Improvements in first-line therapy of advanced non-small-cell lung cancer (NSCLC) have increased the need for effective second-line treatment options. In a Phase II trial of the anticancer drug gefitinib (IRESSA), greater efficacy was observed in Japanese compared with non-Japanese patients. Furthermore, results from a placebo-controlled Phase III trial (IRESSA Survival Evaluation in Lung cancer [ISEL]) showed that treatment with gefitinib was not associated with a statistically significant improvement in survival in either the overall or adenocarcinoma co-primary populations, although there was marked heterogeneity in survival outcomes between patient groups, with patients of Asian origin achieving a significant survival benefit with gefitinib compared with placebo.

Objective: To review the benefit:risk profile of gefitinib in Asian patients with advanced NSCLC.

Research design and methods: We identified and reviewed 31 reports (each with ≥ 25 patients) of clinical experience with gefitinib 250?mg/day in Asia involving a total of > 2000 patients with refractory NSCLC in Japan, China, Korea and Taiwan by searching EMBASE and Medline databases for publications between 1 January 2003 and 1 July 2005.

Results and discussion: In the majority of these reports, objective response rates of > 25% and disease control rates of > 60% have been described. Treatment with gefitinib resulted in a median time to progression of > 3 months and a median survival time of > 6 months in most studies. These 31 reports also demonstrated the efficacy of gefitinib in patients with secondary brain metastases, those with poor performance status (PS) and in patients receiving the drug as first-line treatment. Female gender, adenocarcinoma histology, non-smoking history, good PS and the presence of multiple lung metastases are associated with improved responsiveness to gefitinib. Reflecting the results of previous clinical trials, the reports indicate that gefitinib is generally well tolerated by Asian patients. The incidence of interstitial lung disease appears to be higher in Japanese than non-Japanese patients, although the reasons for this are not clear. Recent findings regarding cellular and genetic factors that may underlie the increased responsiveness to gefitinib among Asian patients are discussed.     

Epidermal growth factor receptor inhibitors in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of the newer cytotoxic agents in NSCLC treatment during the last decade the survival rates of patients have reached a plateau. New strategies are clearly needed to improve treatment outcomes. Epidermal growth factor receptor (EGFR) has a key role in cancer development and progression and has been recognised as a target of increasing importance in NSCLC. Gefitinib, erlotinib and cetuximab are EGFR-targeting agents that are being extensively evaluated in NSCLC. EGFR inhibitors demonstrate significant clinical activity in approximately 10-20% of pretreated NSCLC patients. Somatic mutations in the kinase domain of the receptor have been shown to be associated with enhanced sensitivity to EGFR inhibitors. However, four large Phase III randomised, placebo-controlled trials of gefitinib and erlotinib in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the study drugs. Possible reasons include patient selection, drug scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities.     

Spotlight on Gefitinib in Non-Small-Cell Lung Cancer

Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both docetaxel and platinum-based chemotherapy regimens. Gefitinib represents a significant advance in the treatment of this population; a once-daily oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilization, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favorably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use program. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings. Preliminary data demonstrate the presence of activating mutations in EGFR-TK among patients whose disease was highly responsive to treatment with gefitinib, although such mutations have not been correlated to all patients who benefit from the drug. Further studies are needed to fully elucidate the clinical implications of EGFR mutations and to identify patients likely to benefit from EGFR-targeted therapy.     

Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer

Lung cancer is the leading cause of death worldwide. Current treatment modalities, including chemotherapy, radiotherapy and surgery, provide only limited improvement in the natural course of this disease. Therefore, the development of new therapeutic strategies is highly awaited. This review focuses on recent achievements on a novel class of anticancer drugs targeting the EGFR (Epidermal Growth Factor Receptor). The EGFR family is a group of four structurally similar growth factor receptors with tyrosine-kinase activity (EGFR, HER2/neu, ErbB-3, ErbB-4), which dimerize upon binding with a number of ligands, including EGF (Epidermal Growth Factor) and TGF (Transforming Growth Factor), allowing downstream transduction of mitogenic signals. Overexpression of EGFR and HER2 is frequently found in non-small-cell lung cancer (NSCLC), which accounts for over 80% of all malignant lung tumors, and has been associated with a worse clinical outcome. New agents developed to inhibit EGFR function include monoclonal antibodies and small-molecule receptor tyrosine-kinase inhibitors. In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized. In particular, final results of phase II (IDEAL 1 and 2) and III (INTACT 1 and 2) studies of ZD1839 are reported. In IDEAL trials (ZD1839 single agent in patients pre-treated with chemotherapy) there was clear evidence of tumor regression, symptoms improvement and overall clinical benefit, whereas in the two INTACT trials (ZD1839 in combination with standard platinum-based chemotherapy in chemo-naive patients) ZD1839 did not improve either survival or other clinical endpoints. Possible explanations for these contradictory results and future perspectives are discussed.     

吉非替尼与化疗用于晚期非小细胞肺癌维持治疗疗效的临床观察

目的 表皮生长因子受体酪氨酸激酶抑制剂(Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors,EGFR-TKIs)吉非替尼及细胞毒化疗药物如吉西他滨、培美曲塞均是晚期非小细胞肺癌(Non-Small Cell Lung Cancer,NSCLC)维持治疗的有效手段,为对比两类药物维持治疗的临床疗效,我们进行了本项研究.方法 回顾性分析接受吉非替尼、吉西他滨及培美曲塞维持治疗的65例晚期NSCLC,按照所接受的维持治疗方案种类分为吉非替尼维持治疗组和化疗维持治疗组,分析两组间疾病控制率、无进展生存(Progression-Free Survival,PFS)及总生存(Overall Survival,OS)的差异.结果 65例患者34例为吉非替尼维持治疗(10例已知为EGFR基因突变患者),31例为化疗维持治疗(21例为吉西他滨维持化疗,10例为培美曲塞维持化疗),两种维持治疗方案获得的疾病控制率(70.6％比64.5％,P=0.791)、PFS(6.4月比5.0月,P=0.110)、OS(16.3月比12.0月,P=0.327)比较差异无统计学意义.分层分析发现EGFR突变状态未知时,吉非替尼对比吉西他滨、培美曲塞维持治疗PFS(4.0月比4.0月比5.0月,P=0.462)、OS(14.4月比12.0月比12.2月,P=0.540)比较差异无统计学意义,然而吉非替尼维持治疗组EGFR突变阳性患者较突变状态未知患者PFS(11.2月比4.0月,P=0.001)、OS(31.9月比14.4月,P=0.02)显著延长,差异有统计学意义.结论 晚期NSCLC吉非替尼与化疗维持治疗疗效相似.吉非替尼维持治疗EGFR突变阳性患者较未知患者有明显获益,建议晚期NSCLC予吉非替尼维持治疗时常规行EGFR突变检测.     

Erlotinib: a new therapeutic approach for non-small cell lung cancer

Although treatment with cytotoxic agents has produced modest survival improvement in patients with stage III and IV non-small cell lung cancer (NSCLC), it appears that a plateau has been reached with currently available chemotherapeutic regimens. Increasing knowledge regarding the properties of malignant neoplasms has identified a number of potential therapeutic targets. The epidermal growth factor receptor (EGFR) is one of these targets. Preclinical models have revealed that tumour growth can be inhibited by monoclonal antibodies directed against EGFR and EGFR-specific tyrosine kinase inhibitors. Erlotinib (Tarceva trade mark; OSI Pharmaceuticals, Genentech and Roche), a quinazoline derivative with good oral absorption, is one of several EGFR tyrosine kinases that has been studied in clinical trials. In a Phase I study, mild diarrhoea and mild rash were the most common toxicities. At a dose of 200 mg/day, diarrhoea was the dose-limiting toxicity. The observation that EGFR overexpression is relatively common in NSCLC led to a Phase II trial of erlotinib at the maximum-tolerated dose (150 mg/day) in previously treated NSCLC patients. Erlotinib produced a 12% response rate and there was no apparent relationship between response and tumour EGFR levels. More recent reports suggest that patients who develop a rash have higher responses. Based on its single agent activity, erlotinib has been evaluated in two Phase III trials which compared erlotinib plus chemotherapy to chemotherapy alone in previously untreated NSCLC patients. Erlotinib has also been compared to placebo in a Phase III trial which was limited to advanced stage NSCLC patients whose disease had progressed after two previous chemotherapy regimens. The optimum use of erlotinib in NSCLC will be determined by the results of the completed and future Phase III trials.     

Erlotinib: a new therapeutic approach for non-small cell lung cancer

Although treatment with cytotoxic agents has produced modest survival improvement in patients with stage III and IV non-small cell lung cancer (NSCLC), it appears that a plateau has been reached with currently available chemotherapeutic regimens. Increasing knowledge regarding the properties of malignant neoplasms has identified a number of potential therapeutic targets. The epidermal growth factor receptor (EGFR) is one of these targets. Preclinical models have revealed that tumour growth can be inhibited by monoclonal antibodies directed against EGFR and EGFR-specific tyrosine kinase inhibitors. Erlotinib (Tarceva?; OSI Pharmaceuticals, Genentech and Roche), a quinazoline derivative with good oral absorption, is one of several EGFR tyrosine kinases that has been studied in clinical trials. In a Phase I study, mild diarrhoea and mild rash were the most common toxicities. At a dose of 200 mg/day, diarrhoea was the dose-limiting toxicity. The observation that EGFR overexpression is relatively common in NSCLC led to a Phase II trial of erlotinib at the maximum-tolerated dose (150 mg/day) in previously treated NSCLC patients. Erlotinib produced a 12% response rate and there was no apparent relationship between response and tumour EGFR levels. More recent reports suggest that patients who develop a rash have higher responses. Based on its single agent activity, erlotinib has been evaluated in two Phase III trials which compared erlotinib plus chemotherapy to chemotherapy alone in previously untreated NSCLC patients. Erlotinib has also been compared to placebo in a Phase III trial which was limited to advanced stage NSCLC patients whose disease had progressed after two previous chemotherapy regimens. The optimum use of erlotinib in NSCLC will be determined by the results of the completed and future Phase III trials.     

Epidermal growth factor receptor tyrosine kinase inhibitors in late stage clinical trials

The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated EGFR-dependent signalling is involved in cell proliferation, apoptosis, angiogenesis and metastatic spread. Targeting the EGFR, therefore, represents a promising molecular approach in cancer treatment. Several anti-EGFR agents are in clinical development. Three drugs are currently in Phase II and III development as single agents, or in combination with other anticancer modalities: IMC-225 (cetuximab/Erbitux; ImClone), a chimaeric human-mouse monoclonal IgG(1) antibody, which blocks ligand binding and functional activation of the EGFR; OSI-774 (erlotinib/Tarceva; Genentech/OSI/Roch) and ZD1839 (gefitinib/Iressa; AstraZeneca), two small molecule EGFR-selective inhibitors of tyrosine kinase enzymatic activity, which prevent EGFR autophosphorylation and activation. Iressa is the first EGFR-targeting agent to be registered as an anticancer drug in Japan, in Australia and in the US for the third-line treatment of chemoresistant non-small cell lung cancer (NSCLC) patients. This review will focus on the preclinical background and on the results from the first series of clinical trials with these drugs. Furthermore, continuing clinical trials and a series of open clinical issues for the development of optimal strategies of using EGFR-targeting agents will be discussed.     

Activity of gefitinib in advanced non-small-cell lung cancer with very poor performance status

Advanced non-small-cell lung cancer (NSCLC) patients with poor performance status (PS) are less likely to respond to chemotherapy, or to have an improvement in survival, but more likely to experience toxicity. We retrospectively evaluated the efficacy and tolerability of gefitinib in patients with advanced NSCLC and very poor PS in Taiwan. Patients with stage IIIB, IV NSCLC with an Eastern Cooperative Oncology Group (ECOG) PS of 3-4 received oral gefitinib 250 mg once daily. Totally, 52 patients were included (25 men, 27 women). Forty-three patients (82.7%) were in a PS of 3. Tumor response rate was 25.0% (13/52). Tumor response rate to gefitinib was highest in chemonaive patients 38.1% (8/21) vs. failed 1 chemotherapy regimen 13.3% (2/15) vs. failed 2 or more chemotherapy regimens 18.8% (3/16), p = 0.015. The median overall survival was 2.5 months (response group 9.1 months, stable disease 3.1 months, and progressive group 0.8 month, p < 0.001). Adverse events, mainly skin reactions and diarrhea, were generally mild (grade 1 or 2) except paronychia and acne. Thus, gefitinib has clinically antitumor activity and good tolerability in Taiwan patients with advanced NSCLC and very poor performance status, with a higher response rate than that seen Europe or in European heritage Americans. Chemonaive patients responded better than patients with prior chemotherapy. Formal clinical trials are warranted to evaluate the role of gefitinib in this situation.     

Epidermal growth factor receptor inhibitors in the treatment of non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in both men and women. Despite the introduction of the newer cytotoxic agents in NSCLC treatment during the last decade the survival rates of patients have reached a plateau. New strategies are clearly needed to improve treatment outcomes. Epidermal growth factor receptor (EGFR) has a key role in cancer development and progression and has been recognised as a target of increasing importance in NSCLC. Gefitinib, erlotinib and cetuximab are EGFR-targeting agents that are being extensively evaluated in NSCLC. EGFR inhibitors demonstrate significant clinical activity in ~ 10 – 20% of pretreated NSCLC patients. Somatic mutations in the kinase domain of the receptor have been shown to be associated with enhanced sensitivity to EGFR inhibitors. However, four large Phase III randomised, placebo-controlled trials of gefitinib and erlotinib in combination with standard platinum-based first-line chemotherapy failed to show any survival benefit in patients receiving the study drugs. Possible reasons include patient selection, drug scheduling, trial design or other factors. Active research is ongoing to improve the efficacy of EGFR inhibitors as monotherapy or in combination with other treatment modalities.     

Gefitinib: current status in the treatment of non-small cell lung cancer

Gefitinib (Iressa) is a novel drug approved in 28 countries (as of June 2004), including Japan, the US, Canada and Australia as second- and third-line monotherapy for the treatment of locally advanced or metastatic non-small cell lung cancer refractory to prior chemotherapy. Gefitinib is an orally active, epidermal growth factor receptor (EGFR)-tyrosine kinase (EGFR-TK) reversible inhibitor which blocks EGFR phosphorylation and subsequent signal transduction pathways involved in proliferation, metastasis, angiogenesis and apoptosis inhibition. Recently, mutations in the TK domain of the EGFR have been identified in those patients with refractory non-small cell lung cancer who achieved dramatic tumor responses to gefitinib. Although the role of EGFR-TK mutation status in predicting other clinical benefits with gefitinib, i.e. disease stabilization and symptom improvement, is unclear, these findings, along with increasing knowledge of other potential biomarkers of response, are significant developments towards further optimizing the use of gefitinib. Gefitinib has favorable pharmacokinetic and pharmacodynamic properties and low toxicity. No dosage adjustment is required for patient age, body weight, gender, ethnicity or moderate to severe hepatic impairment due to liver metastases. Several clinical studies on gefitinib as monotherapy have demonstrated clinically significant symptom relief, tumor response and good tolerability after failure of chemotherapy-based treatment in non-small cell lung cancer. These studies led to gefitinib approval in many countries as a new therapeutic option for patients with advanced non-small cell lung cancer that failed prior chemotherapy. In contrast to the clinical benefit imparted by gefitinib as monotherapy in patients previously treated with chemotherapy, gefitinib in combination with standard platinum-based chemotherapy in chemonaive patients did not improve either survival or other clinical endpoints in non-small cell lung cancer. This review provides currently available data from clinical studies on gefitinib as monotherapy or in combination with platinum-containing chemotherapy.     

Vandetanib for the treatment of non-small-cell lung cancer

INTRODUCTION: The use of targeted therapies in the treatment of advanced non-small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways. AREAS COVERED: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens. EXPERT OPINION: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC.     

Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer

Our objective was to evaluate gefitinib (IRESSA), an epidermal growth factor receptor tyrosine kinase inhibitor, versus docetaxel as second-line monotherapy for advanced non-small-cell lung cancer (NSCLC). SIGN (Second-line Indication of Gefitinib in NSCLC; code 1839IL/0503) was a multicenter, randomized, parallel-group, open-label, phase II trial that investigated oral gefitinib (250 mg/day) or i.v. docetaxel (75 mg/m2 every 3 weeks) in patients with advanced NSCLC who had previously received one chemotherapy regimen. The primary objective was assessment of symptom improvement (using the FACT-L Lung Cancer Subscale). Secondary objectives included quality of life (FACT-L total score), response rate (using RECIST), overall survival and safety. This trial recruited 141 patients (68 to gefitinib and 73 to docetaxel) who received treatment for a median duration of 3.0 (gefitinib) and 2.8 (docetaxel) months. Similar efficacy was observed with gefitinib and docetaxel, 36.8 and 26.0% symptom improvement rates, 33.8 and 26.0% quality-of-life improvement rates, 13.2 and 13.7% objective response rates, and 7.5 and 7.1 months median overall survival, respectively. Fewer drug-related adverse events were observed with gefitinib compared with docetaxel (all grades: 51.5 versus 78.9%; Common Toxicity Criteria grade 3/4: 8.8 versus 25.4%). There were no withdrawals or deaths due to drug-related adverse events with gefitinib, while three patients withdrew and three died due to adverse events in the docetaxel group that were possibly drug related. We conclude efficacy with gefitinib was similar to docetaxel, but with a more favorable tolerability profile, in the second-line treatment of advanced NSCLC. These results support further investigation of gefitinib in this disease setting.     

半胱氨酸蛋白酶-8基因多态与吉非替尼治疗进展期非小细胞肺癌疗效及生存的相关研究

目的研究CASP8-6526N ins/del基因多态与吉非替尼治疗NSCL敏感性及患者生存之间的关系。方法入组88例接受吉非替尼单药治疗的ⅢA-Ⅳ期非小细胞肺癌患者,分析临床病理特征以及CASP8-6526N ins/del基因多态与吉非替尼治疗的临床获益率及患者生存的相关性。结果腺癌患者临床获益率及总生存期显著优于非腺癌患者（P=0.009和P=0.048）;既往治疗的无进展生存期与吉非替尼治疗的临床获益率和无进展生存期显著相关（P=0.003和P=0.001）。CASP8-6526N ins/del基因多态与吉非替尼治疗的无进展生存期相关,携带del遗传变异的患者吉非替尼治疗的无进展生存期显著短于携带ins/ins基因型的患者（P=0.039）。多因素预后分析显示病理类型（P=0.020,RR：2.466,95%CI：1.150～5.288）是独立的预后因素。结论促进肿瘤细胞凋亡是吉非替尼抗肿瘤作用的重要部分,CASP8基因多态及病理类型可能成为吉非替尼治疗敏感性及治疗结局的预测指标。     

Epidermal growth factor receptor (EGFR) inhibitor associated skin eruption

EGFR Inhibitors are used to treat Non-Small-Cell Lung Cancer (NSCLC) and colorectal cancer (CRC). A common side effect of EGFR Inhibitors is a follicular/pustular skin eruption. We report a case of gefitinib (Iressa) associated skin eruption. The treatment regimen consisted of triamcinolone 0.1% cream twice daily, clindamycin 1% lotion twice daily and sodium sulfacetamide lotion twice daily. The clinical presentation, etiology, and management options of EGFR Inhibitor associated skin eruptions are discussed.