Erlotinib in non-small cell lung cancer: a review

Erlotinib (Tarceva?, OSI-774; Pfizer, Inc.) is an orally-active, targeted inhibitor of the epidermal growth factor receptor (EGFR/HER1), which is part of a key regulatory pathway in cancer. Patients with advanced, incurable non-small cell lung cancer (NSCLC) may derive a clinical benefit from first- and second-line chemotherapy, but third-line treatment with available cytotoxic agents is not effective. Remarkably, EGFR/HER1 antagonists have demonstrated activity as second- and even third-line treatment for this disease. Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival, progression free survival and time to disease related symptoms (cough, pain, shortness of breath) compared with treatment with best supportive care in patients who have failed standard first- or second-line chemotherapy. This paper reviews the pharmacology, preclinical and clinical data to support the use of erlotinib in NSCLC.     

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.     

Molecularly-targeted therapies for non-small cell lung cancer

Targeting cell-signalling pathways that confer survival advantage to cancer cells has become a major focus of investigation for the treatment of various malignancies. Non-small cell lung cancer (NSCLC), a disease with wide molecular heterogeneity, has become a main testing ground for the evaluation of various targeted agents. Inhibition of the epidermal growth factor pathway with erlotinib results in improved survival and symptom control for patients with advanced NSCLC who progressed following one or two prior chemotherapy regimens. Gefitinib, the first epidermal growth factor receptor (EGFR) inhibitor to be approved by the FDA, failed to demonstrate survival advantage over placebo in a large Phase III trial for patients with advanced NSCLC. The results of this study have raised several important clinical and biological issues that may be relevant for the development of other targeted agents. Recent identification of mutations in the ATP-binding pocket of the EGFR is the first step towards proper patient selection for therapy with an EGFR tyrosine kinase inhibitor. In addition, predictive potential has also been seen with EGFR gene amplification. It is unclear whether monoclonal antibodies against the EGFR may be active independent of the EGFR mutation, as the site of action is different from tyrosine kinase inhibitors. A recent randomised clinical trial that combined the antiangiogenic agent bevacizumab with chemotherapy has demonstrated survival advantage over chemotherapy alone for certain subsets of patients with advanced NSCLC. The exciting results of this study represent an important advance in the treatment of patients with advanced NSCLC.     

厄洛替尼联合参莲胶囊治疗非小细胞肺癌40例患者临床观察

目的观察厄洛替尼联合参莲胶囊治疗非小细胞肺癌40例的疗效及安全性。方法 40例患者均给予厄洛替尼150mg/次,1日1次,口服,30d为一个周期,连续2个周期,同时配合参莲胶囊辅助治疗2g/次,1日3,连服2个月。所有患者在完成化疗2个周期时评估疗效。结果 40例均可评价疗效。全组无完全缓解病例,部分缓解9例（22.5%）,稳定12例（30.0%）,进展19例（47.5%）;主要不良反应以Ⅰ-Ⅱ度为主,其中皮疹21例（52.5%）,胃肠道反应15例（37.5%）,呼吸困难12例（30%）。结论对非小细胞肺癌患者选择厄洛替尼联合参莲胶囊治疗非小细胞肺癌40例治疗效果确切,不良反应轻。     

Recent advances in targeted therapy for non-small cell lung cancer

Non-small-cell lung cancer (NSCLC) is characterized by wide molecular heterogeneity. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under rigorous evaluation. Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, improves survival for advanced NSCLC patients who progressed following one or two prior chemotherapy regimens. Novel molecular predictive markers, such as EGFR mutations and gene amplification, are at present under evaluation to select patients for therapy with erlotinib. Another area of progress is the recent demonstration that bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), extended survival when administered in combination with chemotherapy for patients with non-squamous NSCLC. Promising anticancer activity has also been noted with agents that inhibit the VEGF receptor tyrosine kinase in patients with advanced NSCLC. Inhibitors of the proteosomal complex, histone deacetylase, mammalian target of rapamycin pathway, and other growth factor receptor-mediated signaling are under investigation for treatment of NSCLC. These developments have paved the way for a new era of tailor-made therapies based on clinical or molecular/genetic profiles in the treatment of NSCLC. This article reviews the recent advances in targeted therapy of advanced NSCLC.     

Erlotinib for the treatment of brain metastases in non-small cell lung cancer

Introduction: Brain metastases (BM) are a common and lethal complication of non-small cell lung cancer (NSCLC) with up to 40% experiencing this complication. The use of erlotinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, holds promise in this somewhat refractory cohort of patients, and has become the subject of active clinical investigation.

Areas covered: This review covers the preclinical and clinical studies of erlotonib as it relates to its use in the treatment of NSCLC patients with BM. A literature search in part utilized the PubMed database up through Dec 2015.

Expert opinion: Preclinical and retrospective data for erlotinib provide evidence of CNS penetration, and objective responses in the setting of BM from EGFR mutated NSCLC. Phase I and II data have demonstrated the feasibility of concomitant delivery of erlotinib and WBRT in the treatment of BM from NSCLC. Phase II/III data however, from non-EGFR mutation enriched populations, have demonstrated no benefit in progression free or overall survival with the addition of erlotinib to metastasis directed radiotherapy. Currently the utilization of erlotinib with WBRT or SRS is therefore investigational and may be a reasonable option in erlotinib naïve, EGFR mutated patients with refractory BM.     

厄洛替尼治疗晚期非小细胞肺癌临床研究

目的分析在晚期非小细胞肺癌的临床治疗中应用厄洛替尼的临床疗效、毒副反应等。方法从2009年4月～2013年4月期间收治的晚期非小细胞肺癌患者中选取30例作为研究对象,并给予患者应用厄洛替尼进行治疗,若患者出现病变进展、无法耐受的毒副反应,则终止治疗,期间观察患者在应用该药物后的疗效、毒副反应等。结果研究发现,30例晚期非小细胞肺癌患者,11例患者疾病进展（PD）,12例患者疾病稳定（SD）,7例患者部分缓解（PR）,0例患者完全缓解（CR）,治疗有效例数为7例,占总人数的23．33％。在毒副反应方面,患者在用药后,主要有恶心呕吐、腹泻、皮肤瘙痒以及皮疹等,程度均不严重,通过相应的治疗后得到缓解。结论在晚期非小细胞肺癌患者的临床治疗中应用厄洛替尼,有明显的疗效,且毒副反应较为轻微。     

厄洛替尼一线治疗老年非小细胞肺癌脑转移7例疗效观察

目的探讨厄洛替尼一线治疗老年非小细胞肺癌(NSCLC)脑转移的疗效与安全性。方法对7例确诊的老年非小细胞肺癌患者,应用厄洛替尼150 mg·d-1,直到病情进展。结果厄洛替尼治疗老年非小细胞肺癌脑转移的ORR为57.1%,DCR为85.7%,中位OS为12月,1年生存率为42.9%,2年生存率为28.6%。结论厄洛替尼一线治疗老年NSCLC脑转移,具有较好的临床疗效,毒副反应轻,可耐受。     

一例非小细胞肺癌合并糖尿病患者服用特罗凯严重不良反应的护理

本文就1例非小细胞肺癌合并糖尿病患者服用特罗凯致严重不良反应病例进行分析,并对给予的护理措施进行讨论。     

Afatinib and Erlotinib in the treatment of squamous-cell lung cancer

ABSTRACT

Introduction

Squamous-cell carcinoma (SCC) of the lung represents around 20% of non-small cell lung cancers. Although activating mutations of EGFR are rare in this subtype, its overexpression occurs in more than half the cases. Consequently, many epidermal growth factor receptor (EGFR)-targeted agents have been investigated in patients with SCC.     

非小细胞肺癌靶向治疗新药——厄洛替尼

厄洛替尼是一种口服、高选择性、可逆的表皮生长因子受体(EGFR)酪氨酸激酶(TK)抑制剂,它通过抑制EGFR-TK的自磷酸化反应,抑制信号转导,从而达到抑制肿瘤生长作用。一项Ⅲ期安慰剂对照临床研究结果表明,厄洛替尼每日口服150 mg单药治疗,可显著延长晚期复发性非小细胞肺癌(NSCLC)病人的生存期、延缓疾病进展和症状恶化,且耐受性较好,最常见的不良反应为皮疹和腹泻。本文对厄洛替尼的药动学和药效学特性、临床疗效和药物相互作用以及难治性晚期NSCLC病人的耐受性等作一综述。     

非小细胞肺癌新靶向药物治疗研究进展

非小细胞肺癌(NSCLC)是一种常见的恶性肿瘤,尽管化学治疗适度提高了晚期NSCLC病人的生存率,但总体来说预后仍不乐观。而分子靶向药物治疗具有符合生理、低毒和理论上高效的特点,已越来越成为晚期NSCLC治疗的热点。以肿瘤血管生成为靶点的血管内皮生长因子拮抗药贝伐单抗和抗肿瘤血管生成靶向药物血管内皮抑素显示出明显生存优势;以表皮生长因子受体为靶点的酪氨酸激酶抑制药吉非替尼、厄洛替尼和多激酶抑制药索拉非尼,不良反应少、易耐受、疗效高,显示出较好的应用前景。     

Erlotinib in non-small cell lung cancer: a review

Erlotinib (Tarceva, OSI-774; Pfizer, Inc.) is an orally-active, targeted inhibitor of the epidermal growth factor receptor (EGFR/HER1), which is part of a key regulatory pathway in cancer. Patients with advanced, incurable non-small cell lung cancer (NSCLC) may derive a clinical benefit from first- and second-line chemotherapy, but third-line treatment with available cytotoxic agents is not effective. Remarkably, EGFR/HER1 antagonists have demonstrated activity as second- and even third-line treatment for this disease. Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival, progression free survival and time to disease related symptoms (cough, pain, shortness of breath) compared with treatment with best supportive care in patients who have failed standard first- or second-line chemotherapy. This paper reviews the pharmacology, preclinical and clinical data to support the use of erlotinib in NSCLC.     

Paclitaxel for non-small cell lung cancer

Paclitaxel, a tubulin-binding agent, is widely used for the treatment of non-small cell lung cancer (NSCLC). The combination of paclitaxel and a platinum compound is an approved regimen for the treatment of advanced NSCLC. The dose-limiting toxicity of paclitaxel is myelosuppression when administered on a prolonged infusion schedule, whereas neuropathy is more common with short infusions. Although the 3-weekly schedule of paclitaxel is the commonly utilised regimen for the treatment of advanced NSCLC, the weekly regimens appear to be associated with lesser myelosuppression and neuropathy. A randomised clinical trial is currently underway to compare the efficacy of the weekly versus 3-weekly regimen of paclitaxel, in combination with carboplatin for the treatment of advanced NSCLC. The radiosensitising effect of paclitaxel has led to its incorporation into multi-modality treatment of NSCLC patients in combination with thoracic radiation. Paclitaxel has also demonstrated synergistic interaction with several molecularly-targeted agents and is at present being evaluated in the neoadjuvant and adjuvant treatment settings for early stage NSCLC.     

Erlotinib in non-small-cell lung cancer

Epidermal growth factor receptor (EGFR) plays an essential role in normal cell growth and differentiation, and is involved in tumour proliferation and survival. EGFR overexpression is a common feature in solid malignancies, including non-small-cell lung cancer (NSCLC), and is associated with poor clinical prognosis. Erlotinib is a small-molecule inhibitor of EGFR tyrosine kinase, showing a significant improvement in median survival, quality of life and related symptoms in an unselected population of advanced NSCLC patients in the second- or third-line setting. Erlotinib is well tolerated (with common toxicities including rash and diarrhoea) when administered at a standard oral daily dose of 150 mg. Further investigations are ongoing to contribute to our understanding of the role of erlotinib in NSCLC treatment.     

非小细胞肺癌的靶向治疗策略

在世界范围内,肺癌位居所有癌症致死的首位,且其中大部分为非小细胞肺癌。尽管大量有关含铂化疗或联合其他药物的临床研究不断涌现,非小细胞肺癌患者的预后仍然差强人意。晚期非小细胞肺癌患者的5年生存率约为15%,在过去几年中未有明显提高。目前,肺癌治疗领域的主要成就在于靶向治疗的出现,例如针对表皮生长因子受体(EGFR)靶点的吉非替尼和厄罗替尼,以及针对抗血管内皮生长因子(VEGF)的贝伐珠单抗,均广泛运用于临床。     

Emerging drugs for non-small cell lung cancer

Lung cancer is the leading cause of cancer death in the world. Therapeutic improvements caused by recent cytotoxic agents seem to have reached a plateau. New therapeutic strategies are, therefore, necessary to improve the cure rate. These include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gene therapy and vaccines. The antiepidermal growth factor receptor (EGFR) group includes compounds acting on the extracellular domain of EGFR, such as IMC-C225 and trastuzumab; small molecules inhibiting EGFR phosphorylation, such as ZD 1839 and OSI-774; or compounds that interfere with one of the downstream steps, such as mitogen-activated protein kinase kinase (MEK) inhibitors. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumour activity. Antiangiogenesis inhibitors include matrix metalloprotease inhibitors (MMPIs), such as marimastat, AG3340, BAY 12-9566, BMS-275291 and Col-3. Antiangiogenic agents offer great potential for the treatment of lung cancer, as shown in preclinical models, whereas emerging data suggest that there are limits to their use as monotherapy in advanced disease. Molecules targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) also seem to control tumour progression and may prolong survival. COX-2 inhibitors are another class of agents currently under evaluation in clinical trials for their chemoprevention role in subjects at high lung cancer risk, and also in patients with non-small cell lung cancer (NSCLC) in combination with standard chemotherapeutics. Genetic and immunologic therapies represent two additional promising modalities. All of these therapies are in different phases of clinical testing and have shown encouraging activity alone or in combination with chemotherapy drugs.     

厄洛替尼联合贝伐珠单抗治疗EGFR突变晚期非小细胞肺癌患者的有效性和安全性的Meta分析

目的:系统评价未经化疗的新确诊或复发的EGFR突变晚期非小细胞肺癌患者使用厄洛替尼或联合贝伐珠单抗治疗的有效性和安全性.方法:检索PubMed及其他数据库中截至2020年10月24日所有相关的随机对照临床试验.结果:最终纳入3项符合条件的随机对照临床研究,共计464例患者.Meta分析结果显示,厄洛替尼联合贝伐珠单抗化...