贝伐珠单抗在结直肠癌治疗中的应用

近年来,随着对肿瘤生物学认识的深入,以贝伐珠单抗、西妥昔单抗为代表的分子靶向治疗药物正逐渐丰富着晚期结直肠癌的治疗选择.贝伐珠单抗是一种人源化、人鼠嵌合抗血管内皮生长因子的单克隆抗体,是第一个被美国FDA批准用于治疗晚期结直肠癌患者的抗血管生成药物,以贝伐珠单抗为基础进行的临床研究也证实了它能改善晚期结直肠癌患者的生存期.全文通过回顾近年来发布的结直肠癌治疗领域有关贝伐珠单抗的临床研究,对其在晚期结直肠癌一线、二线和维持治疗以及在结直肠癌术后辅助治疗领域中的应用做一系统综述.     

新药贝伐单抗的临床应用进展

血管内皮生长因子（VEGF）在肿瘤血管生成过程中起着关键作用,并已成为抗肿瘤治疗的重要靶点。贝伐单抗为重组人源化抗VEGF的单克隆抗体,其治疗肿瘤具有良好的效果。目前,FDA已批准贝伐单抗用于转移性结直肠癌、转移性乳腺癌、晚期非小细胞肺癌、转移性肾细胞癌的一线治疗。除此之外,贝伐单抗在肝癌、胃癌、食管癌等其他恶性肿瘤的应用也取得令人鼓舞的结果。现就贝伐单抗在多种恶性肿瘤中的临床应用作一综述。     

贝伐单抗治疗复发或晚期转移性乳腺癌的临床价值

分子靶向治疗是当前乳腺癌治疗领域研究的热点,贝伐单抗是第一个获得批准上市的抑制肿瘤血管生成的药,也是继抗Her-2靶向治疗领域之后另一全新领域。抗肿瘤血管靶向治疗领域;但目前关于贝伐单抗用于乳腺癌的有效性及安全性具有争议。本文汇总国内外关于贝伐单抗治疗乳腺癌的最新研究进展,并评价其临床使用价值。     

贝伐单抗联合化疗治疗晚期结直肠癌5例

血管内皮生长因子（VEGF）是一种重要的促血管生成因子之一,能直接促进血管内皮细胞增殖,从而促进新生血管的生成。许多恶性肿瘤细胞均有自分泌VEGF的功能,肿瘤细胞增殖与其内部新生血管生成密切相关。贝伐单抗（Bevacizumab）是抗VEGF的人源化的单克隆抗体,与VEGF结合,阻止和减弱VEGF与血管内皮细胞表面受体的结合,从而抑制内皮细胞增殖和新生血管生成,起到抗肿瘤的作用。2004年FDA已批准罗氏公司的贝伐单抗（商品名Avastin）用于晚期结直肠癌的一线治疗。我们对北京协和医院肿瘤内科2004年6月～2005年12月使用贝伐单抗联合化疗治疗晚期结直肠癌5例患者的临床资料进行了回顾性分析,现报告如下：     

贝伐单抗治疗晚期大肠癌的研究进展

血管内皮生长因子(VEGF)是目前已知作用最强的促血管形成因子,因而是抗血管生成治疗的主要靶点.贝伐单抗是抗VEGF受体的人源单克隆抗体,可抑制肿瘤血管生成,目前用于一线治疗大肠癌.     

抗血管生成治疗在恶性胸腔积液中的应用进展CSCD

恶性胸腔积液(malignant pleural effusions,MPE)是晚期肿瘤的常见并发症,肺癌和恶性胸膜间皮瘤(malignant pleural mesothelioma,MPM)是MPE最常见的病因。MPE的治疗原则是在针对病因的全身治疗的基础上对胸腔进行局部治疗。血管内皮生长因子(vascular endothelial growth factor,VEGF)在MPE形成中的多个环节起着关键作用。贝伐珠单抗能抑制VEGF的活性,减少MPE的形成,改善患者预后。本综述系统回顾了贝伐珠单抗及其他抗血管生成药物在非小细胞肺癌(non-small cell lung cancer,NSCLC)和MPM相关MPE中的研究进展,阐述了不同抗血管生成药物对MPE的临床疗效和安全性。     

非小细胞肺癌抗血管生成治疗研究进展

非小细胞肺癌（non-small cell lung cancer,NSCLC）的增殖、浸润、转移都需要新生血管的支持,抗血管生成治疗已成为一种重要治疗手段。血管内皮生长因子（vascular endothelial growth factor,VEGF）作为关键的促血管生成因子,是目前NSCLC抗血管生成治疗药物的主要靶点。这些药物主要包括以VEGF或其受体VEGFR为靶点的单克隆抗体,及阻断VEGFR下游信号通路传导的小分子酪氨酸激酶抑制剂（VEGFR-TKI）两类。目前有两种抗血管生成单克隆抗体,贝伐单抗及雷莫卢单抗,被批准联合化疗一线或二线治疗原位进展或转移的NSCLC。多种VEGFR-TKI治疗NSCLC的临床试验均以失败告终,目前仅有安罗替尼在我国被批准用于NSCLC的三线治疗,而尼达尼布联合化疗在二线治疗中也显示了良好的生存获益。本篇综述我们将回顾总结抗血管生成药物单药或与其他抗肿瘤药物联用成功应用于NSCLC治疗的临床研究数据。     

贝伐单抗治疗进展期非小细胞肺癌临床疗效及安全性观察

贝伐单抗是重组人源化血管内皮生长因子（vascular endothelial growth factor,VEGF）的IgG1型单克隆抗体,能与所有VEGF异构体结合,从而阻断VEGF与VEGFR结合,以抑制VEGF活性,是一种抑制血管生成的靶向治疗药物,联合化疗用于非鳞型非小细胞肺癌的一线治疗,可以延长无进展生存期及总生存期,提高有效率;2006年10月美国FDA推荐贝伐单抗联合紫杉醇/卡铂化疗方案用于非鳞型非小细胞肺癌的一线治疗。贝伐单抗治疗的安全性受到广泛关注,最常见的不良反应包括高血压、蛋白尿、血管栓塞、出血等,相关不良反应不容忽视,但高血压、蛋白尿、血管栓塞等可以通过对症处理得到控制,且与常规化疗药物不良反应不相互重叠,与化疗药物联合应用安全性较高,多数患者耐受性良好。本文就贝伐单抗治疗进展期非小细胞肺癌临床疗效及安全性进行综述。      

抗血管生成药物联合EGFR-TKI在晚期NSCLC治疗中的应用

表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）和抗血管生成药物在治疗晚期非小细胞肺癌（NSCLC）方面都已被证实临床获益。近年来研究表明,抗EGFR和抗血管生成药物联合能进一步提高晚期NSCLC的治疗疗效,甚至可以缓解EGFR-TKI耐药现象。根据抗血管生成药物的不同分类,目前临床研究主要包括抗血管内皮生长因子的单克隆抗体贝伐珠单抗联合EGFR-TKI和多靶点抗血管生成的酪氨酸激酶抑制剂联合EGFR-TKI,其中前者的研究结果在安全性和效果方面尤为理想,因而有望成为部分晚期NSCLC患者新的治疗标准。     

贝伐珠单抗治疗脑胶质瘤及放射性脑坏死

贝伐珠单抗作为全球第一个抗血管生成的单克隆抗体,获得美国食品和药物管理局批准用于胶质母细胞瘤的挽救治疗,之后贝伐珠单抗治疗恶性胶质瘤成为研究的焦点,但最新研究结果并不支持其在恶性胶质瘤的一线治疗中应用.另外,该药在放射性脑坏死的治疗上也取得令人鼓舞的效果,确切疗效有待进一步证实.     

Bevacizumab for the treatment of advanced non-small-cell lung cancer

Until recently, advances in non-small-cell lung cancer (NSCLC) care have been limited; new chemotherapy regimens have not significantly impacted patient survival. With our improved understanding of tumor biology, novel biological therapies targeting key tumorigenic processes targeting factors essential for tumor growth, such as angiogenesis, have been developed that improve patient outcomes beyond those achieved with chemotherapy alone. One of these, bevacizumab (Avastin), specifically targets VEGF, which is key to the malignant growth and progression of solid tumors. Bevacizumab-based therapy until progression significantly delays disease progression, has a well-characterized and acceptable safety profile in bevacizumab-eligible patients and was the first treatment to improve the overall survival of patients with advanced NSCLC beyond 1 year, a significant breakthrough in advanced NSCLC care. Furthermore, bevacizumab-based therapy significantly delays disease progression and has a well-characterized and acceptable safety profile. Based on these data, bevacizumab has received approval for the first-line treatment of NSCLC in the USA and Europe. A number of ongoing trials will potentially expand the eligible patient population for bevacizumab and further define its role in NSCLC treatment.     

Emerging safety data for bevacizumab in advanced non-small-cell lung cancer

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, confers improved clinical outcomes in a range of tumor types when administered in combination with chemotherapy. In a pivotal phase III trial (E4599), bevacizumab became the first agent to extend overall survival beyond 1 year when combined with first-line chemotherapy for advanced, metastatic, or recurrent non-squamous non-small-cell lung cancer (NSCLC). In a recent phase III trial (AVAiL; Avastin in Lung Cancer), which investigated the safety and efficacy of 2 bevacizumab doses in combination with cisplatin/gemcitabine, bevacizumab-based therapy significantly delayed disease progression in patients with advanced, metastatic, or recurrent non-squamous NSCLC. Based on these positive data, bevacizumab in combination with chemotherapy has received US and European Union approval for the first-line treatment of unresectable advanced, metastatic, or recurrent predominantly non-squamous NSCLC. Bevacizumab-based therapy has a well-characterized safety profile. Clinically relevant bevacizumab-associated adverse events reported in clinical trials to date include bleeding, hypertension, proteinuria, thrombotic events, wound-healing complications, and gastrointestinal perforations. Emerging safety data for bevacizumab in NSCLC from the recent AVAiL trial indicate that, as in clinical trials in other indications, adverse events were generally manageable using standard clinical techniques and rarely required discontinuation of bevacizumab therapy. In the AVAiL trial, grade ≥ 3 hypertension, bleeding, and proteinuria rates were modestly higher in the bevacizumab arms than in the placebo arm, although the overall incidence of grade ≥ 3 adverse events was similar in the placebo and bevacizumab arms. Recommendations for the monitoring and management of bevacizumab-associated adverse events are discussed.     

Impact of treatment with bevacizumab beyond disease progression: a randomized phase II study of docetaxel with or without bevacizumab after platinum-based chemotherapy plus bevacizumab in patients with advanced nonsquamous non-small cell lung cancer (WJOG 5910L)

ABSTRACT: BACKGROUND: Bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF), shows clinical activity against human cancer, with its addition to standard chemotherapy having been found to improve outcome in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). However, there have been no evidence-based studies to support the continued use of bevacizumab beyond disease progression in such patients treated with the drug in first-line therapy. We have now designed a randomized phase II trial to examine the clinical benefit and safety of continued bevacizumab treatment in patients with advanced nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. METHODS: WJOG 5910L was designed as a multicenter, open-label, randomized, phase II trial by the West Japan Oncology Group of docetaxel (arm A) versus docetaxel plus bevacizumab (arm B) in patients with recurrent or metatstatic nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Patients in arm A will receive docetaxel at 60 mg/m2 and those in arm B will receive docetaxel at 60 mg/m2 plus bevacizumab at 15 mg/kg, with each drug administered on day 1 every 21 days until progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival, with secondary endpoints including response rate, overall survival, and safety, for patients treated in either arm. Trial registration: UMIN (University Hospital Medical Information Network in Japan) 000004715.     

Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC)

Bevacizumab is a monoclonal antibody that specifically inhibits vascular endothelial growth factor, and is the first antiangiogenic agent to be approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). Evidence from two large phase III trials demonstrates that bevacizumab combined with chemotherapy improves outcomes for patients with non-squamous NSCLC. In patients with adenocarcinoma without epidermal growth factor receptor (EGFR) mutation, a median overall survival of 18.0 months is achieved. Several post-registration phase IV studies have confirmed bevacizumab’s efficacy and tolerability profile and have clarified the eligibility criteria. Clinical research is still ongoing to define the role of bevacizumab in different settings, such as single-agent bevacizumab for continuation maintenance therapy in advanced disease, treatment beyond disease progression, adjuvant therapy in early-stage NSCLC, or bevacizumab in combination with other targeted agents. A number of antiangiogenic tyrosine kinase inhibitors (TKI) have also been investigated in phase II and III trials. None of these drugs has proven significant clinical benefit in unselected patient populations. This article reviews the extensive information from randomized trials and large observational studies for bevacizumab in advanced NSCLC, and shortly describes the current clinical development of antiangiogenic monoclonal antibodies, TKIs and related compounds.     

晚期非小细胞肺癌维持治疗进展

晚期非小细胞肺癌(NSCLC)标准一线化疗方案的疗效已达到了一个平台期.研究证实化疗药物、分子靶向药物维持治疗可延长晚期NSCLC患者的生存期.免疫治疗成为晚期NSCLC的维持治疗,还需进一步研究证实.     

The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC

Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types.     

不同剂量紫杉醇联合卡铂一线治疗晚期非小细胞肺癌的临床研究

背景与目的紫杉醇联合卡铂一线治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)临床应用较为广泛。本研究旨在比较不同剂量紫杉醇联合卡铂一线治疗晚期NSCLC患者的毒副反应及疗效。方法 2006年12月-2008年6月,共63例晚期NSCLC患者接受紫杉醇175mg/m2或200mg/m2联合卡铂(AUC5)化疗,前者42例,后者21例,ECOG评分0-1分,3周-4周重复,比较两组近期和远期疗效及毒副反应。结果紫杉醇175mg/m2与200mg/m2化疗组客观有效率分别为28.57%与33.33%(P=0.698),中位P为6.7个月与7个月(P=0.561),MST为18.7个月与19个月(P=0.255),1年生存率为61.9%与66.7%(P=0.711),2年生存率为31%与33.3%(P=0.852)。紫杉醇200mg/m2组3/4级中性粒细胞下降发生率明显高于175mg/m2组,分别为61.9%与33.3%(P=0.031)。结论与200mg/m2化疗组相比,紫杉醇175mg/m2联合卡铂一线治疗晚期NSCLC患者可明显减少3/4级中性粒细胞下降发生率,且疗效及生存期并不劣于较高剂量化疗组。     

The role of bevacizumab in the treatment of non-small cell lung cancer: current indications and future developments

The majority of non-small cell lung cancer (NSCLC) patients present with advanced disease, and despite the improvement in efficacy and safety outcomes with platinum-based chemotherapy, this standard cytotoxic approach has reached a therapeutic plateau, with the prognosis for this clinical condition remaining poor. Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. Bevacizumab, an anti-growth factor vascular endothelial growth factor (VEGF) monoclonal antibody, is the antiangiogenic agent at the most advanced stage of development in the treatment of solid tumors and also in NSCLC treatment. Bevacizumab, combined with platinum-based chemotherapy, has been demonstrated to improve efficacy outcomes over chemotherapy alone in the treatment of nonsquamous advanced NSCLC in two phase III randomized trials. These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment will include the combination of this agent with other targeted therapies in advanced disease (especially with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor) and the integration of this agent into combined modality approaches for the treatment of early-stage and locally advanced disease.     

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study

Background

Bevacizumab is a monoclonal antibody with high antitumor activity against malignant diseases. Previous studies have demonstrated the efficacy of first-line bevacizumab combination therapy in advanced, non-squamous non-small cell lung cancer (NS-NSCLC). SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a subgroup analysis of Chinese patients enrolled in SAiL.

Methods

Chemo-naive Chinese patients with locally advanced, metastatic or recurrent NSCLC were randomized to receive Bev 15 mg/kg every 3 weeks plus carboplatin + paclitaxel for maximum of six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety. Secondary endpoints included time to progression and overall survival.

Results

The Chinese intent-to-treat (ITT) population consists of 198 Chinese patients, among whom 107 (54 %) were non-smokers and 90 (45.5 %) were female. The median cycle of bevacizumab administration was 10 and median duration of bevacizumab treatment was 29.5 weeks. Only eight cases of severe adverse events were observed in the study, which were deemed to be related to bevacizumab. The incidence of AEs over grade 3 in Chinese ITT patients was generally low (<9 %). No new safety signals were reported. Objective response rate in 195 evaluable Chinese patients was 68.8 %, including four complete responses (2.1 %). Time to disease progression (TTP) and overall survival were 8.8 and 18.5 months, respectively.

Conclusions

The safety and efficacy of first-line bevacizumab-based treatment in Chinese population with advanced NS-NSCLC are consistent with those in previous studies as well as in Asian subgroup population from SAiL study. No new safety signals were reported.     

Optimizing chemotherapy for advanced non-small cell lung cancer: focus on docetaxel

Systemic chemotherapy with platinum-based combinations provides modest improvements in both survival and quality of life for patients with advanced non-small cell lung cancer (NSCLC). For first-line treatment of advanced NSCLC patients with a good performance status, the accepted standard of care is a platinum agent combined with docetaxel, paclitaxel, gemcitabine, vinorelbine or irinotecan. Several studies have attempted to identify an optimal platin-based regimen, however, all regimens offer some combination of clinical benefit with characteristic toxicities and no regimen appears clearly superior. Non-platinum regimens have also shown equivalent efficacy compared to platinum combinations, but again, none are clearly superior. Most recently, the existing standard of care is being amended to reflect the survival advantage gained from adding a new targeted agent, bevacizumab, to traditional platinum-doublet therapy for patients with non-squamous NSCLC. Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platin-docetaxel regimens for first-line treatment of advanced NSCLC. Improvements in various lung cancer related symptoms and global quality of life indices have also been noted with docetaxel-based regimens. Based on the efficacy of platin-docetaxel regimens in advanced disease, they are now being incorporated into the adjuvant and neoadjuvant treatment of early-stage disease.