阿帕替尼的抗肿瘤机制研究进展

阿帕替尼是一种新型的高度选择性靶向血管内皮生长因子受体2(VEGFR2)的小分子酪氨酸激酶抑制剂,在多种晚期肿瘤的治疗中显示出了一定的疗效.既往认为VEGFR2拮抗剂主要通过抑制血管生成发挥抗肿瘤作用,但新近研究发现,阿帕替尼可以通过抗血管生成以外的多种机制抑制肿瘤细胞生长,而且这些机制在抗肿瘤作用中可能发挥着重要作用...     

甲磺酸阿帕替尼的研究现状与进展

恶性肿瘤的发生、发展与其血管生成密切相关,其中血管内皮生长因子及其受体（VEGF/VEGFR）信号通路是诱导血管新生最重要的调控途径,也是多种抗肿瘤血管生成剂的关键靶点之一。甲磺酸阿帕替尼（艾坦）是一种新型小分子的酪氨酸激酶抑制剂,高度选择性地作用于VEGFR 2,强效抑制肿瘤血管生成,从而发挥抗肿瘤作用。阿帕替尼Ⅰ、Ⅱ、Ⅲ期注册临床试验结果表明,标准化疗失败的晚期胃癌患者应用阿帕替尼生存获益,且安全性较好。目前,阿帕替尼单药或者联合其他药物治疗肺癌、肝癌、胃癌、结直肠癌和乳腺癌等多种肿瘤的基础与临床研究正在积极开展。本文系统综述与阿帕替尼相关的基础和临床研究的现状与进展,为进一步的临床应用提供参考。     

中国临床肿瘤学会抗肿瘤药物安全管理专家委员会

【摘 要】甲磺酸阿帕替尼片是口服小分子抗血管生成抑制剂新药,主要通过高度选择性地抑制血管内皮生长因子受体-2（VEGFR-2）酪氨酸激酶的活性,阻断血管内皮生长因子（VEGF）与其受体结合后的信号转导通路,从而强效抑制肿瘤血管生成,发挥抗肿瘤作用。上市前的一系列临床研究表明阿帕替尼具有一定的客观有效性和明显的生存获益,严重不良反应的发生率低,患者耐受性良好,已于2014年10月17日经国家食品药品管理监督总局（CFDA）批准作为国家1.1类新药上市,用于晚期胃癌或胃食管结合部腺癌三线及三线以上治疗。为了更好地指导临床上合理、有效地应用阿帕替尼,中国临床肿瘤学会（CSCO）抗肿瘤药物安全管理专家委员会组织了相关领域的多学科专家学者,根据阿帕替尼上市前、后的国内用药情况,参考其他抗血管生成抑制剂的使用经验,共同讨论,多次修改,最终形成了本共识,以供临床医师参考。     

阿帕替尼相关手足皮肤反应表现和治疗研究进展

甲磺酸阿帕替尼片为一种新型小分子单克隆抗体，作用机制是高度选择性竞争细胞内血管内皮生长因子受体-2（vascularendothelial growth factor receptor-2，VEGFR-2）的ATP结合位点，阻断下游信号转导，抑制肿瘤组织新血管生成。手足皮肤反应（hand-foot skin reaction，HFSR）为阿帕替尼常见的不良反应之一，影响患者的生存质量，导致靶向药减量，从而影响抗肿瘤治疗的疗效。常规的西医治疗为尿素和糖皮质激素外用制剂，临床常根据红肿、破溃、结痂等不同皮肤表现的进行中西医结合治疗。本文对阿帕替尼相关HFSR的表现及治疗进展予以综述，以期给临床提供参考。      

阿帕替尼联合其他方法治疗肿瘤的研究进展

 血管新生在肿瘤的生长以及转移过程中发挥重要作用，其中血管内皮生长因子受体2（VEGFR2）是关键的调控因子。甲磺酸阿帕替尼是我国历经十年研制成功的一种小分子酪氨酸激酶抑制剂，可高特异性结合VEGFR2。目前阿帕替尼单药在临床已成功应用于晚期胃癌、非小细胞肺癌、乳腺癌等常见肿瘤的治疗。阿帕替尼与其他抗肿瘤疗法的联用往往可以达到增加药效、减少不良反应的效果。本文主要针对目前报道过的临床实验以及基础研究来简要说明阿帕替尼与其他药物联合治疗用于不同肿瘤的治疗效果以及作用机制。     

阿帕替尼抗肿瘤作用机制研究进展

近年来以血管内皮生长因子(VEGF)及其受体(VEGFR)信号通路为靶点的抗血管生成药物,在恶性肿瘤的治疗中得到广泛应用.阿帕替尼是口服小分子抗血管生成药物,可特异性抑制VEGFR的酪氨酸激酶活性,进而抑制肿瘤的血管生成.2018年发布的《中国临床肿瘤学会(CSCO)胃癌诊疗指南》把阿帕替尼列为胃癌三线治疗的Ⅰ级推荐....     

阿帕替尼治疗恶性肿瘤的临床研究进展

随着抗血管生成靶向治疗的发展,作用于血管内皮生长因子（vascular endothelial growth factor,VEGF）及其血管内皮生长因子受体（vascular endothelial growth factor receptor ,VEGFR）信号通路的抗肿瘤药物越来越受到广泛的关注。血管内皮细胞生长因子受体- 2（vascular endothelial growth factor receptor 2,VEGFR- 2）抑制剂阿帕替尼是一种高效抗血管生成药物,是最新上市的口服分子靶向抗肿瘤药物之一。阿帕替尼在人体生物利用度高,安全性及耐受性良好。上市前后一系列大规模的随机、对照临床试验证实阿帕替尼在多种恶性肿瘤中具有一定的客观有效率和生存获益,如胃癌、非小细胞肺癌（non-small cell lung cancer ,NSCLC ）、乳腺癌等,尤其是在胃癌中。2014年该药在中国批准上市应用于临床治疗晚期胃癌。目前正在进行胃癌、肺癌、肝癌、食管癌、结直肠癌等多种恶性肿瘤的Ⅱ/ Ⅲ期临床试验,以探讨其单独或联合抗肿瘤活性。本文就阿帕替尼抗肿瘤机制、对不同类型肿瘤的临床疗效、安全性及不良反应、药物相互作用、耐药及生物标志物等最新研究进展进行综述,以加深对该药抗肿瘤应用的了解,为临床实践提供参考,并期望为恶性肿瘤患者的治疗带来一些新的选择。      

甲磺酸阿帕替尼治疗晚期非小细胞肺癌的研究现状

甲磺酸阿帕替尼,一种小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI),作用于血管内皮生长因子受体-2(vascular endothelial growth factor receptor-2,VEGFR-2),强效抑制内皮细胞新生血管生成。阿帕替尼是在中国获得批准的第一代口服抗血管生成药物,用于晚期胃癌标准化疗失败的后续治疗。目前阿帕替尼单药或者联合其他治疗在晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)中的临床研究正在积极开展,多数均显示一定生存获益。本文详细介绍近年阿帕替尼在晚期NSCLC中的研究现状,为后期临床应用提供参考。     

甲磺酸阿帕替尼治疗恶性肿瘤的临床不良反应分析

抗血管生成在恶性肿瘤治疗中的作用日益突出，其在转化、维持治疗过程中都发挥重要作用。我国自主研发的抗血管生成靶向药甲磺酸阿帕替尼（apatinib，YN968D1）已批准用于晚期胃腺癌或胃-食管结合部腺癌的三线及三线以上的治疗，并在多个实体肿瘤中探索应用。随着对阿帕替尼研究的深入，其安全性问题受到广泛关注。本文重点介绍了阿帕替尼在临床应用中常见的不良反应，综合分析了现有的临床数据，对比了阿帕替尼与其他常用抗血管生成药物不良反应的优劣，以期帮助临床医生更好地把握该药的安全性，从而为患者提供更加安全、有效的治疗。      

甲磺酸阿帕替尼治疗恶性肿瘤的研究进展

摘 要：分子靶向治疗在恶性肿瘤的治疗中占重要地位,甲磺酸阿帕替尼(apatinibmesylate)是一种新型的抗肿瘤分子靶向药,其机制为作用于血管内皮生长因子(vascular endothelial growth factor,VEGF)及血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)信号通路。全文就甲磺酸阿帕替尼抗肿瘤作用机制、临床试验及基础研究等方面的研究进展进行综述。     

阿帕替尼在非小细胞肺癌中的研究进展

非小细胞肺癌（non-small cell lung cancer, NSCLC）是我国死亡率最高的恶性肿瘤之一。近年来,NSCLC的治疗取得了长足的进步,众多新药的问世显著改善了晚期NSCLC患者的生存期。甲磺酸阿帕替尼是一种新型口服小分子血管内皮生长因子受体酪氨酸激酶抑制剂,目前已被批准用于胃癌的三线治疗。目前,大量研究证实阿帕替尼单药治疗晚期NSCLC也有较好效果。临床前研究提示,阿帕替尼还可改善化疗和EGFR TKI耐药,因此,阿帕替尼联合化疗或EGFR TKI治疗晚期NSCLC也进行了广泛的探索。现就阿帕替尼在NSCLC的基础及临床研究中的进展作一综述。     

Apatinib in gastric carcinoma: A case report of partial response for first‐line treatment in advanced disease

Gastric cancer (GC) is the most common gastrointestinal malignant tumor, with a gradual increasing incidence throughout the world. Mostly GC is diagnosed in its late stage. To date, there is no usable standardized treatment regimen for patients with advanced GC. Apatinib mesylate, small‐molecule vascular endothelial growth factor receptor‐2 (VEGFR‐2) tyrosine kinase inhibitor (TKI), has been approved as third‐line treatment for patients with advanced gastric adenocarcinoma in China, October, 2014. Till now, there is no case report about apatinib as first‐line treatment for patients with advanced GC in literature. We present an 83‐year‐old Chinese man with advanced gastric adenocarcinoma, who received apatinib as first‐line option and obtained clinical benefit within 2 weeks. The lung metastases disappeared completely and the liver metastases shrank significantly. The patient's progression‐free survival was 163 days and overall survival was 201 days. This paper reviews and discusses apatinib as a new targeted drug for patients with advanced GC by comparison with other effective molecular‐targeted therapy.     

Successful treatment using apatinib with or without docetaxel in heavily pretreated advanced non-squamous non-small cell lung cancer: A case report and literature review

Although targeted therapy directed toward driver mutations has produced a significant efficacy benefit for patients with non-small cell lung cancer (NSCLC), many patients do not possess mutations associated with the approved targeted drugs. Angiogenic agents play an important role in the therapeutic strategy for advanced NSCLC. Apatinib is a novel tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2. A phase II clinical trial demonstrated the survival benefit of apatinib monotherapy in advanced NSCLC. Moreover, addition of anti-angiogenic agents to chemotherapy showed robust efficacy in advanced NSCLC, regardless of tumor histology. Here, we present the case of a heavily pretreated lung adenocarcinoma patient who was treated with apatinib and apatinib continuation plus docetaxel re-challenge. He was negative for several driver genes, including EGFR, ALK, KRAS, ROS1, HER2, RET and BRAF. The previous treatment included platinum-based doublets, pemetrexed monotherapy, docetaxel plus bevacizumab, gefitinib monotherapy, nab-paclitaxel monotherapy, irinotecan plus oxaliplatin and radiotherapy. He obtained a partial response after both apatinib monotherapy and apatinib plus docetaxel treatment, with progression-free survival durations of 5 months and 6 months, respectively. This case indicated that apatinib monotherapy or apatinib plus docetaxel might be regarded as a therapeutic option for heavily pretreated patients with advanced non-squamous NSCLC.     

Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases

Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27−32.91; 95% CI 3.64−6.22) and 14.70 (range, 0.27−32.91; 95% CI 0.27−43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p<0.05) and mOS (24.03 vs. 6.07 months, p<0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients.     

Successful treatment of advanced pancreatic liposarcoma with apatinib: A case report and literature review

Pancreatic liposarcoma is a malignant tumor originated from the pancreas mesenchymal tissue and mostly presented in skin, subcutaneous, periosteum, and long bone on both sides. Both conventional chemotherapy and radiotherapy have limited efficacy and poor prognosis for advanced pancreatic liposarcoma. Here, we reported a case of advanced pancreatic liposarcoma and reviewed the literature specific for liposarcoma of the pancreas and discuss the emerging options of treatment. The patient was treated with apatinib and a cross-line rescue therapy combined with paclitaxel after progressive disease. The therapeutic effect of the combination regimen has been evaluated. Apatinib is an oral tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor-2 (VEGFR-2), which has dual effects of anti-angiogenesis and anti-tumor cell proliferation. To our knowledge, this is the first case to report the successful use of apatinib for advanced pancreatic liposarcoma.     

Anti‐angiogenic therapies for gastric cancer

Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various anti‐angiogenic therapies, such as antivascular endothelial growth factor (VEGF) or anti‐VEGF receptor (VEGFR)‐2 monoclonal antibodies, VEGF‐Trap and VEGFR tyrosine kinase inhibitors, the anti‐VEGFR‐2 antibody ramucirumab was shown to prolong overall survival not only as a single agent but also in combination with paclitaxel as a second‐line chemotherapy. Additionally, apatinib, a selective VEGFR‐2 tyrosine kinase inhibitor, prolonged survival as a third‐line or later treatment option in patients with advanced gastric cancer. Preliminary results of studies investigating ramucirumab plus immune checkpoint inhibitors in gastric cancer were encouraging, and further investigations are ongoing. In China, apatinib in combination with cytotoxic agents is being investigated for systemic chemotherapy or maintenance therapy as an earlier treatment option. The clinical activity in gastric cancer of the multikinase inhibitor regorafenib was suggested in a randomized phase II study. A global phase III trial comparing regorafenib with placebo is currently ongoing. Further studies of anti‐angiogenic therapy combined with not only chemotherapy but also immune checkpoint inhibitors are also being pursued, providing hope for improved survival in patients with gastric cancer.