Apatinib as an alternative therapy for advanced hepatocellular carcinoma

Angiogenesis plays an important role in the occurrence and development of tumors. Registered tyrosine kinase inhibitors targeting vascular endothelial growth factor reduce angiogenesis. Apatinib, a tyrosine kinase inhibitor, can specifically inhibit vascular endothelial growth factor receptor 2, showing encouraging anti-tumor effects in a variety of tumors including advanced hepatocellular carcinoma(HCC). This article intends to review the clinical research and application prospects of apatinib in the field of HCC.     

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.     

Apatinib Plus Chemotherapy Shows Clinical Activity in Advanced NSCLC: A Retrospective Study

Apatinib is an oral TKI with antiangiogenic properties, and it is currently approved for the treatment of advanced gastric cancer in China. This agent has also been tested in other human solid tumors, including non-small cell lung cancer (NSCLC). Since the combination of chemotherapy and an antiangiogenic agent has been shown to be a feasible strategy in NSCLC, it is conceivable that a similar approach combining apatinib with chemotherapy may yield clinical activity. With this in mind, we investigated the efficiency of apatinib in combination with pemetrexed or docetaxel in advanced NSCLC. We treated a total of 20 patients with metastatic NSCLC adenocarcinoma with apatinib in combination with either pemetrexed or docetaxel from January 2016 to March 2017. The performance status of these patients was 0 or 1. All of these patients had been previously treated with two or more lines of treatment and had experienced disease progression prior to study enrollment. The overall objective response rate (ORR) was 30%, with 6 patients who had partial response (PR), 10 patients who had stable disease (SD), and 4 patients who had progressive disease (PD). The main adverse events were skin rash, hypertension, palmar–plantar erythrodysesthesia syndrome, diarrhea, and fatigue. Nearly 30% of patients required interruption of treatment as a result of toxicity. Our study demonstrated that apatinib combined with systemic cytotoxic chemotherapy has clinical efficacy in patients with disease-refractory metastatic NSCLC and provides evidence for further studies investigating apatinib-based combination regimens.     

阿帕替尼联合曲妥珠单抗对胃癌细胞的协同增敏作用

目的观察阿帕替尼联合曲妥珠单抗杀伤胃癌NCI-N87细胞的协同增敏作用并探讨可能作用机制。方法CCK-8法检测空白对照组、曲妥珠单抗组(0.1、1、10μg/ml)、阿帕替尼组(1μmol/L)及曲妥珠单抗(0.1、1、10μg/ml)+阿帕替尼(1μmol/L)组对NCI-N87细胞的增殖抑制作用,流式细胞术检测NCI-N87细胞凋亡,Western blotting检测HER-2、VEGFR2、Bax、Bcl-2蛋白表达。结果CCK-8检测提示曲妥珠单抗、阿帕替尼能够抑制NCI-N87细胞增殖,在一定浓度范围内作用呈浓度依赖性和时间依赖性(P<0.01);q值计算提示曲妥珠单抗与阿帕替尼具有协同抑制NCI-N87细胞增殖的作用。流式细胞术检测显示联合组NCI-N87胃癌细胞凋亡较单药组明显升高(P<0.05),其中空白对照组、阿帕替尼组(1μmol/L)、曲妥珠单抗(0.1μg/ml)组及曲妥珠单抗(0.1μg/ml)+阿帕替尼(1μmol/L)组的凋亡率分别为(3.0±1.28)%、(5.8±1.63)%、(8.0±3.92)%和(21.6±6.85)%。曲妥珠单抗+阿帕替尼组与空白对照组、曲妥珠单抗及阿帕替尼单药组比较,HER-2蛋白表达显著下调(P<0.05);曲妥珠单抗+阿帕替尼组与空白对照组比较,Bcl-2蛋白表达、Bcl-2/Bax比值明显降低(P<0.01)。结论阿帕替尼联合曲妥珠单抗可能通过下调HER-2蛋白及调控凋亡相关蛋白Bcl-2、Bax的表达,协同抑制NCI-N87细胞增殖和促进细胞凋亡。     

阿帕替尼治疗晚期及术后复发肺肉瘤样癌的疗效分析

目的探索阿帕替尼治疗晚期及术后复发肺肉瘤样癌的疗效。方法收集2016年6月至2019年8月Ⅲ~Ⅳ期及术后复发的肺肉瘤样癌患者21例,口服阿帕替尼(250~425 mg/d)治疗,30 d为1个疗程,观察并分析疗效及评价安全性。结果21例患者中,完全缓解(CR)为0,部分缓解(PR)为14.3%(3例),稳定(SD)为33.3%(7例),疾病进展(PD)为52.4%(11例);客观反应率(ORR)为13.3%(3例),疾病控制率(DCR)为47.6%(10例)。中位总生存期(mOS)为4.6个月,中位无进展生存期(mPFS)为1.0个月。病灶≥6 cm(或≥5 cm)较<6 cm(或<5 cm)平均OS明显缩短,差异有统计学意义(P<0.05);术后分期Ⅰ~Ⅱ期较Ⅲ~Ⅳ期平均OS明显延长(P<0.05)。位于中央的病灶较周围的病灶平均OS明显缩短,差异有统计学意义(P<0.01)。性别、年龄(>60岁,≤60岁)、吸烟史(是/否)对疗效影响差异无统计学意义。常见不良反应包括高血压38.1%(8例)、蛋白尿23.8%(5例)、手足综合征28.6%(6例)、腹泻28.6(6例)、骨髓抑制38.1%(8例)。结论阿帕替尼治疗晚期及术后复发肺肉瘤样癌具有一定疗效,不良反应可控,病灶大小、位置及分期可能是疗效的独立影响因素。     

Apatinib enhanced anti-tumor activity of cisplatin on triple-negative breast cancer through inhibition of VEGFR-2

BackgroundTriple-negative breast cancer (TNBC) was known as a fast-growing and an aggressive tumor. Cisplatin is the effective cytotoxic drug used for the treatment of TNBC. In addition, apatinib, a VEGFR2 inhibitor, exhibits antitumor activity in patients with TNBC. However, the effects of combination of apatinib with cisplatin on TNBC remain unclear. Thus, this study aimed to investigate the effects of apatinib in combination with cisplatin on MDA-MB-231 cells.MethodsImmunohistochemistry was used to detect the expression of VEGFR2. In addition, CCK-8, flow cytometric, transwell assays were used to measure the cell proliferation, apoptosis, migration and invasion, respectively. Moreover, western blotting was used to detect the expressions of Bax, active caspase 3, p-VEGFR2, p-Akt and p-mTOR.ResultsVEGFR2 was significantly upreguated in patients with TNBC. In addition, the inhibitory effects of cisplatin on the proliferation, migration and invasion of MDA-MB-231 cells were enhanced by apatinib. Moreover, apatinib increased cisplatin-induced apoptosis on MDA-MB-231 cells via increasing the level of Bax and active caspase 3 and decreasing the expression of Bcl-2. Importantly, apatinib enhanced anti-tumor effect of cisplatin on MDA-MB-231 cells via inhibiting the levels of p-VEGFR2, p-Akt and p-mTOR.ConclusionOur findings indicated that apatinib enhanced the anti-tumor effects of cisplatin on MDA-MB-231 cells via inhibition of VEGFR2. Thus, the combination of apatinib with cisplatin may serve as a potential approach in the treatment of patients with TNBC.     

TACE联合小剂量阿帕替尼治疗肝细胞癌合并门静脉癌栓

目的观察TACE联合小剂量阿帕替尼治疗肝细胞癌(HCC)合并门静脉癌栓的价值。方法将90例不可手术切除的原发性HCC合并门静脉癌栓患者随机分为治疗组及对照组,其中治疗组38例于TACE治疗后第3天开始口服小剂量(每日250 mg)阿帕替尼;对照组52例接受单纯TACE治疗。术后随访,比较2组间治疗前后甲胎蛋白水平及生存期的差异,分析2组患者的治疗有效率及术后不良反应情况。结果 2组患者TACE治疗的技术成功率均为100%。2组间治疗前甲胎蛋白水平差异无统计学意义(t=20.15,P=0.08),治疗组术后1、3、6、12个月甲胎蛋白水平均较对照组明显下降(P均0.05)。治疗组术后1、3、6、12、24个月肿瘤治疗有效率分别为89.47%(34/38)、84.21%(32/38)、78.95%(30/38)、34.21%(13/38)和10.53%(4/38);对照组分别为75.00%(39/52)、67.31%(35/52)、25.00%(13/52)、3.85%(2/52)和19.23%(10/52)。治疗组患者术后平均生存期明显长于对照组[(17.12±1.55)个月vs (14.21±2.13)个月,P=0.01]。虽然治疗组术后不良反应手足综合征、皮疹、腹泻、腹痛、消化道出血、蛋白尿、血尿、肌酐及尿素氮升高、眩晕、头痛、高血压、红细胞减少、白细胞减少、血红蛋白水平减低、血小板减少、转氨酶升高、胆红素升高的发生率均明显高于对照组(P均0.01),但其中美国国家癌症研究所(NCI)癌症常见毒性反应事件评价标准3级以上者较少。结论 TACE联合小剂量阿帕替尼治疗HCC在控制肿瘤及其合并癌栓进展方面优于单纯TACE,可有效延长患者生存期。     

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.     

First-line treatment of apatinib in elderly patient of advanced gastric carcinoma: A case report of NGS-driven targeted therapy

Gastric carcinoma (GC) is a common gastrointestinal malignancy with high incidence and mortality worldwide, and most patients are diagnosed in the late stages of disease. Palliative chemotherapy provides a survival benefit for patients with inoperable advanced GC. However, elderly patients who are unable to tolerate chemotherapy had worse prognosis due to lack of effective treatment. Herein we reported a Chinese elderly GC patient using next generation sequencing (NGS)-based tumor DNA analysis. Valuable gene variants of vascular endothelial growth factor (VEGF) A gene amplification were detected. Additionally, a novel NOTCH1-BPHL fusion has been identified. He received antiangiogenic drug apatinib and showed both good clinical and radiographic response, but eventually died of non-cancer related cause, with progression free survival time (PFS) and overall survival time (OS) up to 9.53 months. This was the first GC case with apatinib usage as first-line treatment under the guidance of NGS gene profiling.     

阿帕替尼治疗晚期非小细胞肺癌1例并文献复习

目的 探讨阿帕替尼治疗晚期非小细胞肺癌(NSCLC)的效果.方法 回顾性分析2015年3月河北大学附属医院肿瘤内科收治的1例晚期NSCLC患者的临床资料,并复习国内外文献,分别对晚期NSCLC的治疗原则和阿帕替尼治疗晚期NSCLC的疗效及不良反应进行讨论.结果 晚期NSCLC一线酪氨酸激酶抑制剂治疗失败以后,二线应用阿帕替尼延长了无进展生存期,但在治疗过程中出现了严重的不良反应——3级手足综合征,药物减量后出现进展,影响了患者的总生存期.结论 阿帕替尼在部分晚期NSCLC患者取得了显著的疗效,为晚期NSCLC的二线治疗提供了新的选择.