阿帕替尼治疗晚期胃癌的疗效及对血管内皮生长因子水平的影响

目的初步评价阿帕替尼对晚期胃癌三线治疗的临床疗效及对血清血管内皮生长因子（VEGF）水平的影响。 方法2016年1月至2017年12月，对30例经过一、二线化疗效果失败的晚期胃癌患者给予甲磺酸阿帕替尼治疗，观察晚期胃癌患者的近远期疗效和毒性不良反应，检测治疗前后血清VEGF水平变化。 结果患者口服阿帕替尼14.7（8~22）周，疗效评价完全缓解（CR）3例，部分缓解（PR）13例，疾病稳定（SD）9例和疾病进展（PD）5例，有效率为53.3%（16/30），疾病控制率为83.3%（25/30）。中位随访8.6（5~16）个月，患者中位无进展生存期（PFS）为5.2个月（95% CI：0~8.8个月），总生存率（OS）为9.4个月（95% CI：6.8~12.5个月）。阿帕替尼治疗后血清VEGF明显降低，阿帕替尼有效的患者治疗后VEGF下降明显（P<0.05）。 结论阿帕替尼对一、二线治疗失败的晚期胃癌患者临床疗效确切，能够改善患者的生存质量。血清VEGF水平在一定程度上可以反映阿帕替尼治疗的疗效。     

阿帕替尼在恶性肿瘤中的研究进展

近几年关于抗肿瘤血管生成药物的研究越来越多,血管内皮生长因子受体(vascular endothelial growth factor receptors,VEGFR)在血管形成过程起重要作用。阿帕替尼是一种新型口服小分子VEGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKI),目前主要用于晚期胃癌、乳腺癌和肺癌等治疗,目前已进入Ⅲ期临床试验。相比于同类药物索拉非尼和舒尼替尼,阿帕替尼显现出更高的体外和体内活性,具有很强的抗肿瘤作用。本文就关于阿帕替尼的研究背景、临床研究和药物不良反应进行综述。     

肾细胞癌的靶向治疗药物研究现状

靶向治疗是转移性肾癌的一线及二线治疗手段,其药物从作用机制主要分为两类:血管内皮生长因子(VEGF)/血管内皮生长因子受体(VEGFR)和抑制mTOR途径.最近开发的药物,包括酪氨酸激酶抑制剂、单克隆抗体和mTOR抑制剂,能靶向作用于肾癌的酪氨酸激酶和细胞内通路,产生抗肿瘤作用.本文综述较有前景的靶向药物,包括舒尼替尼( Sunitinib)、索拉非尼(Sorafenib)、帕唑帕尼(pazopanib)、贝伐单抗(Bevacizumab)及替西罗莫司Temsirolimus.     

仑伐替尼联合帕博利珠单抗在恶性肿瘤中的研究进展

仑伐替尼是一种口服多靶点酪氨酸激酶受体抑制剂, 在体内外表现出强大的抗血管生成及抑制肿瘤增殖的能力。帕博利珠单抗是目前研究最为广泛的免疫检查点抑制剂之一, 可以阻断程序性死亡受体-1与其配体相结合, 恢复T细胞杀伤肿瘤细胞的能力。研究发现, 酪氨酸激酶受体抑制剂的抗血管生成作用可以重新编程肿瘤微环境, 使其从免疫抑制状态转变为免疫支持状态, 增强免疫检查点抑制剂治疗肿瘤的效果。本文对仑伐替尼联合帕博利珠单抗治疗晚期恶性肿瘤的基本机制以及联合治疗的最新进展进行综述。     

晚期非小细胞肺癌抗血管生成治疗:文献复习及病例报道

【摘要】〓肺癌是我国死亡率最高的癌症,其中非小细胞肺癌占多数。近年来研究表明,抗血管生成药物在多种实体瘤包括非小细胞肺癌中表现出了显著的疗效。阿帕替尼作用于血管内皮生长因子受体(VEGFR),临床研究证实目前其主要适应症为晚期胃癌。近年来在晚期非小细胞肺癌患者中应用阿帕替尼的临床实践日益增多,但相关报道极少。现将本院在晚期非小细胞肺癌中应用阿帕替尼的临床病例报告如下并做相关文献复习。     

依维莫司在转移性肾细胞癌靶向药物序贯治疗中的应用

肾细胞癌起源于近曲小管上皮,以透明细胞癌为主。血管内皮生长因子(vascular endothelial growth factor,VEGF)和哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)通路的活化导致肿瘤血管生成增加,在肾癌转移中起到关键作用。目前已有多种针对VEGF和mTOR信号通路的靶向药物被批准用于治疗转移性肾细胞癌(metastatic renal cell carcinoma,mRCC)患者,包括血管内皮生长因子受体-酪氨酸激酶抑制剂(VEGFR-TKI)如舒尼替尼、     

VEGF靶向治疗及其生物标志物在晚期结直肠癌中的研究进展

结直肠癌(CRC)是世界范围内癌症发病与致死的主要因素,近几年分子靶向治疗的临床应用为晚期结直肠癌治疗带来了曙光。贝伐珠单抗被批准应用于一线和二线晚期结直肠癌的治疗,促使了以血管内皮生长因子(VEGF)为作用靶点的靶向治疗药物不断涌现,并在临床试验中取得显著疗效。笔者就VEGF靶向治疗及其生物标志物在晚期结直肠癌中的研究进展进行综述。     

胆道恶性肿瘤精准靶向治疗的研究进展

胆道恶性肿瘤(BTC)是一类高度异质性肿瘤, 尽管其在全球范围内定义为罕见癌, 但由于显著的地理差异, BTC在中国的发病率仍在持续上升。目前全球BTC的治疗需求远未被满足, 晚期化疗生存获益有限。随着其基因特征被逐步揭示, 近年来分子靶向治疗、免疫治疗以及药物联合治疗开始蓬勃发展。本文总结成纤维细胞生长因子受体、异柠檬酸脱氢酶、神经营养酪氨酸受体激酶等BTC治疗相关的基因靶点及其抑制剂的研究进展, 并展望了BTC精准靶向治疗未来的方向。     

跨越曲妥珠单抗时代乳腺癌靶向治疗策略

乳腺癌是一个复杂的异质性疾病。随着分子生物学技术的进步,乳腺癌靶向治疗进展很快。从1997年美国食品与药物管理局（FDA）批准抗HER?2的分子靶向治疗药物--曲妥珠单抗治疗晚期乳腺癌,开创了乳癌分子靶向治疗的时代。以后有多靶点药物拉帕替尼、血管表皮生长因子抑制剂贝伐单抗相继用于临床治疗。还有很多批准用于其他恶性肿瘤的靶向药物如吉非替尼、索拉非尼等也有一些II期研究显示了在乳腺癌治疗中的活性。另外,T?DM1等新药也在进行II/III期临床研究。     

仑伐替尼联合帕博利珠单抗在恶性肿瘤中的研究进展

仑伐替尼是一种口服多靶点酪氨酸激酶受体抑制剂,在体内外表现出强大的抗血管生成及抑制肿瘤增殖的能力。帕博利珠单抗是目前研究最为广泛的免疫检查点抑制剂之一,可以阻断程序性死亡受体-1与其配体相结合,恢复T细胞杀伤肿瘤细胞的能力。研究发现,酪氨酸激酶受体抑制剂的抗血管生成作用可以重新编程肿瘤微环境,使其从免疫抑制状态转变为免...     

Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium

BackgroundThe role of upfront cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors is unclear.ObjectiveTo evaluate the relationship between upfront CN and clinical outcomes in the setting of mRCC treated with immune checkpoint inhibitors or targeted therapy.Design, setting, and participantsUsing the International Metastatic RCC Database Consortium, we retrospectively identified patients diagnosed with de novo mRCC treated with immune checkpoint inhibitors or targeted therapy.Outcome measurements and statistical analysisOverall survival (OS) was compared between the two groups using the Kaplan-Meier method and multivariable Cox regressions adjusting for known prognostic factors.Results and limitationsWe identified a total of 4639 eligible patients with mRCC. Among the 4202 patients treated with targeted therapy and 437 patients treated with immune checkpoint inhibitors, 2326 (55%) and 234 (54%) patients received upfront CN prior to treatment start. In multivariable analyses, CN was associated with significantly better OS in both the immune checkpoint inhibitor–treated (hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.41–0.90, p = 0.013) and the targeted therapy treatment (HR: 0.72; 95% CI, 0.67–0.78, p < 0.001) group. There was no difference in OS benefit of CN between the immune checkpoint inhibitor and targeted therapy treatment groups (interaction p = 0.6). Limitations include selection of patients from large academic centers and the retrospective nature of the study.ConclusionsUpfront CN is associated with a significant OS benefit in selected patients treated by either immune checkpoint inhibitors or targeted therapy, and still has a role in selected patients in the era of immune checkpoint inhibitors.Patient summaryBefore effective systemic therapies were available for metastatic kidney cancer, surgical removal of the primary (kidney) tumor was the mainstay of treatment. The role of removing the primary tumor has recently been called into question given that more effective systemic therapies have become available. In this study, we find that removal of the primary kidney tumor still has a benefit for selected patients treated with highly effective modern systemic therapies, including targeted therapies and immune checkpoint inhibitors.     

Early experience with sunitinib, combined with docetaxel, in patients with metastatic breast cancer

Sunitinib malate (SUTENT^®) is an oral, multitargeted tyrosine kinase inhibitor that blocks several pathways central to angiogenesis and tumor cell proliferation and migration, including vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). Sunitinib has demonstrated clinical activity as a single agent in patients with metastatic breast cancer and it is hypothesized that enhanced clinical benefit may be derived by combining sunitinib with chemotherapy or other targeted agents. The current report describes four patients with advanced/metastatic breast cancer who experienced clinically meaningful responses following treatment with sunitinib in combination with docetaxel.     

Recent advances in localized RCC: A focus on VEGF and immuno-oncology therapies

Recent advances in advanced renal cell cancer (RCC) research have produced new drugs and therapies for patients with metastatic disease leading to higher response rates, improvements in progression-free survival, and longer overall survival. These advances have yet to be realized in patients with early-stage kidney cancer, and to date, no drug has been approved for the adjuvant treatment of localized kidney cancer. The current standard of care for localized high-risk kidney cancers is resection of the primary tumor. Here, we review the results of recently completed adjuvant vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) trials in RCC that have been reported, or are awaiting results. Further, we discuss the new immune checkpoint inhibitor adjuvant trials planned. There is hope that these trials may lead to new options and longer survival for patients with localized high-risk kidney cancer.     

Overview and management of toxicities associated with systemic therapies for advanced renal cell carcinoma

The advent of novel targeted agents for metastatic renal cell carcinoma (RCC) has offered clinical benefits over traditional immunotherapy (e.g., interleukin-2 and interferon-α) in both efficacy and safety profiles. The major classes of these targeted therapies for metastatic RCC include the tyrosine-kinase inhibitors, monoclonal antibody against vascular endothelial growth factor, and inhibitors of the mammalian target of rapamycin. Most recently, the success of immune checkpoint inhibitors—notably antibodies directed against programmed death-1 and its ligand—has also been demonstrated in RCC. With such progress in therapy, early detection, and subsequent management of treatment-related adverse events allow for patients to remain on active therapy for as long as possible and also enhance the probability of patients tolerating subsequent second line options. However, despite such impressive gains in efficacy with these new agents, therapeutic progress are primarily palliative in nature—hence, the critical importance of minimizing discomfort and potential harm in this patient population cannot be understated.     

Second-line systemic therapy in metastatic renal-cell carcinoma: A review

Treatment in metastatic renal-cell carcinoma (mRCC) has evolved tremendously in the last decade. The development of newer targeted agents, like vascular endothelial growth factor inhibitors and immunotherapy have changed the treatment paradigm in mRCC patients. Axitinib and everolimus have been used extensively in patients who progressed on prior antiangiogenic therapy. The newer agents including nivolumab, cabozantinib, and lenvatinib in combination with everolimus have all demonstrated overall survival benefit over everolimus. However, with multiple treatment options, optimal choice and sequencing becomes challenging. This article provides an overview of different therapeutic options available as second-line treatment in patients with mRCC along with future directions.     

Postoperative adjuvant therapy for hepatocellular carcinoma with microvascular invasion

Hepatocellular carcinoma (HCC) is one of the most lethal tumors in the world. Liver resection (LR) and liver transplantation (LT) are widely considered as radical treatments for early HCC. However, the recurrence rates after curative treatment are still high and overall survival is unsatisfactory. Microvascular invasion (MVI) is considered to be one of the important prognostic factors affecting postoperative recurrence and long-term survival. Unfortunately, whether HCC patients with MVI should receive postoperative adjuvant therapy remains unknown. In this review, we summarize the therapeutic effects of transcatheter arterial chemoembolization, hepatic arterial infusion chemotherapy, tyrosine protein kinase inhibitor-based targeted therapy, and immune checkpoint inhibitors in patients with MVI after LR or LT, aiming to provide a reference for the best adjuvant treatment strategy for HCC patients with MVI after LT or LR.     

Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of RCC disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. Von Hippel-Lindau (VHL) gene inactivation is observed in most clear cell renal carcinoma, resulting in vascular endothelial growth factor (VEGF) over-expression and driving the malignant phenotype. This review discusses the efficacy of novel therapies targeting the VEGF receptor (VEGFR) (e.g. anti-VEGF antibodies, VEGFR tyrosine kinase inhibitors, mTOR inhibitors), some of which were recently approved by the Food and Drug Administration/European Medicines Evaluation Agency (FDA/EMEA) and represent the new treatment standards in RCC patients.     

恶性胸膜间皮瘤免疫检查点抑制剂临床治疗进展

恶性胸膜间皮瘤(MPM)是一种主要与石棉暴露相关的罕见的高度侵袭性肿瘤,尽管应用不同的方式治疗(如化疗、放疗和手术)患者的疗效仍很差,预后也极差。近年来免疫治疗逐渐成为肿瘤治疗的热点,突破性进展是发现阻断T细胞免疫检测点分子可激活T细胞对肿瘤细胞的杀伤作用。免疫检查点抑制剂改变了肿瘤治疗的临床实践。2011年,CTLA-4抑制剂易普利姆玛(ipilimumab)获得美国食品药品监督管理局(FDA)的批准,成为首个上市的免疫检查点抑制剂。2014年,纳武单抗(nivolumab)获准成为全球首个上市的PD-1抑制剂。之后数年内,包括PD-1/PD-L1抗体在内的多个免疫检查点抑制剂获准用于包括非小细胞肺癌、胃癌和肝癌等在内的多个癌种的适应证。从DETERMINE研究、KEYNOTE-028研究到The PROMISE-Meso研究,都显示免疫检查点抑制剂单药对MPM治疗具有临床疗效和较好的安全性。免疫检查点抑制剂作为一线治疗与化疗的对比研究也在进行中,联合治疗(包括联合应用免疫检查点抑制剂和免疫检查点抑制剂联合化疗)的研究也在不断开展。免疫检查点抑制剂的生物标志物的研究推动了MPM的精准免疫治疗。     

Targeted therapies: Expanding the role of FGFR3 inhibition in urothelial carcinoma

The management of urothelial carcinoma (UC) has rapidly advanced in recent years with new approvals for immune checkpoint inhibitors and antibody-drug conjugates. However, while many UC tumors contain potentially actionable mutations, the role for targeted small molecule inhibitors has been limited. One such target is the fibroblast growth factor receptor (FGFR) family of proteins. Activating mutations and amplifications of FGFR3 are common in UC with higher incidences seen in upper tract as compared to lower tract disease. Consequently, multiple FGFR-directed targeted therapies have been developed and trialed in both UC and other solid tumors harboring FGFR mutations. At current, erdafitinib, an inhibitor of FGFR1-4, is the only approved targeted therapy in metastatic UC following the BLC2001 study, which demonstrated a 49% overall response rate in patients with UC harboring an FGFR3 mutation. Additional FGFR-directed agents also continue to be investigated across multiple disease stages in FGFR-mutated UC including infigratinib, rogaratinib, and AZD4547, among others. Ongoing trials are combining these agents with immune checkpoint inhibitors and chemotherapy regimens. The precision medicine revolution has begun in UC, and FGFR3 inhibitors are leading the charge toward a more personalized, biomarker-driven treatment paradigm.     

Targeted therapy in renal cell carcinoma

Objective To present an update on anti-angiogenic drugs in the treatment of metastatic renal cell carcinoma. Recent findings A better understanding of molecular pathways that are involved in clear cell carcinomas has led to the development of multiple targeted therapies with significant clinical benefits. Two tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor have been shown to improve the progression-free survival of patients in first-line (Sunitinib vs. interferon-α) or second-line treatment (Sorafenib vs. placebo). Temsirolimus, an agent that inhibits the serine–threonine kinase activity of the mammalian target of rapamycin, offers better overall survival than interferon in patients with poor-risk characteristics. Finally, Bevacizumab, which is an antibody directed against VEGF, in association with IFN is providing substantial response rates and increased progression-free survival compared to IFN alone. Conclusion Four major drugs or regimens with proven efficacy are now available in first and second line therapy in metastatic renal cell carcinoma (mRCC). Further studies are needed to determine the optimal combinations of these agents in metastatic disease and to assess their impact in the adjuvant setting.