治疗肝癌进化：索拉非尼与超越

StephenW

Evolution of Treatment for HCC: Sorafenib and Beyond

Lauren Mays Weddle, PhD
Published Online: May 08, 2015


Liver with tumorThe small molecule multikinase inhibitor sorafenib remains the only molecularly targeted therapy approved by the FDA for the treatment of hepatocellular carcinoma (HCC). Ongoing clinical trials are diligently testing the potential for novel targeted agents or combination therapies to further improve patient outcomes in this setting.

Sorafenib tosylate (Nexavar) was approved by the FDA in late 2007 for the treatment of unresectable HCC, a decision based on the findings of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial.1According to this multicenter, double-blind, phase III study, a randomized protocol of either sorafenib or placebo in 602 advanced, untreated patients with HCC, sorafenib led to statistically significant improvement in overall survival compared with placebo.

Sorafenib is a small molecule inhibitor of two tyrosine kinases, the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), as well as members of the Raf kinase family. Its administration has the ability to induce autophagy, which in the setting of cancer can suppress tumor growth.

Compared with a median overall survival of 7.9 months in the SHARP trial’s placebo arm, the use of sorafenib significantly extended this outcome to 10.7 months. While no significant improvement was observed in time to symptomatic progression, the median time to radiologic progression was significantly decreased from 5.5 months to 2.8 months in the placebo versus sorafenib groups, respectively.1Overall, the trial demonstrated that the use of sorafenib could extend median survival and time to progression by nearly 3 months for patients with advanced HCC.

In 2009, these findings were followed with results from a similar trial in the Asia-Pacific region, which also demonstrated the effectiveness of sorafenib in treating advanced HCC.2As the majority of HCC cases occur in areas with endemic hepatitis B (HBV) or hepatitis C virus (HCV) infection, this multinational phase III trial was critical for establishing the safety and efficacy of sorafenib in patients from a relevant geographic region.

In this setting, median overall survival increased by more than 2 months with the use of sorafenib, from 4.2 months to 6.5 months compared with placebo. Time to progression was cut in half, from 2.8 months to 1.4 months, respectively, in those receiving sorafenib compared with controls. Hand-foot skin reactions, diarrhea, and fatigue were the most frequently reported grade 3/4 drug-related adverse events; however, these occurrences rarely led to the discontinuation of patients from the trial.

In response to these findings, a subsequent study went on to measure plasma biomarkers in the patients enrolled in the SHARP trial, in order to identify correlates of prognosis or predictors of sorafenib response.3Two biomarkers of angiogenesis, angiopoietin 2 and VEGF, were found to independently predict survival among patients with advanced HCC. However, none of the biomarkers tested in the study demonstrated significant predictive value when determining patient response to sorafenib.

The Promise of Combination Therapy: Sorafenib Plus TACE

Numerous studies have begun investigating the potential for combining treatment modalities in HCC, in order to further prolong patient survival and promote tumor regression. Efforts have included studies combining sorafenib with transarterial chemoembolization (TACE), stereotactic body radiation therapy (SBRT), as well as various chemotherapy regimens.

TACE is a minimally invasive technique that was originally used to treat patients with liver tumors with emergent humoral hypercalcemia.4Stemming from a combination of diagnostic angiography and transcatheter injection, TACE injects small embolic particles coated with chemotherapeutic agents directly into the tumor’s blood supply in an effort to reduce tumor size. This technique has been used extensively in recent years for the palliative treatment of unresectable HCC, and has begun to show indication in selected patients with early-stage disease.

The combination of TACE and sorafenib has been investigated in several studies for use in patients with intermediate or advanced HCC.5,6While survival outcomes among these studies remain an area of controversy, one recent meta-analysis was able to confirm the benefit of combination therapy in this setting, where TACE plus sorafenib appeared to improve overall survival, time to progression, and objective response rate.5

While it may have the ability to improve outcomes, this systematic review also uncovered the finding that the risk of adverse reactions was significantly increased with the combination of TACE and sorafenib.5Grade 3/4 adverse reactions, including hand-foot skin reaction, diarrhea, rash or desquamation, and hypertension, were elevated in the combination therapy group when compared with TACE alone.

In the multicenter phase II SOCRATES trial completed in late 2014, the combination of TACE and sorafenib appeared to be tolerable in previously untreated HCC patients.7Participants with unresectable HCC and a Child-Pugh score ≤8 demonstrated a median time to progression and overall survival of 16.4 months and 20.1 months, respectively. Complete responses were observed in 7% of patients, with partial responses in 41.8% of patients.

Sorafenib Plus Radiation

Combining sorafenib with radiation therapy has also shown promise in improving responses in HCC. A preclinical study in 2013 demonstrated that by downregulating the phosphorylation of STAT3 and reducing the expression of related proteins, sorafenib was able to overcome radiation resistance in HCC cells.8In other words, the addition of sorafenib to radiation therapy could promote radiation-induced apoptosis among tumor cells that were previously resistant.

A subsequent phase I study investigated the concurrent use of stereotactic body radiation and sorafenib in patients with advanced HCC.9As SBRT may aid in focusing the dose of radiation directly on the tumor, this combination has the potential to enhance sorafenib-induced survival benefits while minimizing the deleterious effects of radiation on normal tissue.

Unfortunately, results presented at the American Society for Radiation Oncology meeting in 2012 emphasized that the concurrent use of sorafenib and radiation therapy still faces several important toxicity-related challenges, where lowering drug dose and irradiated volume may be required.9Due to toxicity risks and advanced tumor burden, the combination of concurrent sorafenib and SBRT was not recommended for locally advanced HCC outside the setting of carefully designed clinical trials. Despite these limitations, response rates in this study reached approximately 40%.

An ongoing phase III study by the Radiation Therapy Oncology Group is now investigating the sequential use of SBRT followed by sorafenib when compared with sorafenib alone.10

Sorafenib Plus Chemotherapy

In late 2010, a phase III study investigated the combination of sorafenib with doxorubicin hydrochloride chemotherapy versus doxorubicin plus placebo in a population of patients with advanced HCC with Child-Pugh A (CP-A) liver disease.11The combination did result in a significant improvement in time to progression, overall survival, and progression-free survival. Moreover, the beneficial effects observed did not adversely impact toxicity profiles compared with monotherapy alone.

Further studies combining sorafenib and doxorubicin are currently underway.12,13These include a phase III study in patients with advanced HCC with metastases to other sites,12as well as a phase II study investigating this combination among patients with advanced HCC who progressed on a first-line sorafenib treatment.13

Sorafenib has also recently been evaluated in combination with another chemotherapy regimen, gemcitabine and oxaliplatin (GEMOX), in the randomized phase II GONEXT trial.14Here, patients with advanced or metastatic HCC (Barcelona Clinic Liver Cancer stage B or C) and a liver disease score of CP-A were randomized to receive sorafenib alone or in combination with GEMOX. Overall, the combination therapy met its primary endpoint of 4-month progression-free survival ≥50%. Compared with sorafenib alone, sorafenib plus GEMOX showed improved response rate, median progression-free survival, and overall survival.

Mixed Results With Other Molecularly Targeted Therapies

In addition to advancements in the combination of sorafenib with TACE, radiation, or chemotherapy, other investigations have taken an alternative approach, attempting to apply novel molecularly targeted therapies to the treatment of HCC. Although the potential for several agents appeared promising in early trials, larger studies have been met with conflicting results.

The phase III study, EVOLVE-1, evaluated the use of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in patients with advanced HCC who were intolerant to sorafenib or who had progressed during or after sorafenib treatment.15Everolimus has been approved for use in several settings, including advanced renal cell carcinoma and progressive neuroendocrine tumors.16Unfortunately, in the setting of HCC, the EVOLVE-1 trial demonstrated that everolimus was unable to improve overall survival or time to progression in the study population when compared with placebo.

A phase II study of dovitinib (TKI258) versus sorafenib in the first-line treatment of advanced HCC also yielded disappointing results.17While sorafenib inhibits VEGFR and PDGFR to delay tumor progression, dovitinib inhibits fibroblast growth factor receptor (FGFR), a third pathway through which tumor angiogenesis can occur. Despite the hypothesis that VEGFR, PDGFR, and FGFR inhibition may further improve upon the responses seen in the SHARP trial, dovitinib demonstrated comparable activity to sorafenib, with no benefit in median overall survival or time to progression.

The oral inhibitor of hepatocyte growth factor receptor (HGFR, or MET) and VEGFR2, cabozantinib, has also gained attention as a promising therapeutic agent.18,19Unlike results with everolimus and dovitinib, cabozantinib demonstrated promising activity in patients with advanced HCC in a recent phase II randomized discontinuation trial, even among those who had received prior treatment with sorafenib.18The ongoing phase III CELESTIAL study was designed thereafter, to evaluate the effects of cabozantinib versus placebo on overall survival in patients with advanced HCC with prior sorafenib use.19

Promising Immunotherapy Approaches on the Horizon

Another area of active research is in the field of antibody-based immunotherapy. Immunotherapy approaches have gained the most traction in melanoma research, where the programmed cell death protein-1 (PD-1) inhibitors, nivolumab and pembrolizumab, as well as the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, ipilimumab, have gained FDA approval.20These agents have also begun to show promise in a variety of other cancer types, which has led to their investigation in the field of HCC.

The inhibition of PD-1, an immune checkpoint receptor that inhibits T cell activation, has shown efficacy against a variety of solid tumor types in phase I clinical trials. This receptor may play a role in HCC as its ligand, PD-L1, is overexpressed on HCC tumors and the PD-1 pathway is involved in the exhaustion of T cells in response to viral hepatitis.21As such, interfering with the PD-1/PD-L1 pathway may promote T cell activation, leading to anti-tumoral responses.

This hypothesis is currently being pursued in a phase I dose-escalation study evaluating the safety of nivolumab in patients with advanced HCC.21,22Cohorts with and without HBV and HCV infection are being assessed in a population of patients with CP-A liver disease and progressive HCC who demonstrated intolerance after one or more lines of therapy.

In another pilot study, a monoclonal antibody against CTLA-4, tremelimumab, is being assessed for the treatment of HCC in combination with either TACE or radiofrequency ablation.23,24Expressed on the surface of activated T cells, the interaction of CTLA-4 with its ligand, B7 (also known as CD80 and CD86), results in the downregulation of T cell activation. As such, the inhibition of this pathway with tremelimumab is thought to promote the proper activation of a T cell response. At the 2014 American Society of Clinical Oncology Annual Meeting, preliminary safety data were reported, demonstrating the feasibility of the first 2 planned dose levels, which support further enrollment to the final planned dose of the trial.23

A novel strategy involving autologous T cell receptor-redirected therapy has also shown promise in a preliminary study published in the Journal of Hepatology early in 2015.25This approach involved a patient with HBV-related HCC, who had residual, chemoresistant extrahepatic metastases after receiving liver transplantation. Unlike the donor liver, these extrahepatic metastases still expressed HBV antigens, leaving them vulnerable to HBV antigen-specific T cells.

In this study, HCC autologous T cells were genetically modified to express a T cell receptor specific to the HBV surface antigen (HBsAg). Findings confirmed that the engineered lymphocytes were able to expand and facilitate a reduction in HBsAg levels. Liver inflammation and other toxicities were not exacerbated as a result of this approach; however, clinical efficacy could not yet be established. Further studies will certainly investigate the potential of this novel therapeutic strategy in HBV-related HCC.25

Overall, despite the success of several molecularly targeted therapies and immunotherapy approaches in the treatment of other malignancies, sorafenib remains the only targeted agent with FDA approval for the treatment of HCC. While progress in the field has been modest, ongoing clinical trials continue to investigate novel approaches and combination therapies that may have the potential to improve patient outcomes in HCC.

Erik Knudsen, PhD, from the University of Texas Southwestern Medical Center, notes that it will become “critically important to consider the incredible diversity of HCC when investigating therapeutic response.”26Knudsen adds that the “plethora of ongoing early stage trials provides hope for more effective regimens.”
- See more at: http://www.targetedonc.com/publi ... thash.1kNbme3C.dpuf

StephenW

进化治疗肝癌：索拉非尼与超越

劳伦梅斯韦德尔，博士
发布时间：2015年5月8日


肝脏tumorThe小分子多激酶抑制剂索拉非尼仍然是肝细胞癌（HCC）的治疗中被FDA批准的唯一的分子靶向治疗。正在进行的临床试验正在努力为测试新型靶向药物或联合疗法的潜力，进一步提高该设置患者的治疗效果。

苯磺酸索拉非尼（多吉美）在2007年底被美国FDA批准用于不能手术切除的肝癌治疗的基础上，索拉非尼肝癌评估随机协议（SHARP）trial.1According这个多中心，双盲，III期临床研究的结果决定，索拉非尼或安慰剂602先进的，未经治疗的肝癌的随机协议，索拉非尼导致与安慰剂相比，总生存期显显著的改善。

索拉非尼是两种酪氨酸激酶的小分子抑制剂，血管内皮细胞生长因子受体（VEGFR）和血小板衍生的生长因子受体（PDGFR），以及对Raf激酶家族的成员。其施用具有诱导自噬，其在癌症的设定可以抑制肿瘤生长的能力。

7.9个月的试用SHARP的安慰剂组的中位总生存期相比，使用索拉非尼的这一结果显著延长至10.7个月。虽然没有显著改善观察时间症状恶化的中位时间到放射进展被显著从5.5个月，而安慰剂与索拉非尼组下降到2.8个月respectively.1Overall，试验证实，使用索拉非尼可以扩展位生存和进展时间近3个月治疗晚期肝癌。

在2009年，这些研究结果与跟随来自于亚太地区，这也证明了索拉非尼的有效性治疗晚期HCC.2As多数肝癌病例类似的试验结果出现地方性乙型肝炎（HBV）或丙型肝炎领域肝炎病毒（HCV）感染，这种多国III期试验是从相关地理区域建立患者索拉非尼的安全性和有效性的关键。

在这种背景下，中位总生存期与使用索拉非尼的增长超过2个月，从4.2个月，与安慰剂相比6.5个月。进展时间减少了一半，从2.8个月到1.4个月，分别在那些接受索拉非尼与对照组相比。手足皮肤反应，腹泻，疲劳是最常见的3/4级药物相关不良事件;然而，这些事件很少导致患者从试验中止。

针对上述调查结果，随后的研究继续以衡量参加了SHARP试验患者血浆生物标志物，以确定预后相关因素或血管生成的索拉非尼response.3Two预测的生物标志物，血管生成素2和VEGF，被发现独立预测生存之间患者晚期肝癌。然而，没有在研究测试的生物标记物，以确定患者的索拉非尼时的反应展示显著预测值。

联合用药的承诺：索拉非尼联合TACE

大量的研究已经开始调查潜在用于组合治疗方式在肝癌中，为了进一步延长患者的存活和促进肿瘤消退。努力包括研究，肝动脉栓塞化疗（TACE），立体定向放射治疗（SBRT），以及各种化疗方案结合索拉非尼。

TACE是一种微创技术，最初是用于治疗患者的肝脏肿瘤的紧急体液hypercalcemia.4Stemming从诊断​​造影导管和注射的组合，TACE涂注入化疗药物栓塞的小颗粒直接进入肿瘤的血液供应，努力减少肿瘤的大小。这种技术已被广泛应用，近年来的姑息性治疗不能手术切除的肝癌，并已经开始显现指示在选定的患者早期疾病。

TACE与索拉非尼的组合已被调查的几个研究用于治疗中晚期HCC.5,6While生存成果，这些研究中仍然是争论的一个领域，最近的一项荟萃​​分析能够证实联合治疗的益处在这一背景下，在TACE加上索拉非尼出现，以提高总生存期，疾病进展时间和客观反应军耗

虽然它可能有改善结果的能力，这个系统的审查也发现了这一发现不良反应的风险与显著TACE和sorafenib.5Grade 3/4的不良反应，包括手足皮肤反应，腹泻的组合增加，皮疹或脱屑，和高血压，当单独与TACE相比升高的联合治疗组。

在多中心II期试验苏格拉底在2014年年底完成，TACE和索拉非尼的组合似乎是在可容忍以前未经治疗的肝癌patients.7Participants不能手术切除的肝癌和Child-Pugh评分≤8表现出位疾病进展时间和总生存期16.4个月和20.1个月。完整的反应中观察到的患者7％，与部分反应的患者的41.8％。

索拉非尼联合辐射

索拉非尼相结合的放射治疗也表明承诺在改善肝癌的反应。的临床前研究，2013年表明，通过下调的STAT3的磷酸化和减少相关蛋白质的表达，索拉非尼是能够克服在HCC cells.8In换言之耐辐射性，增加索拉非尼的放射治疗可促进中辐射诱导的细胞凋亡肿瘤细胞，以前抗性。

随后的I期研究调查的同时使用立体定向放疗和索拉非尼治疗晚期HCC.9As SBRT可能聚焦辐射剂量直接作用于肿瘤的辅助，这样的组合有可能加强索拉非尼诱导的生存利益的潜力，同时尽量减少辐射对正常组织的有害作用。

不幸的是，结果发表在美国放射肿瘤学会会议于2012年强调的是，同时使用索拉非尼治疗和放射治疗仍面临几个重要的毒性相关的挑战，其中降低药物剂量和照射体积可以required.9Due毒性风险和先进肿瘤负荷，同时索拉非尼和SBRT的组合是不推荐使用精心设计的临床试验设置之外局部晚期肝癌。尽管有这些限制，在这项研究中的反应率达到约40％。

当索拉非尼alone.10相比，一个正在进行III期研究的放射治疗肿瘤组目前正在调查的顺序使用SBRT其次是索拉非尼

索拉非尼联合化疗

在2010年年底，第三阶段的调查研究与索拉非尼盐酸阿霉素化疗与阿霉素加安慰剂组合的患者与Child-Pugh分级A（CP-A）肝disease.11The组合晚期肝癌人口也导致显著改善在疾病进展时间，总生存期和无进展生存期。此外，有益效果观察没有不利地与单独治疗相比毒性特征造成影响。

进一步的研究相结合的索拉非尼和阿霉素是目前underway.12,13These包括III期临床试验的患者有转移到其他网站的晚期肝癌，12AS以及一个第二阶段的研究调查中晚期肝癌进展谁在第一代这种组合索拉非尼线treatment.13

索拉非尼最近也被评价与另一种化疗方案，吉西他滨和奥沙利铂（GEMOX），在随机II GONEXT trial.14Here，晚期或转移性肝癌（巴塞罗那临床肝癌阶段B或C）和肝脏疾病得分CP-A的被随机分配到单独的或与GE​​MOX组合接收索拉非尼。总体而言，中西医结合治疗达到了主要4个月无进展生存期≥50％的终点。与单纯索拉非尼相比，索拉非尼联合GEMOX显示改进的响应率，中位无进展生存期和总生存期。

好坏参半的结果与其他分子靶向治疗

除了在索拉非尼与TACE，辐射或化疗的组合进步，其他研究已采取另一种方法，尝试应用新颖分子靶向治疗肝癌的治疗。虽然几家代理商的潜力在早期试验出现了有希望的，更大规模的研究已经会见了相互矛盾的结果。

III期研究，EVOLVE-1，评估使用雷帕霉素靶蛋白（mTOR）抑制剂，依维莫司，患者晚期肝癌谁是不能耐受索拉非尼或谁已被批准期间或索拉非尼后treatment.15Everolimus进步了在一些设置，包括晚期肾细胞癌和神经内分泌逐步使用tumors.16Unfortunately，在肝癌的设置，EVOLVE-1试验表明，与安慰剂相比，依维莫司无法提高总体生存期或疾病进展时间在研究人群。

dovitinib（TKI258）与索拉非尼一线治疗晚期肝癌的II期临床研究也取得了令人失望的results.17While索拉非尼抑制VEGFR和PDGFR延缓肿瘤进展，dovitinib抑制成纤维细胞生长因子受体（FGFR），通过第三途径其中肿瘤血管生成可能发生。尽管VEGFR，PDGFR，FGFR和抑制可能进一步在出现在SHARP试验的反应提高了假设，dovitinib表现出相当的活性索拉非尼，与中位总生存期或疾病进展时间没有任何好处。

肝细胞生长因子受体（HGFR，或MET）和VEGFR2，cabozantinib口服抑制剂，也获得了关注，因为有希望的治疗agent.18,19Unlike结果与依维莫司和dovitinib，cabozantinib表现出有前途的活动中晚期肝癌在最近第二阶段随机试验的终止，即使是那些曾接受过治疗sorafenib.18The正在进行III期研究CELESTIAL其后是谁设计的，评估与索拉非尼前高级use.19肝癌cabozantinib与安慰剂在总生存期患者的影响

有前途的途径免疫的地平线

活跃​​的研究的另一个领域是基于抗体的免疫疗法领域。免疫治疗方法已取得了最牵引在黑色素瘤的研究，其中，程序性细胞死亡蛋白-1（PD-1）抑制剂，nivolumab和pembrolizumab，以及细胞毒性T淋巴细胞相关蛋白-4（CTLA-4）抑制剂，易普利姆玛，已经获得了FDA approval.20These代理商也开始展现出希望在其他各种癌症类型，从而导致其在肝癌的实地调查。

PD-1，免疫检查点受体抑制T细胞活化的抑制，表现出的功效针对在I期临床试验的各种固体肿瘤类型。该受体可能在HCC中发挥作用，因为它的配体PD-L1，过表达对肝癌肿瘤和对PD-1途径参与T细胞的耗竭响应于病毒hepatitis.21As这样，与PD-1的干扰/ PD-L1的通路可能促进T细胞的活化，导致抗肿瘤反应。

这个假设目前正在寻求在I期剂量递增研究评估nivolumab的安全治疗晚期HCC.21,22Cohorts有和没有HBV和HCV感染正在评估患者的CP-A的肝脏疾病，人口渐进肝癌谁后的治疗的一个或多个行证实不容忍。

在另一个试验性研究，针对CTLA-4，tremelimumab单克隆抗体，被评定为肝癌的组合的治疗或者TACE或射频ablation.23,24Expressed活化的T细胞的表面上，CTLA-4的与相互作用对其配体，B7（也称为CD80和CD86），结果在T细胞活化下调。因此，该通路与tremelimumab的抑制被认为是促进T细胞应答的正确激活。在临床肿瘤年会的2014年美国社会，初步安全性数据进行了报道，展示了第一个2计划的剂量水平，其支持进一步扩招到trial.23的最终计划剂量的可行性

一个涉及自体T细胞受体重定向治疗新策略也显示出的承诺发表在肝病杂志初步研究2015.25This方式参与早期HBV相关肝癌，谁接受肝移植术后残留过，化疗耐药肝外转移的患者。不同于供体肝脏，这些肝外转移仍然表达HBV抗原，使他们容易受到乙肝病毒的抗原特异性T细胞。

在这项研究中，肝癌的自体T细胞被遗传修饰以表达特异性的乙型肝炎病毒表面抗原（HBsAg）T细胞受体。结果证实，该工程化的淋巴细胞都能够扩大和促进HBsAg水平的降低。肝脏炎症和其他毒性不作为加剧这种做法的结果;然而，临床疗效还不能确定。进一步的研究将肯定调查这种新的治疗策略的HBV相关HCC.25潜在

总体而言，尽管在其他恶性肿瘤的治疗几个分子靶向治疗和免疫治疗方法的成功，索拉非尼仍然是唯一靶向剂与FDA批准用于治疗HCC。而在该领域的进展一直不大，正在进行的临床试验继续调查新方法和新组合疗法可能有改善患者的治疗效果在肝癌的可能性。

埃里克·克努森，博士，从得克萨斯大学西南医学中心的研究，指出，它将成为“极其重要的调查时，治疗反应考虑肝癌的难以置信的多样性。”26Knudsen补充说，正在进行前期试验的“过多希望提供更多有效的治疗方案。“
- 在查看更多： http://www.targetedonc.com/publi ... thash.1kNbme3C.dpuf

bigben446

StephenW 发表于 2015-5-9 12:45
进化治疗肝癌：索拉非尼与超越

劳伦梅斯韦德尔，博士

这不是google翻译的吧，中文看起来很顺畅