二线Cabozantinib证明对HBV +肝癌有效

StephenW

Second-Line Cabozantinib Proves Effective in HBV+ Liver Cancer
Anita T. Shaffer @Shaffer1
Published: Saturday, Sep 15, 2018
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Tim Meyer, MD, PhD
Tim Meyer, MD, PhD
Cabozantinib (Cabometyx) improved survival outcomes as second-line therapy for patients with hepatocellular carcinoma (HCC) who also had a history of hepatitis B virus (HBV) infection, demonstrating efficacy against a highly prevalent cause of the malignancy, according to study findings presented at the 2018 International Liver Cancer Association (ILCA) Annual Conference.

The data were reported as part of a subgroup analysis of the phase III CELESTIAL trial, in which cabozantinib reduced the risk of death by 24% compared with placebo in patients who had progressed on at least 1 prior systemic therapy for advanced HCC.1,2

Similarly, the multikinase inhibitor showed improved overall survival (OS) in patients with an HBV etiology, although the medians were lower than the full population, lead investigator Tim Meyer, MD, PhD, said in presenting the data at ILCA.1

“The benefit for cabozantinib is maintained,” said Meyer, a professor and director of the University College of London Experimental Cancer Medicine Centre in the United Kingdom, adding that no new safety signals were observed. “The absolute survival is worse in this patient population generally, so the hepatitis B–infected patients have a poor prognosis.”

Meyer said that HBV infection accounts for at least 50% of primary liver tumors diagnosed globally. The virus is a main risk factor associated with HCC in eastern Asia and sub-Saharan Africa, where 80% of cases occur, according to an overview of the disease recently published in Lancet.3 By contrast, hepatitis C and excessive alcohol consumption are the main risk factors in the United States, Europe, and Japan.3

In CELESTIAL, 707 patients were randomized 2:1 to receive cabozantinib at 60 mg daily (n = 470) or placebo (n = 237). In this population, median OS with cabozantinib was 10.2 versus 8.0 months for placebo (HR, 0.76; 95% CI, 0.63-0.92; P = .005). The median progression-free survival (PFS) was 5.2 months compared with 1.9 months for placebo, which was a 56% reduction in the risk of progression or death with the targeted therapy (HR, 0.44; 95% CI, 0.36-0.52; P <.001).

In all, 267 patients (38%) randomized during the trial had HBV; 178 were in the cabozantinib arm and 89 in the placebo group. This group comprised 79% of participants from Asia (n = 175), an area that included Hong Kong, South Korea, Singapore, and Taiwan; 22% of those from Europe and the Pacific (n = 365); and 29% of those from North America (n = 167).

Among all patients classified with HBV etiology, the median OS was 9.7 months (95% CI, 7.9-12.3) for cabozantinib compared with 6.1 months (95% CI, 4.8-7.7) with placebo, a 31% reduction in the risk of death (HR, 0.69; 95% CI, 0.51-0.94). The median PFS was 4.4 months with cabozantinib (95% CI, 3.7-5.6) versus 1.8 months (95% CI, 1.7-1.8) with placebo, which was a 69% reduction in risk (HR, 0.31; 95% CI, 0.23-0.42).

Drilling down further into the study details, Meyer also presented data for patients whose HBV status was confirmed through serology. When the study was launched, Meyer explained, central testing for HBV status via serology was not required and classification by investigators was permitted. As a result, serology testing was not conducted for approximately 35% of the participants who were classified as HBV-positive in both arms.

Of those who were tested by serology,  53% of the cabozantinib group and 58% of the placebo arm were positive for hepatitis B surface antigen (HBsAG) or hepatitis B core antibody (HBcAb). The median OS in the cabozantinib arm for this patient subgroup (n = 95) was 8.9 months (95% CI, 6.4-11.6) versus 5.5 months (95% CI, 4.4-7.8) in the placebo group (n = 52), for an HR favoring cabozantinib of 0.58 (95% CI, 0.37-0.89). The median PFS was 4.3 months (95% CI, 3.5-6.4) with cabozantinib versus 1.8 months (95% CI, 1.7-1.9) with placebo (HR, 0.40; 95% CI, 0.27-0.61).

The baseline characteristics of patients with HBV were balanced between the treatment arms. Patients who received cabozantinib had a median age of 59 years (range, 22-83), 47% had alpha-fetoprotein (AFP) levels ≥400 ng/mL, and 90% had extrahepatic spread (EHS) or macrovascular invasion (MVI). In the placebo arm, the median age was 60 years (34-79), 54% had AFP ≥400 ng/mL, and 91% had EHS or MVI.

In terms of prior therapies, 71% of patients in both arms received 1 prior therapy before joining the trial and about 29% had received 2. All patients had previously taken sorafenib (Nexavar), an established frontline standard in HCC.

Meyer said cabozantinib’s mechanism of action may account for its efficacy as a second-line therapy. The drug targets MET, SXL, and VEGF receptors. “It is known to be active against MET and AXL, which distinguishes it from sorafenib, and MET is known to be a resistance escape pathway so that may be relevant for its activity in the second line,” he said.

Based on the data from CELESTIAL, the FDA has accepted a supplemental new drug application for cabozantinib  for patients with previously treated advanced HCC, according to Exelixis, the company developing the therapy. The FDA is scheduled to render a decision by January 14, 2019.

Cabozantinib was initially approved by the FDA as a treatment for patients with medullary thyroid cancer in 2012. In April 2016, the agent received a new indication as advanced renal cell carcinoma (RCC) following 1 prior antiangiogenic therapy. This approval was further expanded in December 2017 to patients with advanced RCC in the first-line setting. Numerous other trials exploring the agent remain ongoing.
Reference

StephenW

二线Cabozantinib证明对HBV +肝癌有效
Anita T. Shaffer @ Shaffer1
发布时间：2018年9月15日，星期六
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Tim Meyer，医学博士，博士
Tim Meyer，医学博士，博士
根据研究结果显示，Cabozantinib（Cabometyx）改善了肝细胞癌（HCC）患者的二线治疗的生存结果，该患者也有乙型肝炎病毒（HBV）感染病史，显示出对抗高度恶性肿瘤的疗效。在2018年国际肝癌协会（ILCA）年会上。

这些数据作为III期CELESTIAL试验亚组分析的一部分进行了报告，其中cabozantinib在先前至少1次全身治疗晚期HCC的患者中与安慰剂相比降低了24％的死亡风险。

类似地，多激酶抑制剂显示HBV病因患者的总生存期（OS）有所改善，尽管中位数低于完全人群，首席研究员Tim Meyer博士在ILCA上提供数据时表示。

英国伦敦大学实验癌症医学中心教授兼主任梅耶说：“卡博替尼的益处得以维持。”他补充说，没有观察到新的安全性信号。 “一般来说，这个患者的绝对生存率更差，因此感染乙型肝炎的患者的预后较差。”

迈耶说，HBV感染占全球诊断的原发性肝肿瘤的至少50％。根据最近发表在柳叶刀上的疾病概述，该病毒是东亚和撒哈拉以南非洲地区HCC相关的主要危险因素，其中80％的病例发生。相比之下，丙型肝炎和过量饮酒是美国，欧洲和日本的主要风险因素

在CELESTIAL中，707名患者按2：1随机分组接受每日60 mg（n = 470）或安慰剂（n = 237）的cabozantinib。在该人群中，使用cabozantinib的中位OS为10.2而安慰剂为8.0个月（HR，0.76; 95％CI，0.63-0.92; P = .005）。中位无进展生存期（PFS）为5.2个月，安慰剂为1.9个月，目标治疗进展或死亡风险降低56％（HR，0.44; 95％CI，0.36-0.52; P <0.001）。

总共有267名患者（38％）在试验期间随机分配了HBV;卡博替尼组有178名，安慰剂组有89名。该群体占亚洲（n = 175）参与者的79％，其中包括香港，韩国，新加坡和台湾;来自欧洲和太平洋地区的人口占22％（n = 365）;和29％来自北美的人（n = 167）。

在所有归类为HBV病因的患者中，卡博替尼的中位OS为9.7个月（95％CI，7.9-12.3），安慰剂组为6.1个月（95％CI，4.8-7.7），死亡风险降低31％ （HR，0.69; 95％CI，0.51-0.94）。卡波替尼（95％CI，3.7-5.6）的中位PFS为4.4个月，安慰剂组为1.8个月（95％CI，1.7-1.8），风险降低69％（HR，0.31; 95％CI，0.23） -0.42）。

Meyer还深入研究了研究细节，还为通过血清学证实HBV状态的患者提供了数据。 Meyer解释说，当这项研究启动时，不需要通过血清学检测HBV状态，并允许调查人员进行分类。因此，大约35％的参与者在双臂中被归类为HBV阳性，未进行血清学检测。

在通过血清学检测的患者中，53％的cabozantinib组和58％的安慰剂组为乙型肝炎表面抗原（HBsAG）或乙型肝炎核心抗体（HBcAb）阳性。该患者亚组（n = 95）的cabozantinib组中位OS为8.9个月（95％CI，6.4-11.6），安慰剂组为5.5个月（95％CI，4.4-7.8），n = 52，对于喜欢卡博替尼0.5的人力资源（95％CI，0.37-0.89）。卡波替尼的中位PFS为4.3个月（95％CI，3.5-6.4），安慰剂组为1.8个月（95％CI，1.7-1.9）（HR，0.40; 95％CI，0.27-0.61）。

HBV患者的基线特征在治疗组之间取得平衡。服用cabozantinib的患者中位年龄为59岁（范围22-83），47％的患者甲胎蛋白（AFP）水平≥400ng/ mL，90％患有肝外扩散（EHS）或大血管侵犯（MVI） 。在安慰剂组中，中位年龄为60岁（34-79），54％有AFP≥400ng/ mL，91％有EHS或MVI。

就先前的治疗而言，双方中71％的患者在参加试验前接受了1次治疗，约29％的患者接受了2次治疗。所有患者之前服用索拉非尼（Nexavar），这是HCC的既定前线标准。

Meyer说，cabozantinib的作用机制可能是其作为二线疗法的功效。该药物靶向MET，SXL和VEGF受体。 “已知它对MET和AXL具有活性，这使其与索拉非尼区别开来，并且已知MET是阻力逃逸途径，因此可能与其在第二线的活性相关，”他说。

根据CELESTIAL的数据，根据开发该疗法的公司Exelixis，FDA已经接受了为先前治疗的晚期HCC患者接受cabozantinib的补充新药申请。 FDA计划在2019年1月14日之前做出决定。

Cabozantinib最初被FDA批准用于治疗2012年甲状腺髓样癌患者。2016年4月，该药物在先前的抗血管生成治疗后接受了新的适应症作为晚期肾细胞癌（RCC）。 2017年12月，该批准进一步扩大到一线环境中的晚期RCC患者。许多其他试验探索该试剂的试验仍在进行中。
参考

    Meyer T，Baron A，Gordan J，et al。在晚期肝细胞癌（HCC）中卡博替尼（C）与安慰剂（P）的3期CELESTIAL试验中，患有乙型肝炎病毒（HBV）的患者（患者）的结果。发表于：2018年国际肝癌协会年会; 9月14日至16日;伦敦，英国。摘要O-012。 ilca2018.org/wp-content/uploads/2018/08/ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf。
    Abou-Alfa GK，Meyer T，Cheng A-L，et al。 Cabozantinib用于晚期和进展性肝细胞癌患者。 N Engl J Med。 2018; 379（1）：54-63。 doi：10.1056 / NEJMoa171700
    Forner A，Reig M，Bruix J. Hepatocellular carcinoma。柳叶刀。 2018; 391（10127）：1301年至1314年。 doi：10.1016 / S0140-6736（18）30010-2