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2017年6月2-6日，一年一度的美国临床肿瘤学会（American Society of Clinical Oncology，ASCO）年会在芝加哥举办。当地时间6月4日上午的消化系统（非结直肠）肿瘤口头报告专场上，将公布METIV-HCC试验的III期结果，该试验在MET-高表达肝细胞癌（HCC）患者中将二线tivantinib（ARQ 197）与安慰剂进行比较。
Tivantinib是一种选择性口服MET抑制剂，在一项II期研究中，该药物与安慰剂相比较，可以改善MET高表达肝细胞癌（HCC）患者的总生存期（OS）和无进展生存期（PFS）。
主要研究
这是一项随机安慰剂对照III期试验（NCT01755767），招募的患者为：晚期HCC、Child Pugh A、ECOG PS≤1；骨髓、肝脏、肾功能良好；既往未接受肝脏移植手术；索拉非尼治疗后影像学进展或不耐受；通过集中免疫组织化学确定肿瘤MET高表达（在≥50%的肿瘤细胞中MET≥2）。
入组的患者按照2:1随机分配接受口服tivantinib或者安慰剂，根据血管浸润（VI）、肝外扩散（ES）、AFP（＞200ng/mL）进行分层，这些患者接受治疗直至疾病进展或者出现不可接受的毒性。
每8周借助CT/MRI进行缓解评估（RECIST 1.1）。主要终点是OS，次要终点包括PFS和安全性，均在意向治疗（ITT）人群进行评估。
主要结果
从2012年12月到2015年12月之间，澳大利亚、美国、欧洲和新西兰有1209例患者同意入组，589例MET高表达，43例初步随机分配剂量240mg BID，而后因中性粒细胞减少率高减少剂量，340例随机分配剂量120mg BID：226例接受tivantinib治疗，114例接受安慰剂（ITT人群）。
不同组之间的患者特征平衡良好：306（90%）名患者为男性；中位年龄67岁；PS 0:207人（61%）；VI：117人（34%）；ES：197人（58%）；AFP≤200：195人（57%）；接受索拉非尼治疗出现影像学进展：275人（81%）。
中位OS（95% CI）在tivantinib组和安慰剂组分别为8.4个月（6.8-10.0）和9.1个月（7.3-10.4），HR=0.97（0.75-1.25），P值为0.81。
中位PFS在tivantinib组和安慰剂组分别为2.1个月（1.9-3.0）和2.0个月（1.9-3.6），HR=0.96（0.75-1.22），P值为0.72。
在VI（HR 1.19，0.79-1.79）、ES（HR 1.09,0.78-1.52）和AFP＞200ng/mL（HR 1.00，0.71-1.41）患者中，没有观察到总生存期差异。
在tivantinib组和安慰剂组中，＞3级的不良事件发生率分别为55.6%和55.3%。
Tvantinib组中，最常见的＞3级不良事件是腹水（7.1%）、整体恶化（5.8%）、贫血（4.9%）；而最严重的不良事件是整体恶化（4.9%）。剂量结束30天内死亡的发生率分别为，tivantinib组22.1%，安慰剂组15.8%（最常见的原因是整体恶化3.5%，肝功能衰竭2.6%）。
在晚期MET高表达的HCC患者中，其中这些患者之前接受索拉非尼治疗已失败，与安慰剂相比较，口服tivantinib 120mg并不会改善总生存期或者无进展生存期。临床试验编号：NCT01755767
原文摘要：
Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC)：Results of the METIV-HCC phase III trial.（Abstract4000）
Authors：Lorenza Rimassa, Eric Assenat,et al
Session Type：Oral Abstract Session
Background: Tivantinib (T), a selective, oral MET inhibitor, improved overall survival (OS) and progression-free survival (PFS) versus placebo (P) in a phase II study in MET-High HCC pts.
Methods：This randomized, placebo-controlled phase III trial (NCT01755767) enrolled pts with: advanced HCC; Child Pugh A; ECOG PS ≤1; adequate bone marrow, liver, kidney functions; no liver transplant; radiographic disease progression (PD) after or intolerance to sorafenib; tumor MET-High (MET ≥2+ in ≥50% of tumor cells) by centralized immunohistochemistry. Pts were randomly assigned 2:1 to oral T or P, stratified by vascular invasion (VI), extrahepatic spread (ES), AFP ( < / > 200ng/mL), treated until PD or unacceptable toxicity. Response (RECIST 1.1) was evaluated by CT / MRI every 8 weeks. Primary endpoint of OS and secondary endpoints including PFS and safety were assessed in the intent-to-treat (ITT) population.
Results：From Dec 2012 to Dec 2015, 1209 pts were consented in Australia, the Americas, Europe, New Zealand: 589 MET-High, 43 initially randomized at the dose of 240mg BID, then reduced due to high neutropenia rate, 340 randomized at 120mg BID: 226 to T, 114 to P (ITT population). Characteristics of pts were balanced between arms: 306 (90%) male; median age: 67; PS 0: 207 (61%); VI: 117 (34%); ES: 197 (58%); AFP ≤200: 195 (57%); radiographic PD on sorafenib: 275 (81%). Median OS (95% CI) was 8.4 months (m) (6.8-10.0) in T, 9.1 m (7.3-10.4) in P, HR = 0.97 (0.75-1.25), P = 0.81. Median PFS (95% CI) was 2.1 m (1.9-3.0) in T, 2.0 m (1.9-3.6) in P, HR = 0.96 (0.75-1.22), P = 0.72. No OS difference was seen in pts with VI (HR 1.19, 0.79-1.79), ES (HR 1.09, 0.78-1.52), AFP > 200ng/mL (HR 1.00, 0.71-1.41). Grade (G) > 3 AEs were 55.6% in T, 55.3% in P. In T, most common G > 3 AEs were ascites (7.1%), general deterioration (5.8%), anemia (4.9%); most common serious AE was general deterioration (4.9%). Deaths within 30 days of last dose were 22.1% on T vs 15.8% on P (most common causes: general deterioration 3.5%, hepatic failure 2.6%).
Conclusion：Tivantinib at the 120mg BID dose did not improve OS or PFS over placebo in patients with advanced MET-High HCC who failed previous treatment with sorafenib. Clinical trial information: NCT01755767
