三期多国、随机、双盲、安慰剂对照研究：替沃扎尼（ARQ 197）联合厄洛替尼对比厄洛替尼单药治疗既往治疗的局部晚期或转移性非鳞状非小细胞肺癌患者。
Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer.
机构信息
Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ.
出版信息
J Clin Oncol. 2015 Aug 20;33(24):2667-74. doi: 10.1200/JCO.2014.60.7317. Epub 2015 Jul 13.
PURPOSE
Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC).
PATIENTS AND METHODS
Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety.
RESULTS
The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%).
CONCLUSION
E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.
目的
MET 受体酪氨酸激酶抑制剂替沃替尼与厄洛替尼联合应用于临床前和早期临床研究中，显示出增加的抗癌活性。我们的研究旨在证实该联合疗法在先前接受过治疗的非小细胞肺癌（NSCLC）患者中的疗效和安全性。
方法
先前接受过一种至两种全身治疗方案（包括铂类双药）治疗的晚期非鳞状 NSCLC 患者，按 1:1 比例随机分配接受厄洛替尼 150 mg 每日一次加口服替沃替尼 360 mg 每日两次（E + T）或厄洛替尼加安慰剂（E + P）治疗，直至疾病进展。肿瘤标本评估 EGFR 和 KRAS 突变、MET 表达和 MET 基因扩增。主要终点是总生存期（OS）。次要和探索性目标包括无进展生存期（PFS）、分子亚组的 OS 和安全性。
结果
该研究纳入了 1048 名患者，并在中期分析时因无效而停止。与 E + P 相比，E + T 并未改善 OS（中位 OS 分别为 8.5 个月和 7.8 个月，风险比 [HR]，0.98；95%CI，0.84 至 1.15；P =.81），尽管 PFS 有所延长（中位 PFS 分别为 3.6 个月和 1.9 个月；HR，0.74；95%CI，0.62 至 0.89；P <.001）。探索性亚组分析表明，高 MET 表达的患者 OS 改善（HR，0.70；95%CI，0.49 至 1.01）。与 E + P 相比，E + T 最常见的不良反应为皮疹（分别为 33.1%和 37.3%）、腹泻（分别为 34.6%和 41.0%）、乏力或疲劳（分别为 43.5%和 38.1%）和中性粒细胞减少症（3 级至 4 级；分别为 8.5%和 0.8%）。
结论
E + T 耐受良好，可提高 PFS，但未能改善非鳞状 NSCLC 总体人群的 OS。
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