卡博替尼治疗晚期和进展性肝细胞癌患者。
Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.
机构信息
From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (G.K.A.-A.); Royal Free Hospital and University College London, London (T.M.); National Taiwan University Hospital, Taipei (A.-L.C.), and the Department of Medical Oncology, Liouying Chi Mei Hospital, Tainan (Y.C.) - both in Taiwan; USC Norris Comprehensive Cancer Center, Los Angeles (A.B.E.-K.), UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco (A.P.V., R.K.K.), and Exelixis, Alameda (C.H., A.E.B.-H., G.S.) - all in California; Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano (L.R., T.P.), the Department of Medical and Surgical Sciences, University of Bologna, Bologna (L.B.), and Medical Oncology Unit 1, Istituto Oncologico Veneto, IRCCS, Padua (V.Z.) - all in Italy; Asan Medical Center, University of Ulsan College of Medicine, Seoul (B.-Y.R., M.-H.R.), and the National Cancer Center, Goyang (J.-W.P.) - both in South Korea; Trakya University School of Medicine, Edirne, Turkey (I.C.); Groupement Hospitalier Nord, Lyon (P.M.), and Hôpital Haut-Lévêque, Centre Hospitalier Universitaire Bordeaux, Bordeaux (J.-F.B.) - both in France; the Department of Medical Oncology, Academic Medical Center, Amsterdam (H.-J.K.); and the Chinese University of Hong Kong, State Key Laboratory in Oncology in South China, Hong Kong (S.L.C.).
出版信息
N Engl J Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002.
BACKGROUND
Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma.
METHODS
A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate.
RESULTS
At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%).
CONCLUSIONS
Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .).
背景
卡博替尼抑制酪氨酸激酶，包括血管内皮生长因子受体 1、2 和 3、MET 和 AXL，这些激酶参与肝癌的进展和索拉非尼耐药的发生，索拉非尼是晚期疾病的标准初始治疗药物。这项随机、双盲、3 期试验评估了卡博替尼与安慰剂在先前接受过治疗的晚期肝癌患者中的疗效。
方法
707 例患者以 2:1 的比例随机分配接受卡博替尼（60mg 每日一次）或匹配安慰剂。入组患者曾接受过索拉非尼治疗，在至少一种用于治疗肝癌的系统治疗后疾病进展，并且可能接受过两种用于晚期肝癌的先前系统治疗方案。主要终点为总生存期。次要终点为无进展生存期和客观缓解率。
结果
在第二次计划的中期分析中，与安慰剂相比，卡博替尼显著延长了总生存期。卡博替尼组的中位总生存期为 10.2 个月，安慰剂组为 8.0 个月（死亡风险比，0.76；95%置信区间[CI]，0.63 至 0.92；P=0.005）。卡博替尼组中位无进展生存期为 5.2 个月，安慰剂组为 1.9 个月（疾病进展或死亡的风险比，0.44；95%CI，0.36 至 0.52；P<0.001），客观缓解率分别为 4%和<1%（P=0.009）。卡博替尼组 68%的患者和安慰剂组 36%的患者发生 3 级或 4 级不良事件。最常见的高级别事件是掌跖红斑感觉迟钝（卡博替尼组 17%，安慰剂组 0%）、高血压（卡博替尼组 16%，安慰剂组 2%）、天门冬氨酸氨基转移酶水平升高（卡博替尼组 12%，安慰剂组 7%）、乏力（卡博替尼组 10%，安慰剂组 4%）和腹泻（卡博替尼组 10%，安慰剂组 2%）。
结论
在先前接受过治疗的晚期肝癌患者中，卡博替尼治疗组的总生存期和无进展生存期长于安慰剂组。卡博替尼组的高级别不良事件发生率约为安慰剂组的两倍。（由 Exelixis 资助；CELESTIAL ClinicalTrials.gov 编号，NCT01908426）。
Zotero 插件