Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.
Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.
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DOI：
10.1056/nejmoa1717002
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发表时间：
2018-07-05
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影响因子：
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通讯作者：
Kelley RK
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作者：
Abou-Alfa GK;Meyer T;Cheng AL;El-Khoueiry AB;Rimassa L;Ryoo BY;Cicin I;Merle P;Chen Y;Park JW;Blanc JF;Bolondi L;Klümpen HJ;Chan SL;Zagonel V;Pressiani T;Ryu MH;Venook AP;Hessel C;Borgman-Hagey AE;Schwab G;Kelley RK
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，其涉及肝细胞癌的进展和对索拉非尼（晚期疾病的标准初始治疗）的耐药性的发展。这项随机、双盲、3期试验评估了卡博替尼与安慰剂相比在先前治疗的晚期肝细胞癌患者中的作用。共有707名患者以2：1的比例随机分配接受卡博替尼（60 mg，每日一次）或匹配的安慰剂。合格患者既往接受过索拉非尼治疗，在至少一次肝细胞癌全身治疗后发生疾病进展，并且可能接受过最多两次晚期肝细胞癌全身治疗方案。主要终点是总生存期。次要终点为无进展生存期和客观缓解率。在第二次计划的中期分析中，试验显示卡博替尼的总生存期显著长于安慰剂。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（死亡风险比为0.76; 95%置信区间[CI]为0.63至0.92; P = 0.005）。卡博替尼组的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为0.44; 95%CI为0.36至0.52; P<0.001），客观缓解率分别为4%和小于1%（P = 0.009）。卡博替尼组中68%的患者和安慰剂组中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肿（卡博替尼组17%，安慰剂组0%）、高血压（16% vs. 2%）、天冬氨酸转氨酶水平升高（12% vs. 7%）、疲劳（10% vs. 4%）和腹泻（10% vs. 2%）。在先前治疗过的晚期肝细胞癌患者中，用卡博替尼治疗导致比安慰剂更长的总生存期和无进展生存期。卡博替尼组的高级别不良事件发生率大约是安慰剂组的两倍。（由Exelixis资助; CELESTIAL ClinicalTrials.gov编号，NCT 01908426。）
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. 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. 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%). 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.)