Kudo Masatoshi, Kang Yoon-Koo, Park Joong-Won, Qin Shukui, Inaba Yoshitaka, Assenat Eric, Umeyama Yoshiko, Lechuga Maria José, Valota Olga, Fujii Yosuke, Martini Jean-Francois, Williams J Andrew, Obi Shuntaro
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Liver Cancer. 2018 May;7(2):148-164. doi: 10.1159/000484620. Epub 2017 Dec 8.
An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors.
The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model.
Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians.
Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.
对于在索拉非尼治疗期间病情进展或不耐受的晚期肝细胞癌（HCC）患者，仍存在未满足的治疗需求。一项关于血管内皮生长因子受体1 - 3抑制剂阿昔替尼联合最佳支持治疗（BSC）的全球随机II期试验（ClinicalTrial.gov编号：NCT01210495），与安慰剂/BSC相比，并未延长总生存期（OS），但在部分患者中显示无进展生存期有所改善。进行亚组分析以确定潜在的预测/预后因素。
使用Cox比例风险模型，分析该II期研究数据，以评估阿昔替尼/BSC在亚洲患者、非亚洲患者以及亚洲亚组（日本、韩国或中国大陆/香港/台湾）患者中的疗效和安全性，以及基线微小RNA和血清可溶性蛋白的预测/预后价值。
202例患者中，78例来自非亚洲，124例来自亚洲（37例日本患者、36例韩国患者和51例中国患者）。在非亚洲患者、亚洲患者或亚洲亚组中，阿昔替尼/BSC与安慰剂/BSC的总生存期无显著差异。然而，在一项探索性分析中，当将不耐受先前抗血管生成治疗的患者排除在数据集之外时，阿昔替尼/BSC在亚洲患者，尤其是日本患者中显示出较好的总生存期。非亚洲患者和亚洲患者对阿昔替尼/BSC的耐受性均良好。4种循环微小RNA（包括miR - 5684和miR - 1224 - 5p）的存在，或基线时基质细胞衍生因子1的蛋白水平低于或等于中位数，与接受阿昔替尼/BSC治疗的亚洲或非亚洲患者的较长总生存期显著相关。
在非亚洲患者、亚洲患者或亚洲亚组中，阿昔替尼/BSC并未比安慰剂/BSC延长生存期，但在一部分日本患者中观察到阿昔替尼/BSC有较好的总生存期。排除不耐受索拉非尼的患者群体可能更适合晚期HCC新药临床试验。由于这些结果非常初步，有必要进一步研究。本研究中确定的几种基线微小RNA和可溶性蛋白的潜在预测/预后价值需要在大量患者的前瞻性研究中进行验证。
