Supplementary Material for: Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma

<b><i>Background and Aims:</i></b> The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. <b><i>Approach and Results:</i></b> We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009–2012, <i>n</i> = 267; period 2: 2013–2016, <i>n</i> = 352; period 3: 2017–2019, <i>n</i> = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, <i>p</i> &lt; 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (<i>p</i> = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; <i>p</i> &lt; 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. <b><i>Conclusions:</i></b> The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

**<i>研究背景与目的：</i>** 随着多款多靶点分子靶向药物（molecular target agents, MTAs）的陆续上市，晚期肝细胞癌（hepatocellular carcinoma, HCC）患者的预后有望得到改善。然而，序贯使用多靶点分子靶向药物的临床影响尚未得到充分验证。**<i>研究方法与结果：</i>** 本研究回顾性收集了2009年6月至2019年3月期间，877例接受任意多靶点分子靶向药物作为晚期肝细胞癌一线全身治疗患者的完整临床病程数据。根据一线多靶点分子靶向药物的给药时间，将研究人群分为3组：队列1（2009–2012年，n=267）、队列2（2013–2016年，n=352）、队列3（2017–2019年，n=258）。随后对比了3组患者使用的多靶点分子靶向药物数量、总生存期（overall survival, OS）以及多靶点分子靶向药物治疗时长，并针对晚期和非晚期肝细胞癌患者分别开展亚组分析。结果显示，接受多线多靶点分子靶向药物治疗的患者比例随时间显著提升（队列1、2、3分别为1.1%、10.2%、42.6%，*p*<0.001）。3组患者的中位总生存期分别延长至10.4、11.3、15.2个月（*p*=0.016）。与之类似，多靶点分子靶向药物的中位治疗时长也得到延长（队列1、2、3分别为2.7、3.2、6.6个月，*p*<0.001）。本研究还证实，总生存期与多靶点分子靶向药物治疗时长的相关性随时间逐步增强（队列1：0.395，队列2：0.505，队列3：0.667）。上述变化趋势在晚期肝细胞癌患者中尤为显著，而在非晚期肝细胞癌患者中则相对有限。**<i>结论：</i>** 多靶点分子靶向药物的可及性持续提升，逐步改善了晚期肝细胞癌患者的预后，尤以晚期HCC患者的获益更为突出。