Background: Sorafenib has consistently served as the control arm in multiple randomized clinical trials (RCTs) evaluating novel therapies for advanced hepatocellular carcinoma (HCC) for more than a decade. Analyzing trends in clinical outcomes of patients treated with sorafenib for the same indication over time offers the opportunity for unique insight into the evolution of clinical trial conduct and potential non-drug factors impacting outcomes. Methods: We identified RCTs in patients with treatment-naïve advanced HCC where sorafenib was compared to another systemic therapy or placebo. We extracted trial-level demographic, clinicopathologic, and outcome data (overall survival [OS], progression-free survival [PFS], objective response rate [ORR], and duration of therapy). Sample-weighted linear regression was used to identify temporal trends with significance set at p ≤ 0.05. Results: Sixteen RCTs (9 phase III and 7 phase II) enrolling 4,086 patients treated with sorafenib were included in the analysis. Included trials enrolled patients from 2005 to 2019. OS has significantly improved by 4.5 months from 2005 to 2019 (p = 0.048) over time. Thirteen studies provided data on PFS using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with no significant change over time (p = 0.69). ORR assessed by RECIST 1.1 has significantly improved by 6.0% over time (p = 0.003). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.0037). There was no significant change in patient demographics were identified over time to explain the OS findings. Conclusion: The median OS of patients with advanced HCC treated with sorafenib has improved significantly over 15 years. At the same time, the median duration of therapy with sorafenib has decreased. The reason for these findings was not explained by changing demographics of patients enrolled in these trials and has implications for ongoing clinical trials.
Gastrointest Tumors 2022;9:19–26

中文翻译：

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一线索拉非尼治疗晚期肝细胞癌患者随机对照试验的临床结局趋势

背景：十多年来，索拉非尼一直作为评估晚期肝细胞癌 (HCC) 新疗法的多项随机临床试验 (RCT) 的对照组。随着时间的推移，分析接受索拉非尼治疗的相同适应症患者的临床结果趋势，提供了对临床试验实施的演变和影响结果的潜在非药物因素的独特见解的机会。方法：我们在未接受过治疗的晚期 HCC 患者中确定了随机对照试验，其中将索拉非尼与另一种全身疗法或安慰剂进行了比较。我们提取了试验水平的人口统计学、临床病理学和结果数据（总生存期 [OS]、无进展生存期 [PFS]、客观缓解率 [ORR] 和治疗持续时间）。样本加权线性回归用于识别显着性设置为p ≤ 0.05 的时间趋势。结果： 16 项随机对照试验（9 项 III 期和 7 项 II 期）纳入了 4,086 名接受索拉非尼治疗的患者，并被纳入分析。纳入的试验招募了 2005 年至 2019 年的患者。从 2005 年到 2019 年，OS 显着改善了 4.5 个月（p= 0.048) 随着时间的推移。13 项研究使用实体瘤反应评估标准 (RECIST) 1.1 提供了 PFS 数据，随时间没有显着变化 ( p = 0.69)。随着时间的推移，由 RECIST 1.1 评估的 ORR 显着提高了 6.0% ( p = 0.003)。自 2005 年首次临床试验入选以来，索拉非尼治疗的中位持续时间从 23.1 周减少到 12.2 周 ( p = 0.0037)，减少了 53%。随着时间的推移，患者人口统计数据没有显着变化来解释 OS 结果。结论：15 年来，接受索拉非尼治疗的晚期 HCC 患者的中位 OS 显着改善。与此同时，索拉非尼治疗的中位持续时间有所缩短。这些发现的原因无法通过参加这些试验的患者人口统计数据的变化来解释，并且对正在进行的临床试验有影响。
胃肠道肿瘤 2022；9:19–26