Brown Timothy J, Gupta Arjun, Sedhom Ramy, Beg Muhammad S, Karasic Thomas B, Yarchoan Mark
Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Penn Center for Cancer Care Innovation, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Gastrointest Tumors. 2021 Dec 22;9(1):19-26. doi: 10.1159/000521625. eCollection 2022 Mar.
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.
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 ≤ 0.05.
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 ( = 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 ( = 0.69). ORR assessed by RECIST 1.1 has significantly improved by 6.0% over time ( = 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 ( = 0.0037). There was no significant change in patient demographics were identified over time to explain the OS findings.
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.
十多年来，索拉非尼一直作为多个评估晚期肝细胞癌（HCC）新疗法的随机临床试验（RCT）中的对照臂。分析索拉非尼治疗相同适应症患者的临床结局随时间的变化趋势，可为深入了解临床试验开展的演变以及影响结局的潜在非药物因素提供独特机会。
我们确定了初治晚期HCC患者的RCT，其中将索拉非尼与另一种全身治疗或安慰剂进行了比较。我们提取了试验水平的人口统计学、临床病理和结局数据（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确定时间趋势，显著性设定为≤0.05。
分析纳入了16项RCT（9项III期和7项II期），共4086例接受索拉非尼治疗的患者。纳入的试验纳入了2005年至2019年的患者。从2005年到2019年，OS随时间显著改善了4.5个月（P = 0.048）。13项研究使用实体瘤疗效评价标准（RECIST）1.1提供了PFS数据，随时间无显著变化（P = 0.69）。根据RECIST 1.1评估的ORR随时间显著提高了6.0%（P = 0.003）。自2005年第一项临床试验入组以来，索拉非尼的中位治疗持续时间减少了53%，从23.1周降至12.2周（P = 0.0037）。随着时间推移，未发现患者人口统计学有显著变化可解释OS结果。
索拉非尼治疗的晚期HCC患者的中位OS在15年中显著改善。与此同时，索拉非尼的中位治疗持续时间缩短。这些发现的原因无法通过参与这些试验的患者人口统计学变化来解释，并且对正在进行的临床试验有影响。
