Department of Medicine, Division of Medical Oncology, BC Cancer - Vancouver Site, University of British Columbia, Vancouver, BC, Canada.
Department of Medicine, Division of Medical Oncology, Dalhousie University, Halifax, NS, Canada.
J Natl Cancer Inst. 2021 Feb 1;113(2):123-136. doi: 10.1093/jnci/djaa119.
Systemic therapy for hepatocellular carcinoma (HCC) consisting of the tyrosine kinase inhibitor sorafenib has remained unchanged for over a decade, although results from phase III targeted therapy trials have recently emerged. This review considers available phase III evidence on the use and sequencing of targeted therapy for intermediate and advanced non-locoregional therapy (LRT) eligible HCC and discusses implications for clinical practice.
Published and presented literature on phase III data reporting on targeted therapy for advanced HCC that was not eligible for loco-regional therapies was identified using the key search terms "hepatocellular cancer" AND "advanced" AND "targeted therapy" AND "phase III" OR respective aliases (PRISMA).
Ten phase III trials assessed targeted therapy first-line and eight following sorafenib. In the first-line, atezolizumab plus bevacizumab statistically significantly improved overall survival (OS) and patient-reported outcomes (PROs) compared with sorafenib, while lenvatinib demonstrated non-inferior OS. Following progression on sorafenib, statistically significant OS improvements over placebo were seen for cabozantinib and regorafenib in unselected patients and for ramucirumab in those with baseline α-fetoprotein≥400 ng/mL. Based on improved OS and PROs, atezolizumab plus bevacizumab appears to be a preferred first-line treatment option for intermediate or advanced non-LRT eligible HCC. Phase III data informing sequencing of later lines of treatment is lacking. Therefore, sequencing principles are proposed that can be used to guide treatment selection.
Ongoing trials will continue to inform optimal therapy. Multiple targeted therapies have improved OS in intermediate or advanced non-LRT eligible HCC, although optimal sequencing is an area of ongoing investigation.
索拉非尼为基础的系统疗法一直是治疗肝细胞癌（HCC）的标准方案，已逾十年未变，尽管近年来出现了靶向治疗的 III 期临床试验结果。本文回顾了 HCC 局部治疗（LRT）以外的中晚期 HCC 靶向治疗的 III 期证据，并探讨了其对临床实践的影响。
通过关键词“hepatocellular cancer” AND “advanced” AND “targeted therapy” AND “phase III” OR 别名（PRISMA），检索评估晚期 HCC 靶向治疗的 III 期研究，收集靶向治疗作为一线和二线治疗晚期 HCC 的 III 期临床试验数据。
10 项 III 期临床试验评估了靶向治疗作为一线治疗，8 项评估了索拉非尼后的二线治疗。在一线治疗中，阿替利珠单抗联合贝伐珠单抗与索拉非尼相比，在总生存期（OS）和患者报告的结局（PRO）方面具有统计学意义的改善，而仑伐替尼则显示 OS 非劣效。在索拉非尼进展后，卡博替尼和瑞戈非尼在未选择的患者中，雷莫芦单抗在基线甲胎蛋白（AFP）≥400ng/ml 的患者中，与安慰剂相比，OS 均有显著改善。基于 OS 和 PRO 的改善，阿替利珠单抗联合贝伐珠单抗似乎是局部治疗以外的中晚期 HCC 的首选一线治疗选择。目前缺乏关于后线治疗排序的 III 期数据。因此，提出了排序原则，可以用于指导治疗选择。
正在进行的试验将继续为最佳治疗提供信息。多种靶向治疗改善了局部治疗以外的中晚期 HCC 的 OS，但最佳排序仍是一个正在研究的领域。
