前言：肝细胞癌：新兴疗法、药物靶点和基础知识空白

StephenW

前言：肝细胞癌：新兴疗法、药物靶点和基础知识空白
亚历山德罗·里佐
& 热纳罗·帕米奥蒂
第 331 页 | 2022 年 2 月 17 日接收，2022 年 2 月 22 日接受，接受的作者版本在线发布：2022 年 2 月 23 日，在线发布：2022 年 3 月 2 日

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关键词：肝细胞癌免疫治疗阿特珠单抗贝伐单抗乐伐替尼派姆单抗卡瑞利珠单抗杜瓦鲁单抗经动脉化疗栓塞免疫治疗
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肝细胞癌约占所有原发性肝脏恶性肿瘤的 75%。几种肝病与 HCC 的发展有关，包括肝炎病毒感染、肝硬化和非酒精性脂肪肝病 (NAFLD)，其中一些病因——尤其是后者——被认为在改变对系统性治疗。巴塞罗那临床肝癌 (BCLC) 0/A 和中期 BCLC B 疾病的 HCC 患者通常接受潜在的治愈方法，如根治性手术、肝移植和局部区域治疗，如化疗栓塞、射频消融等。相反，BCLC C HCC 患者接受全身治疗，包括酪氨酸激酶抑制剂。在过去十年中，我们见证了癌症免疫疗法的兴起，免疫检查点抑制剂 (ICI) 彻底改变了数量众多的血液和实体恶性肿瘤的治疗前景。 ICI 的作用机制基于抑制免疫检查点相关分子，例如程序性细胞死亡 1 (PD-1)、细胞毒性 T 淋巴细胞相关抗原 4 (CTLA-4) 和淋巴细胞激活基因 3。 LAG-3)。 Atezolizumab、pembrolizumab、nivolumab 和其他 ICI 已在多种情况下在 HCC 患者中进行了评估，作为单一疗法报告了有争议和令人失望的结果。然而，在 III 期 IMbrave150 试验的结果之后，基于免疫的组合最近产生了一些范式转变。本研究比较了抗血管生成药物贝伐单抗加 PD-L1 抑制剂阿特珠单抗与索拉非尼单药治疗的组合，在客观缓解率 (ORR)、无进展生存期 (PFS) 和总生存期（OS）。 IMbrave150 的更新结果也证实了这些结果，强调了接受阿特珠单抗 - 贝伐单抗治疗的患者的中位 OS 超过 19 个月。如果 HCC 免疫疗法最终似乎以组合方法的形式在这种情况下找到了它的作用，那么问题仍然存在，值得仔细研究和讨论。在这种情况下，一些新的药物和策略正在评估中，并有可能改变 HCC 的治疗前景。

在本期研究药物专家意见特刊中，HCC 领域的国际专家研究了临床和临床前研究中正在积极研究的关键方法。特别是，他们对临床试验中的有前景的药物以及最新的治疗策略和药物靶点进行了批判性分析并整合了自己的观点。继续关注这个空间；以 HCC 为重点的专家文章将继续出现在该期刊的春季和夏季后期刊中。

StephenW

Foreword: hepatocellular carcinoma: emerging treatments, drug targets, and fundamental knowledge gaps
Alessandro Rizzo
& Gennaro Palmiotti
Page 331 | Received 17 Feb 2022, Accepted 22 Feb 2022, Accepted author version posted online: 23 Feb 2022, Published online: 02 Mar 2022

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KEYWORDS: Hepatocellular carcinomaImmunotherapyAtezolizumabBevacizumabLenvatinibpembrolizumabCamrelizumabDurvalumabtransarterial chemoembolizationimmunotherapy
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Hepatocellular carcinoma accounts for approximately 75% of all primary liver malignancies. Several hepatic diseases have been associated with the development of HCC, including hepatitis virus infection, liver cirrhosis, and nonalcoholic fatty liver disease (NAFLD), and some of these etiologies – especially the latter – have been suggested to play a role in modifying response to systemic treatments. HCC patients with Barcelona Clinic Liver Cancer (BCLC) 0/A and intermediate-stage BCLC B disease usually receive potentially curative approaches, such as radical surgery, liver transplantation, and locoregional treatments, such as chemoembolization, radiofrequency ablation, etc. On the contrary, patients with BCLC C HCC are treated with systemic treatments, including tyrosine kinase inhibitors. Over the last decade, we have witnessed the emerging of cancer immunotherapy, with immune checkpoint inhibitors (ICIs) revolutionizing the therapeutic landscape of an impressive number of hematological and solid malignancies. ICIs base their mechanism of action on the inhibition of immune checkpoint-related molecules, such as programmed cell death-1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3). Atezolizumab, pembrolizumab, nivolumab, and other ICIs have been assessed in HCC patients in several settings, reporting controversial and disappointing results as monotherapies. However, immune-based combinations have recently produced some paradigm shifts, following the results of the phase III IMbrave150 trial. This study compared the combination of the antiangiogenic agent bevacizumab plus the PD-L1 inhibitor atezolizumab versus sorafenib monotherapy, reporting statistically significant and clinically meaningful benefits in several clinical outcomes, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). These results have been also confirmed by the updated results of IMbrave150, highlighting a median OS of more than 19 months in patients receiving atezolizumab – bevacizumab. If HCC immunotherapy finally seems to have found its role in this setting in the form of combination approaches, questions remain and deserve scrutiny and discussion. Several novel agents and strategies are under assessment in this setting and have the potential to modify the therapeutic landscape of HCC.

In this special issue of Expert Opinion on Investigational Drugs, international experts in the field of HCC examine key approaches under active investigation in clinical and preclinical research. In particular, they present critical analyses and integrate their own perspectives on promising agents in clinical trials and the latest therapeutic strategies and drug targets. Keep watching this space; expert articles with a focus on HCC will continue to appear in later spring and summer issues of the journal.