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在刚刚闭幕的肝病学领域国际年度压轴盛会——美国肝病研究学会年会（AASLD2023）上，美国约翰霍普金斯大学医学院Mark Yarchoan 教授，应邀在“Role of Systemic Therapy from Early to Advanced Stages of HCC”专题中，介绍了肝细胞癌（HCC）新辅助和辅助治疗的相关新进展，并于会后接受《国际肝病》专访时进一步点评局部联合系统治疗、个体化治疗、精准医学策略，以及创新疗法在中晚期HCC的应用及前景，访谈视频和中英文对照访谈原稿分享如下。

 

01

系统联合疗法带来生存突破，但总体反应率仍有待提高

 

《国际肝病》

中晚期HCC的当前治疗策略，其疗效如何？有哪些挑战和局限性？

 

Mark Yarchoan教授：在过去几年中，一些新的治疗方法已经显示出改善中晚期HCC患者的结果。这些疗法包括贝伐珠单抗联合PD-L1疗法（阿替利珠单抗），酪氨酸激酶抑制剂（阿帕替尼）联合PD-1疗法（卡瑞利珠单抗），以及同时使用两个检查点抑制剂的联合疗法（度伐利尤单抗+曲美木单抗）。

 

我认为，相比以往旧标准所采用的索拉非尼治疗，以上这些新疗法均改善了患者生存。从Ⅲ期临床试验看，患者的总生存期（OS）和无进展生存期（PFS）均有所延长。

 

尽管这些联合疗法确实带来了HCC治疗领域的突破，但患者对治疗的反应率仍然仅有20%～30%，其中仅10%的患者能够实现长期生存。因此，尽管我们已经取得了重大进展，使生存率增加了一倍，但未来我们仍然有很多工作需要去做。

 

英文原文

 

<Hepatology Digest>: What is the efficacy of current treatment strategies for intermediate and advanced stage HCC, and what are the challenges and limitations associated with them?

 

Dr. Mark Yarchoan: In the last couple of years, we have a number of new therapies that have shown improved outcomes for patients with intermediate and advanced HCC. These include combination of bevacizumab and PD-L1 therapy, combination of TKI and PD-1 therapy that is rivoceranib, combination of camrelizumab and the dual combination of dervalumab and tremelimumab, so 2 checkpoint inhibitors together.

 

I think all these therapies have improved survival versus our old standard of care sorafenib, which has been the comparative use in all these phase III studies, with increasing overall survival response rate and PFS in general versus our old therapy.

 

Now that said, although all these combinations are truly represent a breakthrough for HCC, response rates are still in a range of 20 to 30% and very durable survival is only seen in about 10% of patients.

 

And so, we clearly have a lot of work left to do. So even though we have made major strides and essentially doubled our survival, there is a lot of work left to do.

 

02

局部治疗联合系统治疗，有望成为中期HCC的新标准

 

《国际肝病》

在中期HCC治疗中，局部治疗与系统性治疗的联合应用是如何改善患者的预后和生存率的？它们之间的协同作用如何？

 

Mark Yarchoan教授：我认为中期HCC是异质性很强的肿瘤。一些肿瘤应该使用局部治疗方案，一些肿瘤应该使用系统治疗方案，另外一些则可能会从联合治疗方案中获益。通常情况下，肿瘤越多就越需要进行系统治疗，可能需要综合多个标准进行疾病负担评估和决定是否采用系统治疗。

 

最近刚刚发布的一份报告显示，在局部治疗的基础上增加贝伐珠单抗和度伐利尤单抗可延长HCC中期患者的PFS。这可能代表了一种新的治疗标准，但是需要更多的数据来证明。总体而言，我认为我们正在朝着局部治疗和系统治疗相结合的模式发展。此外，最近开展的研究表明，即使是晚期肝癌，也可以考虑局部治疗。因此，我认为这是一个不断发展的领域。

 

就协同作用而言，有一种观点认为，局部治疗可以诱导免疫原性细胞死亡，使肿瘤更容易被免疫系统发现，就像在SARS-CoV-2疫苗中看到的那样。我不知道这是否真的有效但是临床确实表现出了协同作用。局部区域治疗可以在最紧迫的区域减轻疾病负担，而系统治疗在身体各处都发挥作用。所以，我认为这是一个不断发展的范例。

 

英文原文

 

<Hepatology Digest>: How does the combination locoregional therapy with systemic therapy improve the prognosis and survival rates for patients with intermediate and advanced stage HCC, and what are the synergistic effects between these treatment modalities?

 

Dr. Mark Yarchoan: You know, I think intermediate stage HCC is a very heterogeneous group of tumors. Some of these tumors should be treated with locoregional therapy, some of these tumors should be treated with systemic therapy and then some of these tumors probably benefit from the combination. In general, the more tumor that is present the greater the need for systemic therapy and many of us use a cut off up to seven criteria. That is the assessment of the total disease burden to decide when systemic therapy may be useful.

 

There is a press release that was just announced this week that the addition of bevacizumab and durvalumab on top of locoregional therapy prolonged progression free survival in patients with intermediate stage disease. So, this may represent a new standard of care, but we need to see the data. But overall, I think that we are moving towards a paradigm where locoregional therapy and systemic therapy may be combined for intermediate stage disease. And in addition, locoregional therapy may be considered even in cases of advanced stage disease that is liver predominant as suggested by the recent launch study. So, I think this is an evolving space.

 

In terms of synergy, you know, there is this idea that locoregional therapy can induce an immunologic immunogenic cell death and make the tumor more visible to the immune system, as seen in SARS-CoV-2 vaccine. I do not know whether that is truly going to hold up but there is clinical synergy, and that local regional therapy can address the most pressing areas of disease burden while systemic therapy works, works everywhere. So I think this is an evolving paradigm here.

 

03

基因测序等新技术，有望带来个体化、精准治疗的新时代

 

《国际肝病》

对于中晚期HCC患者，个体化治疗策略和精准医学在当前及未来的治疗中有何作用？如何根据患者的基因特征、肿瘤微环境等因素来制定个体化的治疗方案？

 

Mark Yarchoan教授：我们现在对肝癌的治疗选择仍然是“一刀切”的。系统治疗的选择往往是为了避免副作用而不是其他理由，例如有出血风险的患者倾向于避免使用贝伐珠单抗等。

 

显然，我们中的许多人都在等待一个新时代的到来，那时我们可以根据肿瘤微环境中的生物标志物定制治疗方案。但是现在这些生物标志物的应用还没有发展成熟。如今，诸如PD-L1表达水平和肿瘤突变程度这类的生物标志物对于系统治疗方案的选择并没有起到很大帮助。

 

我确实认为未来会有针对HCC基因组亚群的治疗方法，例如KRAS抑制剂、IDH-1抑制剂。我们偶尔会在HCC中发现这些基因型。最令人兴奋的是，基于Wnt/β-catenin抑制剂的疗法即将面世。所以，基于肿瘤测序获得的基因信息进行合理治疗可能是一个并不遥远的新时代。

 

英文原文

 

<Hepatology Digest>: What is the role of personalized treatment strategies and precision medicine in the current and future management of intermediate and advanced stage HCC patients? How can individualized treatment plans be developed based on factors such as patient's genetic profile, tumor microenvironment, and other relevant factors?

 

Dr. Mark Yarchoan: Yeah, I think it is a great question. We are still very much in a one size fits all management of HCC today and the selection of systemic therapy is often based on avoidance of side effects more than anything else. So, patients who are at risk of bleeding who tend to avoid bevacizumab you know etcetera.

 

Obviously, many of us are looking forward to an era where we can customize the therapy based on biomarkers within the tumor microenvironment, but those biomarkers are really not ready for prime time. Today biomarkers such as PD-L1 expression and tumor mutation burden have really not been very useful for the selection of systemic therapies.

 

I do think that there are therapies that are coming that are specific for genomic subsets of HCC, for example inhibitors of KRAS, inhibitors of IDH 1, which we occasionally find in HCC, and most excitingly, I would say, inhibitors of Wnt/β-catenin, those therapies are coming. So, they are it may be an era that is not too far away, where sequencing of the tumor may lead to genomically informed rational therapies.

 

04

系统治疗或可成为治愈HCC的重要手段

 

《国际肝病》

在中晚期HCC的创新疗法方面，近年来有哪些重要的突破和进展？这些创新疗法如何改变现有的治疗格局？

 

Mark Yarchoan教授：我认为，一个明显的趋势是进行系统治疗的时间点越来越早。患者的病情是逐步发展的，从早期到中期再到晚期，以往系统治疗作为晚期疾病的保守治疗方法。而现在，在过去的几年里，我们有越来越多的数据表明，包括辅助化疗甚至是新辅助化疗在内的系统治疗，在疾病中期时也可以起到很好的治疗效果，例如在术前使用系统治疗可以缓解患者的病情并消除微转移的病灶。因此，我想说，这代表了系统疗法的突破，不仅可以用于治疗晚期患者，并且有望用于达到治愈患者的目标。

 

英文原文

 

<Hepatology Digest>: What are the significant breakthroughs and advancements in innovative therapies for intermediate and advanced stage HCC in recent years, and how do these innovations change the current treatment landscape?

 

Dr. Mark Yarchoan: You know, I think the trend that is been obvious is that systemic therapy is moving earlier and earlier. It used to be that patients really progressed in a stepwise fashion from early to intermediate to advanced, and systemic therapy was reserved for advanced stage disease. And now, really just in the last couple of years, we have more and more data that systemic therapy can be useful in intermediate stage disease and as adjuvant therapy from the recent IMbrave050 study and perhaps even neoadjuvants, so use of systemic therapy before surgery to downstage patients and to eliminate micro metastatic disease. So, I would say that this represents a breakthrough for systemic therapies used not only to treat advanced stage patients but also hopefully to cure patients.

 

 

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