编者按：最近，免疫检查点抑制剂联合方案——阿替利珠单抗+贝伐珠单抗被确立为不可切除肝细胞癌（HCC）的新一线治疗标准。这为肝癌的治疗选择开辟了新的局面，但同时也带来了有关治疗选择和用药顺序的新问题。2021年第56届欧洲肝脏研究学会年会（EASL2021）暨国际肝脏会议TM（ILC2021）上，意大利Humanitas大学研究医院胃肠肿瘤科主任Lorenza Rimassa教授主持“How do you decide the best 1st and 2nd line option for HCC patients?”专题讨论，并应《国际肝病》记者邀请就HCC的关键未决问题和未来前景分享个人观点。

 

《国际肝病》：随着阿替利珠单抗联合贝伐珠单抗治疗为不可切除HCC的新一线标准治疗，以及后续多种组合方案的进展，您认为不可切除HCC的治疗前景将发生怎样的变化？

 

Lorenza Rimassa教授：根据IMbrave150试验的结果，我认为阿替利珠单抗与贝伐珠单抗的组合是不可切除HCC的新治疗标准。在某些国家或地区，该组合已经获得上市批准，因此成为晚期HCC一线治疗标准。在其他尚未获得批准的国家，我相信在不久的将来它也会成为新的治疗标准。因此，目前在一线治疗中，除不适合阿替利珠单抗或其他免疫肿瘤药物，以及贝伐珠单抗的患者外，仑伐替尼或索拉非尼的标准治疗地位将不会继续存在。

 

: With the combination of atezolizumab and bevacizumab as the new first-line standard of care for unresectable hepatocellular carcinoma (HCC), and the progress of subsequent multiple combinations, how do you think the treatment landscape of unresectable HCC will happen?

 

Prof. Lorenza Rimassa: I think the new combination of atezolizumab and bevacizumab is the new standard-of-care based on the results of the IMbrave150 trial. In some countries, the combination is already approved, so this combination is already standard-of-care in first-line. In other countries, it is not yet approved, but it will be the new standard-of-care in the near future. So the current standard-of-care of lenvatinib or sorafenib in the first-line will not persist in that setting, except for people who are not suitable for atezolizumab plus bevacizumab. This will be the new standard-of-care in first-line for patients who are candidates for a combination treatment. For other patients who are not suitable for immune-oncology drugs or bevacizumab, then lenvatinib or sorafenib can still be a good option in first-line.

 

《国际肝病》：随着新疗法的到来，您认为临床医生需要作出怎样的调整？我们如何根据新的可用数据重新考虑HCC的序贯治疗，重新为HCC患者确定最佳的一线和二线选择？

 

Lorenza Rimassa教授：我认为这是一个非常重要的问题，也是一个非常困难的问题。医生应该了解这些新数据，并了解不可切除HCC患者的治疗方案已经或将要改变。因此，首先，他们需要了解新数据。然后，对于二线和三线，这是一个较难回答的问题，因为我们还没有任何关于阿替利珠单抗+贝伐珠单抗后线治疗的数据。

 

根据处方说明书，只有索拉非尼可以在阿替利珠单抗+贝伐珠单抗之后使用，因为它是唯一被批准用于HCC的药物。但是，如果我们从科学的角度和应用的理论依据来考虑，我认为没有任何理由不给予患者索拉非尼、仑伐替尼或其他激酶抑制剂或将来的免疫检查点抑制剂联合方案治疗。

 

目前，在阿替利珠单抗+贝伐珠单抗之后，我认为我们会使用之前的一线治疗索拉非尼或仑伐替尼，然后是之前的二线治疗（瑞戈非尼、cabozantinib和ramucirumab）。如果我们查阅指南，如ESMO指南，可以发现，指南中确实认可索拉非尼、仑伐替尼、瑞戈非尼、cabozantinib和ramucirumab等基于前期试验获批的所有疗法，用于阿替利珠单抗+贝伐珠单抗的后续治疗。

 

我认为，我们还需要获得建立在真实世界数据基础上的治疗建议，观察真实世界中不同酪氨酸激酶抑制剂或其他药物在阿替利珠单抗+贝伐珠单抗后的应用中是否存在任何差异。目前已有试验正在或计划对阿替利珠单抗+贝伐珠单抗后的不同组合进行评估。

 

: With the advent of new therapies, what adjustment do you think clinicians need to make? How can we reconsider the sequential treatment of HCC based on the new available data and re-determine the best first-line and second-line options for HCC patients?

 

Prof. Lorenza Rimassa: I think this is a very important question, and a very difficult question. Physicians should be aware of these new data, and be aware that the treatment algorithm for patients with unresectable HCC has changed or will be changing. So first, they need to be aware of the new data. Then, for second- and third-line, this is a difficult question, because we don’t have any data yet for subsequent lines after atezolizumab plus bevacizumab. 

 

According to labels, only sorafenib can be used after atezolizumab/bevacizumab because it is the only drug that has been approved for hepatocellular carcinoma. But if we think from the scientific point of view and the rationale for use, I don’t see any reason to not prescribe sorafenib, lenvatinib or other types of kinase inhibitors, or in the future, combinations of checkpoint inhibitors. 

 

At present, after atezolizumab plus bevacizumab, I think we will use the previous first-line treatment of sorafenib and/or lenvatinib, and then the previous second-line treatments (regorafenib, cabozantinib and ramucirumab). But if we look, for example, at the ESMO Guidelines, after atezolizumab plus bevacizumab they do accept all the other approved therapies based on previous trials of sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab. 

 

I think we need to generate recommendations not from clinical trials, but maybe real world data, to see if there are any differences between the different tyrosine kinase inhibitors or other drugs after atezolizumab plus bevacizumab. There are ongoing and planned trials testing different combinations after atezolizumab plus bevacizumab.

 

《国际肝病》：这些免疫联合治疗在晚期患者取得了非常好的效果，您如何看新疗法在早中期HCC的应用前景？

 

Lorenza Rimassa教授：已经有一些早期HCC研究数据，但不完全来自阿替利珠单抗与贝伐珠单抗的组合，这些结果提示免疫治疗加入新辅助治疗非常有希望提高手术前的反应率。从这些试验数据的转化结果，我们可以发现新辅助免疫治疗后的肿瘤免疫微环境完全改变。所以我认为在未来，阿替利珠单抗+贝伐珠单抗将成为适合手术且有缩小肿瘤需求的患者的一种选择，可能会开展相关临床试验。

 

对于中期HCC患者，已经有试验正在进行中，阿替利珠单抗+贝伐珠单抗对比局部治疗（例如TACE）用于中期但肿瘤负荷显著的患者。我们将在未来看到对这些患者进行全身治疗是否优于局部治疗。此外，也有联合局部治疗与全身治疗的试验。

 

因此，关于阿替利珠单抗和贝伐珠单抗的两个重要新应用（早期和中期治疗），我们还没有明确结果，但预计在不久的将来可以看到。

 

: These immune combination therapies have achieved very good results in advanced HCC patients. How do you see the application prospects of these new therapies in early and mid-stage HCC?

 

Prof. Lorenza Rimassa: Another important question. There are already some data in early stage HCC, not exactly with the combination of atezolizumab/bevacizumab, but with immunotherapy in the neoadjuvant setting that are very promising with improved response rates before surgery. Looking also at the translational results of these trial data, we can see that the tumor immune microenvironment completely changes after neoadjuvant immunotherapy. So I think in the future, atezolizumab plus bevacizumab will be an option for patients who are candidates for surgery and maybe need a downsizing of the tumor. There will probably be clinical trials in this setting. 

 

For patients with intermediate stage HCC, there are already ongoing trials with atezolizumab/bevacizumab versus locoregional treatment such as TACE in patients with intermediate stage disease but with significant tumor burden. We will see in the future if a systemic treatment will be better than locoregional treatment in these patients. There are also trials combining locoregional treatment and systemic treatment. So there are two important new settings for atezolizumab plus bevacizumab for which we don’t yet have data, but expect them in the near future.

 

《国际肝病》：对于HCC的诊疗，您认为仍有哪些难点和热点需要我们关注和进一步探索？您怎么看HCC的未来治疗前景？

 

Lorenza Rimassa教授：对于HCC的诊断，我认为目前有太多患者仍然是基于AASLD指南中的放射学特征来确诊的。现在我们有不同的治疗选择，我们需要生成转化数据来尝试确定生物标志物，通过这些生物标志物来决定哪些患者应该接受哪种药物治疗。我认为活组织检查应该作为强制性评估手段，这样我们可进行组织学检查以证实诊断无误，并获得肿瘤组织来用于转化研究。

 

值得注意的是，近年来，肝内胆管癌的发病率有所增加。在某些情况下，我们根据放射学检查结果以HCC的方式治疗患者，但后来证实他们罹患的是肝内胆管癌，我们没有为患者做到最好。所以，对于诊断，我们首先需要的是肝活检，而不是放射学标准。

 

在治疗方面，前面我们已经或多或少地讨论了其中的一些内容。我们有不同的HCC治疗选择。未来，我们将对早期和中期疾病进行全身治疗。例如，我们将使用阿替利珠单抗+贝伐珠单抗联合局部区域治疗来治疗中期患者。聚焦到晚期HCC，正如我所说的，我们将阿替利珠单抗+贝伐珠单抗作为新的治疗标准，但目前也有其他组合的III期临床试验在进展中，例如两种不同的检查点抑制剂联合（抗PD-1或抗PD-L1+抗CTLA4），或一种多激酶抑制剂与一种免疫检查点抑制剂联合。所以，也许在未来，希望晚期HCC患者的一线治疗可以有多种联合方案。

 

我们需要找到肿瘤FISH生物标志物、血液生物标志物或临床生物标志物，以确定哪些患者应接受哪种组合治疗。此外，我们还需要定义治疗流程，以便在一种联合治疗之后，我们知道可以在二线、三线及后线治疗中开具何种用药处方。

 

: Regarding the diagnosis and treatment of HCC, what difficulties and hotspots do you think still need our attention and further exploration? What do you think of the future treatment prospects of HCC?

 

Prof. Lorenza Rimassa: For the first part of the question for the diagnosis of HCC, I think there are still too many patients with HCC who are diagnosed according to radiological characteristics based on the AASLD Guidelines. Now that we have different treatment options, we need to generate translational data to try to identify biomarkers by which to decide which patients should be treated with which drug. I think a biopsy is mandatory so we have a histological examination confirming the correct diagnosis and for tumor tissue for translational research. 

 

It is also important to note that in recent years, intrahepatic cholangiocarcinomas have increased in incidence. In some cases, we treat patients like they have HCC based on radiological findings, but then they have intrahepatic cholangiocarcinoma and there is a wrong diagnosis and we are not doing the best for our patients. So first, for diagnosis, we need a biopsy, not radiological criteria. 

 

For the second part of the question, we have more-or-less discussed some of this already. We have different options. In the future, we will have systemic therapies for early and intermediate stage disease. For example, we will be treating intermediate stage patients with atezolizumab/bevacizumab combined with locoregional therapy. We currently don’t know what we might be doing in the advanced setting. If we want to focus on the advanced setting, as I have said, we have atezolizumab/bevacizumab as the new standard-of-care, but there are ongoing phase III trials combining two different checkpoint inhibitors, anti-PD-1 or anti-PD-L1 plus anti-CD4, or combining a multikinase inhibitor plus an immune checkpoint inhibitor. So maybe in the future, and hopefully for those patients, we will have different combinations available in first-line. 

 

We will need to find tumor FISH biomarkers, blood biomarkers or clinical biomarkers to select which patients would be treated with which combination. We also need to define the treatment algorithm so that after one or the other combination, we know what we need to prescribe in the second-line, third-line and so on.

 

来源：《国际肝病》编辑部