Dr. Lorenza Rimassa talked about the first-line and second-line selection of liver cancer under the new immune therapy, and the prospect of early and medium-term treatment

 

Editor's note: Recently, the combined regimen of altelizumab and bevacizumab as immune checkpoint inhibitors has been established as a new first-line treatment standard for unresectable hepatocellular carcinoma (HCC). This opens up a new situation for the treatment options of liver cancer, but at the same time, it also brings new problems related to the treatment options and medication sequence. In 2021, the 56th Annual Meeting of the European Society for the Study of the Liver (EASL2021) and the International Conference on the Liver TM(ILC2021) were hosted by Professor Lorenza Rimassa, Director of Gastrointestinal Oncology, Research Hospital of Humanitas University, Italy, "How do you decide the best 1st and 2nd lineOption for HCC patients?" Thematic discussion and sharing of personal views on key outstanding issues and future prospects of HCC at the invitation of the hepatology digest reporter.

<Hepatology Digest>: 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.

<Hepatology Digest>: 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.

<Hepatology Digest>: 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.

<Hepatology Digest>: 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.