Ghassan K. Abou-Alfa, MD, MBA: Dr Ahmed Kaseb brought up a very interesting point that I would like to spend some time on, with some very thoughtful thinking. After looking at the nuances and the details of the therapy, if a patient has hepatitis C, I do this, and if the patient has hepatitis B, I do that.

I would like to dissect this a little further. I’ll start with Anthony again. Pressures of choice—let’s go back all the way to the scenario of first line with the choice of sorafenib-lenvatinib; and then second-line cabozantinib, ramucirumab, and also regorafenib. And let’s take a scenario, especially with hepatitis B. What will be your preferred choice, or you are too agnostic to the diagnosis, the etiology?

Anthony B. El-Khoueiry, MD: This is a challenging area because we actually do not have definitive data on therapy and etiology. As you know, we have lumped all these patients together. We at times are stratified by etiology, but none of the trials is definitive. As Dr Kaseb mentioned, with sorafenib there are some post hoc analyses showing that the hepatitis C subset of patients seems to particularly benefit from this. I think it would be reasonable to consider that data when treating a hepatitis C patient.

The lenvatinib study had significant accrual from Asia and hepatitis B patients, and they seemed to do well. Again, this is based on subgroup analyses. Subgroup analyses cannot be used as definitive guidance to guide the clinical practice. But there’s certainly a hypothesis generating, and you know one could consider them. I guess I’m giving a complicated answer because I do not believe that we have definitive data on how to treat different etiologies differently.

However, I would respect the idea of individualizing therapy. I think that’s great. Where it’s useful to interject therapy is liver function. We talk about the good Child-Pugh B patients—B7, B8—who don’t have refractory ascites who are not actively telepathic, and whom we might treat with systemic therapy. As you said in your introduction, all the trials took Child-Pugh A patients. So how do we treat Child-Pugh B? We extrapolate.

It’s important to remember that the data are limited, and we have data from sorafenib from registry studies, like GIDEON, and from your initial study with the phase II with sorafenib, where there was a Child-Pugh B small number of patients. At least we have some safety data for sorafenib with Child-Pugh B.

Similarly, we have some data with nivolumab in a perfective cohort in CheckMate040. We have patients with B7 and B8, cirrhosis were enrolled. Again, they were the good B7, B8 patients, as I mentioned earlier, but at least they showed similar safety to nivolumab in Child-Pugh A and a relatively similar response rate of about 12%. That’s a subgroup where I’m cautious because we don’t have data, for example, about the safety of the other agents. And it’s important, too, to maybe develop more data in that space.

Ghassan K. Abou-Alfa, MD, MBA: Thanks for bringing this up, Anthony. Actually, it’s nice and it really reassures us. At the same time, it perplexes us with the multiple dimensions that we need to look into in regard to HCC [hepatocellular carcinoma] patients. Among them are etiology, as we also heard about the extent of cirrhosis.

But let me stick to the etiology component for a second. Catherine, because you are an expert and you are a hepatologist, if you have the hepatitis C—I mean, it looked like they just were standing out like at a coffee shop and they were given B and C back-to-back. What’s the difference?

Catherine T. Frenette, MD: Hepatitis B and hepatitis C are very different viruses. They just happened to be labeled with letters. Hepatitis B is a virus, and as you know it’s very predominant in Asians. But that virus actually gets into the nucleus of the hepatocyte, and it actually can integrate itself into the genome of the hepatocyte.

Ghassan K. Abou-Alfa, MD, MBA: As DNA of course.

Catherine T. Frenette, MD: As DNA, exactly. That will then turn on oncogenes and can cause hepatocellular carcinoma in the absence of cirrhosis and chronic liver damage, and they can have very normal livers. Hepatitis C on the other hand stays in the cytoplasm of the cell, which is actually why we can cure hepatitis C relatively easily, whereas hepatitis B we can’t cure yet; we can just suppress it.

Ghassan K. Abou-Alfa, MD, MBA: I like the yet, by the way. I know there’s work going on there.

Catherine T. Frenette, MD: We’re working on it, exactly. Generally patients get cancer from hepatitis C once they’ve developed more advanced disease with bridging fibrosis or cirrhosis, and it’s that chronic damage over time that then causes the hepatocellular carcinoma.

Ghassan K. Abou-Alfa, MD, MBA: Before we go back to systemic therapy, but while we’re on the subject of the virus itself—and admittedly, I’m taking advantage of having 2 great hepatologists with us. Catherine already described the differences, and I would like Pierre to tell us the story we hear quite a bit sometimes: a patient who has hepatitis C or related HCC, they have the virus, they have the disease. And let me be very clear, the disease is stage IV metastatic. The spread of which is not a good story in regard to the extent of the disease. Would you treat the virus?

Pierre Gholam, MD: Clearly in the subset of patients who have advanced disease, one has to weigh the potential benefits from cure of hepatitis versus the life limitations that cancer might subject the patient to. The AASLD [American Association for the Study of Liver Diseases] liver society and the Infectious Diseases Society of America have joined HCV [chronic hepatitis C] guidelines, which is published online at HCVGuidelines.org, which anybody can access. And it states very generically that any patient who has hepatitis C is a candidate for therapy, assuming they have some reasonable life expectancy. The life expectancy generally of a year or more is considered enough for one to justify treatment.

Therefore, in the era of the time when we can potentially offer many of our patients with BCLC [Barcelona Clinic Liver Cancer] stage C metastatic disease treatments that could potentially make them, in multiple lines of therapy, live more than a year, there is some pretty good justification to doing this. They may also be—and I will completely state that this is a controversial benefit of “improving liver function in the short term,” which may allow patients to tolerate therapy better. This, of course, depends on where in the spectrum of liver disease the patient is. If they have Child-Pugh C cirrhosis and a MELD [model for end-stage liver disease] score of 38, the likelihood that curing hepatitis C is going to dramatically improve their liver disease is not very high. Certainly, if they have a lesser extent of disease, that may be a benefit that they allow them to benefit from more systemic therapies.

I will finish on 1 note. There was a controversy a few years ago based on the finding, primarily from the Barcelona group and subsequently from others, that in patients who had HCC treated for cure—meaning whether it’s R0 resection, ablation for cure—there appeared to be an increase in the rate of recurrence in the first 6 months after cure of hepatitis C. Whether this is true is somewhat controversial, but what is not controversial anymore is that curing hepatitis C outside that very specific scenario seems to decrease their lifetime risk of HCC, so we should not be delaying or postponing therapy in those settings.

Ghassan K. Abou-Alfa, MD, MBA: It is very important, and by all means we are very keen on waiting for further data that will guide us further regarding how to treat patients. I 100% agree with Dr Gholam in that if a patient has early stage III disease—ie, the patient is going for transplant—by all means, treating the hepatitis C is critical because, of course, the potential of recurrence of the whole activation of the virus leading to cirrhosis, etc, is there.

On the other hand, in regard to more advanced disease, admittedly we don’t know yet. There were reports—they were really more like single case reports—of a certain worsening of the hepatitis, or of the hepatocellular carcinoma, the hepatitis C. What does it mean? We’re not sure yet, but it’s something to be further evaluated. I like how Pierre put it: we have to put the priorities here. Understandably, in the setting of very advanced HCC, the cat is out of the bag already. The start of the management of systemic disease, and especially with the advance of all the therapies we’re having, is going to be very critical.

Transcript Edited for Clarity