Ghassan K. Abou-Alfa, MD: As we all know, we were stuck with 1 drug, sorafenib, and that was it. That’s how easy our job was. Now we have 2 drugs with positive data in the first-line setting. Sorafenib, of course, is FDA approved. We have ample experience, 10 years or more, using that therapy.

In addition to that, we have lenvatinib. We saw and heard about the data, which showed noninferiority compared to sorafenib after it showed a doubling of progression-free survival and a response rate of up to 40.6% by modified RECIST. And, by the way, by RECIST 1.1, exactly as Manish was also suggesting, this was close to 24%. Clearly, these are for use in the first-line setting. What do you do as second-line therapy? Usually, our answer is to enroll a patient onto a clinical trial. And interestingly, out of nothing, we have drugs that are already approved in the second-line setting. Let’s start by talking about regorafenib. This was the first one to get approval. Ruth, what’s regorafenib?

A. Ruth He, MD, PhD: Regorafenib is really a very close cousin to sorafenib. It has very similar targets to sorafenib. When it was tested, a lot of us wondered if it would work. In the RESORCE trial, regorafenib was tested in comparison with placebo in patients who had received sorafenib treatment. There was a survival benefit of 1 month or more. So, from the study, it looks like patients do benefit if they progress on sorafenib.

Ghassan K. Abou-Alfa, MD: You’re right. If anything, this study was positive, contrary to some perceptions regarding why a drug so close to sorafenib might make a difference. Interestingly, we know that regorafenib has certain particularities that differ from sorafenib. There is a theory that, for example, IGF-1 and IDH, which really are overexpressed after resistance or a failure to respond to sorafenib, might actually activate themselves. The IC50 with regorafenib is pretty high and could be quite effective.

This really led to the study, which showed a survival improvement for patients who received prior sorafenib. If they progressed on it, they were randomized to regorafenib versus placebo. There was a clear survival advantage. Manish, what are your thoughts on sorafenib followed by regorafenib? Is there any advantage there, regarding survival? What do you know about that?

Manish R. Sharma, MD: There have been studies, that have now reported, looking at sequencing of sorafenib followed by regorafenib. The number that sticks out, in my mind, is 26 months. It was an incredible number. A couple of years ago, we were stuck below 1 year. When you look at the sequencing—when sorafenib is used, and when regorafenib is followed—if we can get to a 26-month survival, that’s pretty incredible. I was as shocked as anybody about these data being positive. Even though we had it open at our institution, I was shocked to see that positive data. I was excited about it. It really does give us a viable option.

I think there are some challenges with using regorafenib. It was first approved in colorectal cancer, and there was a lot of perception out there, in the community, about how tolerable it was. Then, these amazing data came out in hepatocellular carcinoma. And so, we’re trying to create a better perception for the drug, to try to convince people that it may be worth using. I think that’s a challenge in the community setting, where people may not be as familiar with the drug. It has not gained much popularity in colorectal cancer, and I worry that this may impact its use in HCC.

Ghassan K. Abou-Alfa, MD: Well, in a way, you’re right. But on the other hand, in defense of the experience that we have had with side effects or adverse events with sorafenib, it created a certain familiarity to the drug. We didn’t necessarily have this in colorectal cancer. As such, there may be a more inviting perspective, in regard to using regorafenib in that setting.

Interestingly, this was not a planned analysis. If anything, it was really preset based on the data from regorafenib versus placebo. They found this cumulative survival for patients who were on sorafenib and continued on with regorafenib. This number is rather impressive.

Transcript Edited for Clarity.