An Evolving Treatment Paradigm for Hepatocellular Carcinoma - Episode 15

Anti-VEGF Therapy in Metastatic HCC


Ghassan K. Abou-Alfa, MD: Of course, we’re going to do a deeper analysis of the data for the c-MET component, to really better understand where we are.

We already spoke about 5 drugs with positive data. Three of them are already FDA approved. We have sorafenib, which has really been the one that has been used since 2007. In regard to first-line, yet-to-be-approved therapy, lenvatinib is expected any minute. Then, for second-line therapy, we have the conditional approval for the checkpoint inhibitor. We also have positive data for cabozantinib, which I expect there will be some approval for at some point in time. And, of course, we have regorafenib, which is kind of married to sorafenib with prior exposure. We see impressive data, and it is already FDA approved. Quite a bit is going on.

Mark, we heard about and read a press release that reviewed ramucirumab with positive data. We don’t have the data yet, but it will be nice to at least bring up some points about that. Any thoughts?

Mark W. Karwal, MD: Yes. Ramucirumab was studied in patients who had progressed after sorafenib. It’s a pure VEGF inhibitor, monoclonal antibody. It just missed reaching its endpoint of survival versus placebo. When those data were analyzed, when they looked at the hazard function for survival, you could see that as the AFP went up, the hazard function for survival went up.

And so, the company—give them credit. They did the work and said, “Let’s do the right study.” They cut the line at 400 ng/ml, because that’s where it seemed to be of most benefit. REACH-2 was born, and that was the same kind of study. There was progression on sorafenib. This was a randomized trial (2:1), of ramucirumab versus placebo. The study showed an overall survival advantage.

Ghassan K. Abou-Alfa, MD: Tell us a little bit more about AFP. What’s AFP?

Amit Singal, MD: AFP is basically a serum protein that can be clinically secreted by HCC. You talked about anti-VEGF. As your VEGF level rises, you can have a higher AFP. I think this is why there’s actually biologic plausibility for why AFP may be a marker here. At least from a hepatology standpoint, AFP has traditionally been used more often as a screening marker, or surveillance marker. We use it in combination with ultrasound for surveillance. This is, I think, the thing that’s been missing from the treatment landscape—these treatment selection biomarkers. You mentioned that it’s been about a decade of sorafenib. We didn’t need to have treatment selection biomarkers. It was sorafenib for all advanced HCC.

Now, as we start to have more and more therapies, I think treatment selection biomarkers can be helpful. That’s why we’re starting to look at some of these subgroup analyses. This is, I think, the thing that’s most exciting here. This is one of the few trials in which we do have a treatment selection biomarker. People can argue as to whether it’s the most elegant one, but it’s something. And so, for AFP-high patients, we have something that we can try to use.

Ghassan K. Abou-Alfa, MD: Mark, this brings me back to the lenvatinib story. Is there any story there, in regard to the AFP levels or the outcomes?

Mark W. Karwal, MD: Well, in the lenvatinib studies, as you mentioned earlier, there was a dis-balance. There was a randomized trial of nearly 1000 people. The median and mean AFP values were higher in the lenvatinib arm than in the sorafenib arm.

Ghassan K. Abou-Alfa, MD: Yes, that’s important as well. So, there is definitely more to come. Frankly, none of us know the data until we see it. We’re all eager to really understand what’s coming from there.

Transcript Edited for Clarity.