Second-Line HCC: A Historical Perspective

Transcript:Arndt Vogel, MD: What can we do in patients that have progressed on sorafenib or are intolerant to sorafenib? So far, we have not have too many options in our daily clinical life. One important point is whether the liver function of our patients is still good. And I think this is what we have really learned in the last 5 to 10 years with all of the negative second-line trials we had, unfortunately. But they clearly told us that if patients have progressed on the sorafenib, if they have good liver function, they still have a reasonable life expectancy of around 7 to 8 months. So, it’s worthwhile to really invest here and try to introduce new second-line therapies.

We do not have an approved second-line therapy available at the moment, so we are trying to find options. One option, of course, is always to include patients in clinical trials. Outside of clinical trials, it depends. Today, we do have evidence from recent trials that some drugs might work; for example, ramucirumab in patients with high AFP levels. We have quite promising data for patients who are treated with immunotherapies. So, here we can discuss with the health providers whether we can use any of these potentially active drugs with our patients even outside of clinical trials. But this is clearly something we should not recommend on a general basis, and it’s clearly a great problem we still have for our patients that are in good performance status with good liver function.

Richard Finn, MD: We’ve been trying for a long time to improve on sorafenib’s activity in the first-line setting of liver cancer. To date, no agent has been shown in phase III studies to improve survival more than we’ve seen in sorafenib. And you could argue, the larger unmet need is in the second-line setting for patients who have been on sorafenib and then their disease is progressing. There have been several phase III studies that have been looked at. One of the first studies to read out was with brivanib, a small VEGF FGF (fibroblast growth factor) molecular inhibitor that looked very promising in a single arm phase II study and actually in phase III did not meet its endpoint versus placebo. Since there’s nothing approved in the second-line setting, the standard of care in the control arm for the phase III studies has been placebo.

The mTOR inhibitor, everolimus, was evaluated in a phase III study based on some promising biological insights into the importance of mTOR signaling in liver cancer. But, unfortunately, that study was negative, as well. And ramucirumab, the monoclonal antibody to vascular endothelial growth factor, was evaluated in the second-line setting versus placebo in an all-comers population. Unfortunately, that study was negative for improving overall survival. Interestingly, in that study, in a retrospective analysis, there looked to be perhaps a benefit in patients who had a high baseline alpha-fetoprotein (AFP). And now there is a new prospective study, the REACH-2 study, which is evaluating ramucirumab, but only in those patients with an elevated AFP.

There are other ongoing phase III studies in the second-line setting. Tivantinib, which is a small molecule inhibitor of the c-Met kinase, or hepatocyte growth factor receptor, was evaluated in second-line versus placebo in patients who have high c-Met expression in their tumor, based on immunohistochemistry. That study has completed accrual, and we’re waiting for results. And, similarly, cabozantinib, a c-Met VEGF multikinase inhibitor, has been evaluated in the second-line setting in phase III, and we are awaiting those results, as well.

Lastly, regorafenib was evaluated in a phase III study, a multikinase inhibitor that showed some early activity in a single arm phase II study. These data were presented recently, and it was a positive study, the first positive study to show a benefit in second-line liver cancer.

Transcript Edited for Clarity