Darren S. Sigal, MD: Going to the point of advances in systemic therapy for HCC is the fact that now there’s an approved second-line agent for patients with advanced hepatocellular carcinoma, and that agent is called regorafenib. And regorafenib is very structurally similar to sorafenib, with important differences. And it was looked at in what’s called the RESORCE trial, which was a phase III study with a 2:1 randomization between regorafenib and placebo. What it showed is that in the second-line setting, there was an improvement in overall survival from 7.8 to 10.6 months.

The advances in hepatocellular carcinoma systemically have also translated not just from the frontline setting but also to the second-line setting. There’s an agent called regorafenib that was shown in the RESORCE trial to improve overall survival in the second-line setting. This was a large study, phase III, that randomized patients in a 2:1 fashion to regorafenib or placebo.

There was an improvement in overall survival from 7.8 to 10.6 months. The important thing to remember about this study is that patients had to have progressed on sorafenib. What often happens in second-line studies and subsequent-line therapy studies is that patients are allowed to accrue with intolerance. But this was very stringent criteria for progression, so this was a true population of people who progressed after frontline therapy.

In addition to the data from the RESORCE trial, there are some other recent data using other agents that also have shown an improvement in overall survival, one of which is called cabozantinib, in the CELESTIAL trial, as well as immune checkpoint inhibitors such as nivolumab, which was recently given accelerated approval for at least the second-line setting of HCC, as well as some other agents that we’ll speak about later.

Catherine T. Frenette, MD: What factors help you decide between going to another tyrosine kinase inhibitor versus immunotherapy?

Darren S. Sigal, MD: Up until recently, regorafenib was the only second-line agent approved, and so there was not really a difficult decision process to undertake. Now, with the recent accelerated approval of nivolumab, there’s really a decision point that needs to be considered. And I think it’s important to take into account that regorafenib was a large phase III study. Nivolumab was approved on a phase I/II trial, a smaller number of patients. And it was not a randomized study. And so, I think that those are important factors to consider. But beyond that, you always have to look at the patient characteristics and comorbidities. And one of the significant toxicities, or potential toxicities, with regorafenib is liver dysfunction. And that’s an important factor especially when somebody likely has underlying cirrhosis and primary liver cancer. And so, that might be an important decision point to favor immune therapy.

It’s also important to keep in mind that in the nivolumab trial, PD-L1 was not a predictive factor benefit as it has been in other studies. However, microsatellite instability may still be predictive, as may be additional predictive biomarkers that are identified over time. So, I think that when you decide one versus the other, a lot of it depends on comorbidities and the strength of prior data.

And the final point is toxicity profile of the agents. Nivolumab, or checkpoint inhibitors in general, are typically very well tolerated. The risk for autoimmunity is real but low, and regorafenib has some important toxicities to be aware of. Most importantly is the fatigue that can happen because it can sometimes be profound. Also, there are unique cutaneous toxicities, hand-foot skin reactions that are distinct from other oral agents that we think of. And so, we need to monitor liver function. People can have loose stools, and so all these factors come into play.

Transcript Edited for Clarity