R. Kate Kelley, MD: We now have quite a few options at our disposal here, with regorafenib being an option in people who have tolerated sorafenib in at least the 400-mg dose. Cabozantinib was recently approved just last week in both second line and third line, so that being a distinction compared with regorafenib. And also pembrolizumab and nivolumab are both approved in the United States now, with accelerated approvals largely based on single-arm phase II data. I do have to say that I have a tendency to use an immunotherapy drug in the second line in certain cases, particularly in patients who did not respond well to a first-line TKI [tyrosine kinase inhibitor], either lenvatinib or sorafenib, in part because we don’t have randomized phase III data to guide this decision yet. I think right now, the fact is that there are potential robust and durable responses that we have seen consistently across trials. Whether it’s the cabiralizumab trial or the pembrolizumab trial or the nivolumab trial, we know that there’s the roughly 17% response rate across those studies. I think in patients who did not respond well to a tyrosine kinase inhibitor, I prefer to try an immunotherapy agent in the hope that they are somebody who derives benefit before they decompensate and are unable to receive any therapy.

Now, in someone who had a prolonged benefit on a first-line tyrosine kinase inhibitor such as regorafenib or such as lenvatinib or sorafenib, I do tend to use a TKI next if there was mild progression and prolonged benefit similar to the data we see from the RESORCE trial, which shows us such nice survival benefits in those patients who had response to sorafenib followed by regorafenib. And, similarly, I think the data are coming that cabozantinib in sequence also achieves prolonged benefit. So that’s generally my strategy in second line.

Josep Llovet, MD, PhD: Very good. So there are results for that question of patients with very aggressive tumors. So you have a patient who has been on sorafenib or lenvatinib in the frontline but also already has the progression at 4 months and has aggressive tumor, AFP [α-fetoprotein] of thousands, and extrahepatic disease and so on and so forth. With these aggressive tumors, now we also have ramucirumab for those. But, looking at the subgroup analysis, certainly regorafenib works well for these patients. Cabozantinib works well. And, as you have said, if the patient is lucky enough to have an immune-hot tumor, is responsive to nivolumab/pembrolizumab, it will be also a plus. So in these very aggressive tumors, how do you manage to decide which is the best option?

R. Kate Kelley, MD: This is going to define the next decade of research. We spend a lot of time after sorafenib trying to find the next treatment options, and I think we have our work cut out for us with the current trials to really look into the biospecimens and correlative analyses to try to understand what are the noninvasive markers that can help us identify those immune responsive tumors or the immune subclass that you’ve defined and how to define that in a clinical setting, rather. But, in the short-term, without that answer at hand, I do try to use an immune therapy in the second or third line, at least, and then sequence the TKIs to the best of our ability. With the advent of ramucirumab, as well, that adds an extra tool for the high-AFP population.

Masatoshi Kudo, MD, PhD: As for second-line agents that we have currently, regorafenib is approved, and cabozantinib and ramucirumab will be approved; they are not yet approved in Japan. In the United States last week, cabozantinib was approved. But in United States, nivolumab and pembrolizumab was also approved. So in the United States, you have many choices. And after sorafenib or after lenvatinib, you have 4 second-line agents and the 2 checkpoint inhibitors. But in Japan currently, we only use regorafenib. But soon ramucirumab or other agents will be approved.

Transcript Edited for Clarity