Ghassan K. Abou-Alfa, MD: That brings me back to regorafenib and, of course, in a way also sorafenib, because they have potentially similar side effect profiles. So, Ruth, help us a little bit. If you want to pinpoint the top things of concern that can occur for patients who are receiving regorafenib, what are they?

A. Ruth He, MD, PhD: So, the side effects we usually observe are increased blood pressure, hand-foot reaction, fatigue, diarrhea, very similar side effects compared to sorafenib. But usually it’s manageable. And if we provide a good education to the patients, communicate with the patients well at the beginning at the start of the treatment or even be more conservative in terms of dosing, a lot of those patients, we can manage them well and control the side effects while they’re on the treatment.

Ghassan K. Abou-Alfa, MD: Fair. So, this brings me a little bit of my intent for Cath, bring in the debate that we’re all living every day. And Anthony, here we already heard—we’re barely into the program—about 2 great drugs. One is called regorafenib, which is a TKI that’s to be followed by sorafenib after progression and another one is nivolumab, as you nicely stated it. And what shall I choose?

Anthony El-Khoueiry, MD: OK. Well, first, I actually wanted to make an important comment, that we kind of collectively overlooked, that all of these clinical trials were in Child-Pugh A patients. So, all of these benefits we talk about are with patients with preserved liver function. In practice, we tend to push the envelope a little bit and treat patients who did not exactly fit the clinical trial criteria. A little bit higher bilirubin, maybe Child-Pugh B 7 or 8, but as long as they’re not fully decompensated. But I think we have to be careful there because, as we mentioned earlier in the program, liver cirrhosis is a competing cause of death. And there are registry data that always show that the survival is correlated with the Child-Pugh status. Patients who have bad liver function may die of their cirrhosis sooner than their cancer. So, patient selection is important.

Going back to your question. I think the sorafenib/regorafenib sequence was based on careful selection of patients, right? They were Child-Pugh A. They had to have tolerated sorafenib at a dose of 400 mg daily or higher for 20 of 28 days and had to have radiologic progression on sorafenib. So it is a select patient population. And in this population, there was great benefit as was seen in that phase III trial. With the nivolumab data, again, they were limited to Child-Pugh A, and both patients who were sorafenib naïve or experienced were allowed. So, there was no requirement to have tolerated sorafenib to a certain extent, etc. The reason I’m mentioning this is, because this may be one of the easier differentiators, that if someone did not tolerate sorafenib at all, or tolerates it very poorly, it may be easier to go to nivolumab rather than to go the sequence with regorafenib.

Ghassan K. Abou-Alfa, MD: So, in a way, I’m trying to count, tie it up a little bit with the debate. But in other words, you’re ready. If a patient received sorafenib, they are eligible for regorafenib; however, still you might go for the nivolumab rather than regorafenib.

Anthony El-Khoueiry, MD: Currently we have no comparison. We don’t know whether the sorafenib/nivolumab sequence is better than sorafenib/regorafenib or vice versa. So, it’s a choice that the physicians have currently. I think, in patients who have poor tolerance of sorafenib, it would make sense to go with nivolumab as the first choice. Beyond that, there are not great biomarkers or great ways to differentiate between the two. The side effect profile is certainly different. Again, going back to that. The frequency of treatment is different. Regorafenib is oral, nivolumab is an infusion every 2 weeks, at the moment. Some physicians think that the chance of a higher response rate with nivolumab, it’s conducive to use it in patients who may be symptomatic or actually need to have a response. Again, it’s a 20% response rate overall but those responses can be deep and long lasting. So, that may be a motivation in someone who’s symptomatic or who may not make it to a third-line therapy. But besides that, it is very difficult to use a scientific rationale to choose between the two.

Ghassan K. Abou-Alfa, MD: I totally agree. So, if anything, we heard Dr. El-Khoueiry really stating his self-debate because, admittedly, it could be any of us. Because nowadays, we started with 1 drug, which is sorafenib. Out of nothing, we have in the market already 2 drugs, being regorafenib as well as nivolumab. And, of course, as it was stated, we really don’t have yet a full clarity about which therapies are to be chosen. If anything, it’s just the best that we have this information. No question regorafenib is active, and it’s active especially in sequence to the sorafenib. And it’s already approved based on the phase III trial. And as we said, the survival improvement of the 2 together will jump beyond the 2 years.

In addition to that, we heard about nivolumab, which already has an approval by the FDA for the second-line setting, but pending what other activities we might see from further trials that will be coming onboard and reported onboard hopefully soon.

Transcript Edited for Clarity