Transcript:Arndt Vogel, MD: The mechanism of action for regorafenib is quite similar to the mechanism of action of sorafenib, and the drugs are very similar. There is only one fluorine atom that is different between sorafenib and regorafenib. But, with that, regorafenib has a much broader spectrum of activity and there are more kinases and pathways that are inhibited. At the moment, we think there are 3 main modes of actions. One would be on the tumor cell itself, one on the microenvironment, and finally also it has some anti-angiogenic activity by inhibiting VEGF receptor pathways, for example. And all these 3 together most likely led to the success we saw in the recent trials in regorafenib in patients with HCC. And, with that, we had the first clinical trial that was really successful in HCC in second line.

Richard Finn, MD: As the first positive phase III study in advanced liver cancer, whether first or second line since sorafenib’s approval, this is a hallmark study. The improvement in overall survival looks to be the similar magnitude that we saw in sorafenib. And, while you could argue this is not a cure, it is an incremental advance. We have gone from having only sorafenib, and when patients progress on sorafenib really having limited options outside of clinical trials, to now having a drug that has been shown definitively to improve survival. We saw a 3-month median improvement with sorafenib, now we’re seeing a median 3-month improvement with regorafenib for patients who get both drugs. I think we’re going to continue to see an improvement in the natural history of advanced liver cancer. It also needs to send the message that there is a plan for patients, that as patients progress beyond chemoembolization, we now have more options for management in that continuum of systemic therapy.

I think one of the challenges, over the past decade, in only having one systemic therapy for the treatment of advanced liver cancer, even though it’s been proven to improve overall survival, has been the perception that systemic treatment doesn’t work for this disease. And, that, maybe has led to a bias of relying more on locoregional therapy, probably longer than it is proven to be of benefit. I think now with the RESORCE data, with the availability of 2 systemic agents that individually have been shown to improve survival, we need to keep that in mind, so that patients are candidates to get treatment. If patients receive chemoembolization beyond progression from that approach, then we might miss the window of opportunity to give patients effective systemic management.

There’s no doubt that chemoembolization helps patients with liver-confined disease, but, again, it’s not a cure. Patients will progress beyond that. And every time a chemoembolization is done, no matter how selective it is, it does induce some damage to the liver. The most frequent side effects are liver-related side effects. And, if we TACE beyond progression to the point that a patient experiences significant liver dysfunction or decline in performance status, they may never be a candidate for not only first-line therapy, but then maybe even second-line therapy.

Arndt Vogel, MD: I think these findings will have an impact on our daily clinical practice because, so far, we only had one systemic therapy available, one line of therapy with sorafenib, which we use in general for around 4 to 5 months, at best, in our patients. Now, we have an option for patients for second-line therapy, and we have an impressive overall survival in this group of more than 10 months, which means we now have to think even more about the points we have discussed before. How long should we do local therapies, for example, TACE, and when would be the best time point to switch to systemic therapy, now having 2 lines of therapy available, of course, in selected patients that tolerate these multi-tyrosine kinase inhibitors?

Saying that, these drugs are probably not drugs that we can use in all of our patients. Some patients just do not tolerate these tyrosine kinase inhibitors, but those who do tolerate them, they have really 2 options, now available. If you look at the overall survival, or if you look at the survival in the RESORCE data from patients from the beginning of sorafenib and then the median overall survival, it was more than 20 months, which was really very good outcomes data.

Transcript Edited for Clarity