Ghassan K. Abou-Alfa, MD: But talks about approval, believe it or not, we are living our life with one drug, sorafenib. Out of nothing, we’re talking about 2 in the first-line setting, with an expectation for one of them, lenvatinib, to get an FDA approval soon. But already we have 2 drugs approved in the second-line setting, like something totally new to us. So, tell us a little bit about regorafenib.
Arndt Vogel, MD: So, regorafenib has also been tested in a large phase III clinical trial, and the trial was also positive. Regorafenib is very similar to sorafenib, but the spectrum of kinase inhibition is different. And, therefore, there was clearly a rationale to test regorafenib after sorafenib failure. And we had a lot of discussion on tolerability of regorafenib in other cancers, so I think it was a wise decision to focus here, in HCC, on patients who do tolerate TKIs, specifically sorafenib. So, this trial was designed to test whether regorafenib is better than a placebo in second-line treatment for patients who have received sorafenib, who have tolerated sorafenib, and who have progressed on sorafenib. In this predefined group of patients, there was a significant overall survival benefit that was very similar to the survival benefit we have seen for sorafenib in first-line setting, 7.8 months to 10.6 months. So, that’s 2.8 months’ improvement in median overall survival, and I think this is clearly an indication of an efficacious drug. And with that, it was approved, I think, worldwide for second-line treatment in this group of patients.
Ghassan K. Abou-Alfa, MD: No question. It’s something fascinating, and we thought it’s really a very close cousin, no more than that, in regard to sorafenib. But now we know that there are certain variables. We only have biologic concepts. We don’t have them proven. But, for example, IGF and IDH probably could be overexaggerated in regard to expression after a progression on sorafenib. And, as such, having the regorafenib—which has IC50s in regard to those—might very well be a good, impactful therapy in that regard. And I think, interestingly, add to the data that you just showed, Arndt, in regard to the regorafenib versus placebo, and my understanding, even though it was not planned study, is that the cumulative survival for sorafenib followed by regorafenib is 26 months.
Arndt Vogel, MD: Yes, and I think this is also very impressive. I mentioned the numbers before for the local therapies, TACE, median overall survival is 20 months. Patients who have an earlier disease, there are more stage B patients. And I think we need to start to do this cross-trial comparison, and again, this is retrospective analysis, a selected group of patients, patients who were candidates for clinical trials in the first- and second-line settings. So, we have to be careful, but still, if you look at the combination, 26 months is the new benchmark we can achieve with systemic therapies. And this is also true for the second drug you mentioned, and I have to remind you that this is a global problem. We have only one, in Germany at least, approved drug in the second-line setting. Nivolumab is not yet approved in Germany. But I think for immunotherapy, we have also very impressive data in second-line therapy. And in first-line therapy, it’s even more impressive: 28 months for nivolumab. Again, no control arm, so we need to be careful, and we have to wait for the phase III data. But I think what we have so far in second-line therapy—15 months for nivolumab and 30 or so months for pembrolizumab—there’s a clear indication that immunotherapy works in second-line HCC.
Ghassan K. Abou-Alfa, MD: Well, thanks for the reminder, but at the same time, you bring me to a very important point. We’re going to break from the TKIs. We’ll come back to them in a second, but let’s talk about checkpoint inhibitors.
Richard S. Finn, MD: Yes, I think the FDA made a fairly aggressive move, but it’s not unique to liver cancer. I think we’ve seen with other diseases with checkpoint inhibitors that they are making aggressive approvals based on smaller studies or single-arm studies. And you could argue whether or not it was the right decision, and we’ll know that when we see randomized data. But, needless to say, it’s a great thing for patients, because they get an option. I think we’re convinced that these drugs are relatively safe in this population, and there are certainly patients who do really well. And the approval label is a response rate of about 15% with a duration of response of, like, 16 months. So, if you respond to one of these drugs, your response is probably going to be fairly durable.
The holy grail is, who are these patients, and as far as we know, PD-1 expression, PD-L1 expression hasn’t correlated with this. This is an area of great interest as far as biomarker work. I think in the context, this approval came after we had seen the results of the RESORCE study, after its approval in early 2017. And the sequence of sorafenib to regorafenib, 26 months is a very provocative number. And I think the challenge for us as we get new drugs approved is, what is our choice for second-line therapy? Well, I’m sure we’ll talk about the cabozantinib data. At this ASCO, we’re going to see data on ramucirumab in a biomarker-selected group, the high AFP group.
So, I think we want to try to make decisions on high levels of evidence, but at the same time, while we’re waiting for that evidence to filter in, we need to try to get our patients at least to second-line therapy to get that option of treatment, which brings us to another point that we touched on earlier. In order to get a patient to second-line treatment, we need to get them to frontline treatment appropriately. And if patients get caught in that whirlpool of repeated chemoembolization beyond where the data support its use, and patients start decompensating—so they start having evidence of liver dysfunction—and then we send them to the oncologist or hepatologist—whoever manages them in systemic treatment, depending where you live—but they’re getting to systemic treatment late in their disease course, then there’s no way they’re going to maximize frontline treatment, let alone second-line treatment, and now even third-line treatment. And so, I think we need to be aware that systemic treatment for liver cancer is no longer a 1-drug pony. There are a lot of options that are evolving rapidly, and I think probably if we glean from other diseases that have a lot of choices, patients who get treated sequentially with effective drugs probably do better.
Transcript Edited for Clarity Brought to you in part by Eisai