Ghassan K. Abou-Alfa, MD: Let’s talk about one more thing about the local therapy. I’ll go back to you, Dr. Vogel, because understandably, we know that the yttrium-90 radioembolization is not yet approved in Japan. How about in Europe?

Arndt Vogel, MD: So, we can use it. The question is, when should we use it and how should we use it? And we now have 3 clinical trials that kind of address the relevance of Y-90 in HCC, and all 3 trials are negative. So, we have 2 head-to-head comparisons that did not show improvement in overall survival in the protocol-treated patient group. And we also have the SORAMIC trial, reported at EASL, which looked at the combination of sorafenib with Y-90, and also this trial was negative. So, there was no significant improvement in overall survival, and this is also something that is similar to what we have seen in colorectal cancer. So, in all clinical trials where we looked at the value of Y-90, all of these trials are negative. So, should we not use Y-90? I think that’s also difficult, because we have used it for a long time. And I think everybody will remember 1 single patient who had a dramatic response on the Y-90.

So, there are clearly some patients who do have a benefit, and I think there is also certain space for the treatment with Y-90. But I think we really need to be very critical about the use of Y-90. I see it more like a salvage treatment, or we really need to better define these early patients—patients without liver cirrhosis, maybe one single, big nodule—who might be candidates, and this is also something we have seen in the SORAMIC trial. So, I think we have negative trials. I always try to stress this, that the trials are negative. They have not shown superiority, they have not shown noninferiority. They are negative, so we shouldn’t use it uncritically. On the other hand, there are certainly some patients who have a benefit, so we have to define, in the future, really where the exact place for Y-90 is.

Ghassan K. Abou-Alfa, MD: Fair, fair, fair. Richard, pretty much combining sorafenib with anything that is radioembolization did not work. Are we really missing something, or are we really choosing the wrong agent? Should we consider something else to combine with the local therapy or is it not going to work regardless?

Richard S. Finn, MD: Well, I think we want to design studies based on a strong hypothesis. And I think the initial excitement came out of this idea that you do a chemoembolization, you induce ischemia. Ischemia is a strong driver of VEGF production, and then you come in with a drug like sorafenib that blocks the VEGF receptor, and we should see a benefit. But the important thing, especially when we’re looking at overall survival when we’re doing a combination study, is you’re betting that there’s synergy in those 2 interventions, in this case TACE and sorafenib versus just the sequential use. Because if you do TACE and then at progression you get sorafenib, I would say outside of the 1 study we heard about, the TACTICS study, that the data strongly support there’s no reason to do it in combination, which raises and goes to the heart of your question: Is it just that sorafenib is not the right drug?

But we also did a study that was stopped early with brivanib in this population. Even though the study was stopped earlier, there were still several hundred patients accrued, and there was no strong signal that it was going to be better. So, I think we need to question these hypotheses about ischemia and antiangiogenesis. Maybe that’s not the way to go. There are some interesting data. I hate to come back to it all the time, but immuno-oncology is an interesting area of cancer medicine right now.

But there was a study from the NCI. Tim Greten’s group did a study with either chemoembolization or radiofrequency ablation, any way to induce tumor damage for patients who actually even have advanced disease. And the idea was that you would release antigens and then use, in this case, CTLA-4 blockade, tremelimumab. And they showed very interesting activity, so maybe that will be the next generation. But it’s very hard to design these studies. These are very complex studies. These groups of patients are very heterogeneous in their outcomes.

Ghassan K. Abou-Alfa, MD: Absolutely right. If anything, really, we don’t have a good understanding about yet what to combine TACE with, if we need to combine it with anything. But you’re right. At the moment, the high focus is really trying to combine checkpoint inhibitors plus a TACE. Will it really work or not? Hard to tell. Would it really carry on to something else like, for example, a triple combination of TACE plus a checkpoint inhibitor plus a TKI? We don’t know yet where it is going to take us altogether. But, nonetheless, it is fascinating that we are—instead of what we saw in the SARAH study, which is really more of a split between the locally advanced disease and metastatic disease—trying to see what we can serve for both populations; for example, the sorafenib versus an yttrium-90—based therapy. Now we’re looking at the SORAMIC, which is combining them and still did not work. And really we thought it’s not going to be the worst, but really the management is not working either. So, we just have to wait and see what’s going to happen in that regard.

Transcript Edited for Clarity Brought to you in part by Eisai