Ghassan K. Abou-Alfa, MD: One other thought that we are trying to bring up here in the discussion: Is it really a marriage or a divorce? Is it really comparing the radioembolization against sorafenib, or is it the chemoembolization against sorafenib, or is it really trying to combine therapies? Riad, there have been efforts looking at the combination of chemoembolization plus systemic therapy. What are your thoughts on that concept, especially chemoembolization plus sorafenib?

Riad Salem, MD: There’s no doubt that given sort of the migration of how patients flow from stage to stage, the best results we’re going to get are with combinations. In fact, all patients get combination treatments. It depends on whether it happens at the same time or in a sequential fashion. The SPACE trial, as an example, is drug-eluting beads plus or minus sorafenib. There was a very minor improvement in time to progression, but nothing clinically significant. There’s also the TACTICS clinical trial by the Japanese, which uses TTUP [time to untreatable progression] as an endpoint to see whether the addition of sorafenib was beneficial. Neither of those studies was able to show an overall survival endpoint. The problem with overall survival, of course, is post-treatment progression. Every study is going to be confounded by post-treatment progression, and that endpoint is going to be more and more challenging. In fact, it is one of the challenges that I’ve observed in my career while treating BCLC [Barcelona Clinic Liver Cancer]-As and Bs.

So right now, it’s a nice proof of concept. If we are able to treat people for a fewer number of times by adding sorafenib, that would be beneficial. I think the TACTICS trial is interesting. There’s also some discussion as to what TTUP actually means and whether that’s actually something that is objective and can be reproduced. So we continue to study that. Obviously, other combinations, which we’ll discuss later on, are very interesting. Obviously, combination studies are very, very attractive. That’s what patients are going to get. We just have to figure out the optimal timing.

Ghassan K. Abou-Alfa, MD: Peter, what about checkpoint inhibitors plus TACE [transcatheter arterial chemoembolization]?

Peter Galle, MD, PhD: Again, this opens the door. After SPACE and after, particularly, TACE 2, which was a very nice, well-controlled trial, we learned that the added toxicity is, in the end, probably not able to be compensated by a survival benefit. So we are stuck. Toxicity is the issue. We see very severe side effects with checkpoint inhibitors in some patients. But for the most part, they are very well tolerated. And then the additional aspect, at least in theory, is that the combination with this measurement—where you probably increase the load of tumor antigens, which are presented to the immune system, in combination with immunotherapy—is nice. So that’s very promising.

There are many limitations, which are complex. Any sort of addition will be not only a treatment of a tumor but, as we know, also a problem where the cirrhotic liver produces new tumors. That’s also something to be taken care of by a treatment. Is immunotherapy doing that job? We don’t know. So there are many open questions, but this is an interesting potential combination.

Transcript Edited for Clarity