Ghassan K. Abou-Alfa, MD: This brings me to another layer of discussion, which is, if you recall, we spoke about the different layers of the BCSE. We spoke about the horizontal connection between the different lines of therapy. But there was always this kind of collusion, which I spoke about in the beginning: can we make more BCSE patients who are eligible for local therapy get more systemic therapy? Or, can we make BCLC (Barcelona-Clinic Liver Cancer) patients get for more local therapy other than the systemic?

And if anything, I recall that I spoke about that almost 10-plus years ago in an editorial in JCR (Journal of Cancer Research) and it’s more of a marriage than a divorce. Talk about that marriage. Can you please tell us, Catherine, about what’s going on in the world of Yttrium-90 (Y-90)-plus systemic therapy?

Catherine Frenette, MD: Looking at the Y-90 data that are out there, right now the guidelines say there isn’t a big randomized phase III controlled trial of Y-90 trying to exactly figure out where it fits into the landscape of HCC treatment. We all know that there’s response. There are 2 large studies just recently presented looking at Y-90 versus sorafenib, which really resulted in equivalent overall survival, although, of course, Y-90 has less side effects for that duration. There are several studies going on with the combination of Y-90 with sorafenib. We know that sorafenib has also been studied with chemoembolization, although some of those trials are very difficult to complete and interpret. So, I think we should combine systemic therapies with some of our local regional therapies, or potentially even getting back into the adjuvant and neoadjuvant around resection, which sorafenib didn’t pan out with, but maybe one of these other TKIs will. I think there’s a lot of exciting studies that need to happen in HCC to really answer some of these questions.

Ghassan K. Abou-Alfa, MD: I’m glad you bring this up in regard to the SARAH study, which is Yttrium-90 plus sorafenib. Catherine already suggested that. But can you tell us more, Ruth, about the story with TACE plus sorafenib?

A. Ruth He, MD, PhD: So, there are 2 randomized studies that have evaluated the combination of TACE plus sorafenib. And those studies turned out to be negative. I think it’s a difficult study design because it’s difficult to control how much TACE—like how many, like the vessel distribution when the TACE treatment is delivered. And also, the intervention radiologist expertise in how to give TACE treatment. So, it’s very difficult to design the study. The conclusion from the study is the combination has not generated better results.

Anthony El-Khoueiry, MD: No, I totally agree. If anything, the TACE study that was done by Dr. Lencioni was negative. Adding to this, the phase II study from the UK was negative, and we still have 1 more study to be reported, which is ECOG 1208. And you’re right, there’s a big concern about if the activation of the tumor after the TACE is really to be governed only or controlled by a TKI, or it could be a role for something else. And that something else brings me back to Anthony in regard to the combination of TACE plus a checkpoint inhibitor.

Anthony El-Khoueiry, MD: Before I answer that, can I nuance the Y-90 story from my perspective? I think the challenge we have with Y-90 is the 2 trials that Catherine mentioned, which were randomized studies of Y-90 versus systemic therapy. Those studies were designed actually as superiority trials. And so, by definition, they were actually negative studies. So, we cannot say that the survival was equivalent. It was numerically in the same range but there were not inferiority studies to say those therapies are equal in those patients.

Catherine Frenette, MD: Good point.

Anthony El-Khoueiry, MD: Yes. I think our understanding of where to fit Y-90 still has to evolve a bit more. Going back to your question. So, combining locoregional therapy with immunotherapy is something that’s gaining traction now with many trials, a lot of investigator-type initiated trials that are evolving. I think there’s a strong rationale for it. Briefly in a simplified fashion, that is the rationale that the local ablative therapy—whether it’s chemoembolization, Y-90, or ablation—can increase antigen release and stimulate the immune system even further and complement the anti—PD-1–targeting strategy. We will see if that pans out. So far, from the early data that were seen from Tim Greten at the NCI, where he combined tremelimumab, an anti–CTLA-4 antibody, with some ablative therapy, that is feasible. But we don’t have outcome data yet. But certainly, this will be something that we will see a lot of over the next few years.

Ghassan K. Abou-Alfa, MD: Absolutely, absolutely. If anything, there’s a clinical trial that’s currently ongoing of TACE plus nivolumab that we will see where it’s going to take us in regard to the safety and the practicality of that combination. But also in addition to that, there are other aspects of therapies that we did not necessarily touch on: combinations among the vaccinia virus with JX-594, which is a tyrosine kinase. It is altered and given as an intratumor injection in addition to giving sorafenib onboard, which is the Pexa-Vec study that is still ongoing. So, there’s plenty going on in that field and, as we just heard from all of us, in regard to the combination of local versus systemic therapy.

Transcript Edited for Clarity