R. Kate Kelley, MD: With the advent of so much progress in advanced disease, another common question that we’re facing is, what is happening in locoregional therapy? And this may differ regionally and globally, actually. I guess one question for you is, how do you perceive all of this progress in the advanced setting to impact upon what we do in locoregional therapy for earlier stages of disease?

Josep Llovet, MD, PhD: First of all, after sorafenib, all the scientists and physician-scientists involved in the field and all the companies were thinking about second-line treatment. But, after the second-line drugs are used, there is no third-line trial. This is happening because what we are now focusing on is improving the frontline. Once we improve the frontline, once we have either a drug or a combination of drugs that actually are significantly better than sorafenib and lenvatinib, de facto sorafenib and lenvatinib will move as second line. And those in second-line de facto will move at the third-line. And at the same time, if you have now, with the combination therapies, outstanding data, it may so happen that these data are already competitive with chemoembolization that is the standard of care at the intermediate stage.

So we have some preliminary data with the lenvatinib-pembrolizumab combination and atezolizumab-bevacizumab, with objective response between 30%, 40%, 45%, which now sounds very appealing for advanced HCC [hepatocellular carcinoma]. TACE [transarterial chemoembolization] achieves an objective response of 50% to 60% in intermediate, so we don’t know of these combinations what may bring to intermediate stage. But, certainly, what I envision is that if these combinations are effective in frontline, not only will that have an impact in the lines of therapy in advanced, but it also will be able to treat intermediate HCC [hepatocellular carcinoma], either in combination with chemoembolization or even as single agent head-to-head.

R. Kate Kelley, MD: It also brings to mind the OPTIMA study I saw from Dr. Kudo et al from the 2018 ASCO [American Society of Clinical Oncology] Annual Meeting, showing that response. The best data we have for TACE, in part from your work in the early 2000s, was really in just frontline TACE with just the first TACE exposure. And I thought the Kudo data were interesting from the oncology perspective, now that we have later lines, to see that the efficacy of TACE has a significant decrement. The more TACEs that a patient receives, the response rate seems to decline somewhat in a retrospective registry study. And the toxicity likewise inversely seems to increase with subsequent exposure, which stands to reason, given that there is toxicity to the background liver with each incident. But I guess it really is incumbent upon us to try to study this better now that we have more tools at our disposal.

Arndt Vogel, MD, PhD: In general, in HCC we can use locoregional and systemic therapies, and this is, I think, the most important point about the treatment of HCC, because they have many different disciplines involved in the Tumor Board and we need to decide together whether a patient receives locoregional therapies or systemic therapies. Locoregional therapies include surgery; treatment from the interventional radiologist, like TACE for example; or radiofrequency ablation, and then we have the systemic therapies for patients with more advanced disease.

In general, we have guidelines that recommend for which patient we should use which treatment. And for patients in which the tumor is basically just in the liver without vascular infiltration and if the tumor is not too big, we usually recommend locoregional therapies. And then it depends on many things like tumor size and number of tumors and liver function for which patient gets which therapy. If the tumor is too big or if you have vascular infiltration, we usually would recommend today systemic therapy.

Masatoshi Kudo, MD, PhD: In Asia-based practice for advanced HCC, systemic therapy is the standard of care. However, in Asia, the transarterial embolization is frequently performed for advanced HCC with vascular invasion. And in Japan, specifically in Japan, for patients with advanced HCC with the vascular invasion, arterial infusion chemotherapy is frequently performed. Otherwise, locoregional therapy is not performed on advanced HCC.

Transcript Edited for Clarity