TACE and Systemic Therapy in HCC

Richard S. Finn, MD: With that in mind, it’s a good segue into our evolving role of TACE [transarterial chemoembolization] with systemic treatments. Is the whole BCLC [Barcelona Clinic Liver Cancer staging system] going to shift to the left, in that we’re going to offer patients systemic treatment earlier? Dan, how do you see the paradigm evolving that way and in your practice?

Daneng Li, MD: That’s a great question, and I think there are multiple areas we have to consider. As our treatment armamentarium gets bigger and bigger, we need to determine whether combination strategies are the appropriate way, in terms of combining newer systemic therapies that we are seeing have impressive response rates in the advanced setting, and translating it into the BCLC stage B setting with TACE vs TACE. There are several ongoing trials looking at that combination.

Secondly, I think the other role is to say that it is time to take systemic treatment vs TACE. As you mentioned, TACE was done in an era when we didn’t have many systemic treatments. And as our systemic treatment options get better and better and the response rates get higher and higher, is it time to go up against TACE in that intermediate stage, and see whether there’s a benefit? There’s some rationale that systemic therapy can preserve liver function much better compared with TACE over time, so that might be beneficial for patients.

Finally, I think there’s the role of sequential therapy. As I mentioned before, there is this idea of whether incomplete TACE can induce hypoxia and increase angiogenesis, so is there a way to prime the tumor with systemic therapy so that patients can get additional benefit with TACE? I think that’s going to be very important.

Amit mentioned the study with Masatoshi Kudo, MD, PhD, that compares lenvatinib with TACE for those patients who have bulky tumors, and those are definitely patients who can benefit. In that trial, about 62% of patients in the lenvatinib arm, while there was tumor necrosis, went on to receive TACE, interestingly. The patients who had CRs [complete responses] were those patients who were primed with lenvatinib and then sequentially received TACE. There may be a role for that, to prime the liver tumor from an antiangiogenic perspective, and then treat it with TACE.

Richard S. Finn, MD: That’s an interesting idea that’s been around for some time. We know that TACE induces ischemia and embolizes the tumor, and ischemia is a very potent driver of VEGF expression and secretion, and that was the rationale for looking at many VEGF inhibitors in liver cancer, especially in combination with TACE.

Josep, there have been 5, 6 TACE/systemic treatment studies to date. Most of them have concentrated on sorafenib, and then there was a study with brivanib, which never finished because the brivanib program was shut down eventually. At ASCO GI [the American Society of Clinical Oncology Gastrointestinal Cancers Symposium] this year and the year prior, we saw another study with sorafenib, the TACTICS study, which looked a little different than the others. Can you comment on this idea that Dan brought up about using VEGF receptor inhibitors, whether its sorafenib, lenvatinib, cabozantinib, regorafenib, ramucirumab, in this population?

Josep M. Llovet, MD: Yes. There are 2 issues here you are bringing up. One is when to introduce systemic therapies in patients in the intermediate stage, and the other question is should we do that in combination with TACE, or as a combination of systemic therapies, for instance, without TACE? To the first question, I would say that the trials as you know have all been negative. All the phase 3 trials, and there are not many, even fewer phase 2 trials, have been mostly negative. These trials are not providing enough robust data to establish that as a treatment of choice.

Therefore, what is going to change the role of systemic therapies is the introduction of immune therapies in the intermediate setting. The role of antiangiogenic agents will also be a stage to boost the immune response. It’s like what happened with bevacizumab, what happened with lenvatinib, as we already know, all these combinations are boosting immunity. Twenty percent, 25%, of patients may respond to a single agent, but certainly you are broadening that. This is amazing.

We are broadening the population, not only in terms of objective response, but in terms of disease control rate, up to 90% of the patients in advanced disease, with these combinations. So, this concept is what I think is going to switch the field of intermediate stage. In my view, enough attempts have been made for the combination of TACE with a single-agent antiangiogenic. It’s not flying, and I think that what’s going to fly is the testing of immune response.

The second question is what about all these patients who are not responding? There is a switch; there is a migration. Certainly, I think this is a critical point because when sorafenib was the only systemic therapy, there were no other locational efforts to, let’s say, educate physicians to treat the patients with systemic therapy upon progression with TACE, and these efforts never fly. Now without any effort, the physician is already convinced with the data that are out there, that upon progression with TACE, you have 3 lines of systemic therapy. You can start with atezolizumab-bevacizumab, and follow with sorafenib, or the other treatment options, you can use lenvatinib. The physician is now confident to treat patients who progress after TACE with systemic therapy, and this is growing.

Transcript Edited for Clarity