Redefining Treatment Approaches in Advanced HCC - Episode 5

Combination Therapy for HCC Treatment

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Experts discuss recent data surrounding emerging combinations of TACE plus systemic therapies for patients with BCLC stage B or C HCC.

Richard S. Finn, MD: Laura, you and Riad Salem, MD, at Northwestern University Feinberg School of Medicine have made several pivotal contributions in the locoregional space with the use of Y-90 [yttrium-90 radioembolization]. Whether it’s Y-90 or TACE [transarterial chemoembolization], which has the evolution of systemic treatment, the data from phase 3 studies using systemic treatment in that BCLC [Barcelona Clinic Liver Cancer staging system] B population, the activity of some of the TKIs [tyrosine kinase inhibitors] and their VEGF ability, or the approval of lenvatinib in the frontline setting influenced how you practice at Northwestern, per se?

Laura M. Kulik, MD: Yes, it has. Even though we use Y-90, and we have used it in this space of advanced patients, particularly when they have V1, V2, generally not V4. We have always been of the mindset—

Richard S. Finn, MD: Sorry to interrupt. Up to V1, V2, V3 are veins within the liver in tumor invading veins, and V4 is outside the liver.

Laura M. Kulik, MD: Correct, the main portal vein. When sorafenib was the only available agent, we have then gone on to use sorafenib, which was not proven in any randomized controlled trials. More recently we have been using lenvatinib. We have been using a combination approach. I will say also that there have been increases in the amount of systemic therapy and more data in terms of who was a good candidate for not only TACE but also radioembolization.

At ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium] this year, Etienne Garin, MD, PhD, talked about the DOSISPHERE-01 trial, a randomized controlled trial in which patients received the standard dose of 120 Gy of Y-90 to the tumor vs boosting this dose to 205 Gy, while keeping the remaining liver about 120 Gy or less. They found that the objective response was around 70% in the people who had the boosted dose vs 30% in the 120 Gy arm. Overall survival was also improved. This trial may shift treatment in that if you can’t treat the patient with Y-90 in this manner because their liver function is too poor, their tumor is too large, whatever it may be—that you shouldn’t even try to treat them with Y-90 and should treat with systemic therapy instead.

There have been advances in selection that are going to help us, and the whole point of this combination—especially when you use lenvatinib as Masatoshi Kudo, MD, PhD, did, and then clean it up with TACE or Y-90—is similar to what we do with Y-90 with resection. We’re trying to minimize the amount of liver that we are either cutting out or the amount of liver that we are exposing to an agent that could cause further decline, such as radiation or hypoxemia from chemoembolization.

Richard S. Finn, MD: So far, we haven’t had positive studies using TACE in combination with systemic treatment or clearly defined sequences—TACE and then immediate systemic treatment. There’s a lot of activity. There are a lot of new drugs that have moved into that space.

Daniel, can you give us an overview of the ongoing phase 3 studies? There are probably dozens of smaller phase 1 and 2 studies, but there are several phase 3 studies that are ongoing looking at some exciting combinations with TACE.

Daniel H. Ahn, DO: In contrast to looking at combination of antiangiogenic agents with locoregional therapies, with 4 negative studies, 1 phase 2 and 3 large phase 3 studies, there’s been a shift in terms of looking at other combination strategies. One strategy that looks promising I/O [immuno-oncology] in combination with some of these locoregional therapies. The preclinical data suggest that with the use of locoregional therapies, this can potentially change the local immune microenvironment, which can have synergistic effects in combination with I/O. There are several large studies that will eventually pan out and help us better understand the role of I/O in combination with TACE or other locoregional strategies.

One of these studies is EMERALD-1, which looks at the combination of durvalumab, an anti–PD-1 inhibitor, and TACE. They did open a third exploratory arm looking at antiangiogenics in combination with anti–PD-1, so they did add an investigational arm of bevacizumab and durvalumab with TACE, and that’s currently ongoing.

There is another large international phase 3 study, TACE-3, which is the combination of nivolumab and TACE. We also have CheckMate 74W, which is looking at the combination of 2 I/O agents, nivolumab and ipilimumab, in combination with TACE. These strategies will hopefully allow us to better understand the role of I/O in combination with locoregional strategies. As many have already mentioned, can these treatment strategies potentially lead to more synergistic effects or enhance the current efficacy that we have with some of these strategies?

Richard S. Finn, MD: There’s 1 more study I want to comment on, the LEAP-012 study, a study that I’ve been involved in with Josep Llovet, and this is a study looking at pembrolizumab and lenvatinib. Like the other combinations that looked very promising in phase 2, obviously we’ve seen activity with single-agent I/O. We’re seeing what appears to be synergistic activity with I/O and either pure VEGF inhibition with bevacizumab or with a multikinase VEGF inhibitor like lenvatinib, in combination with these I/O agents that are raising the response rates in systemic disease. We’re now looking at moving into earlier-phase disease.

It will take some time for these studies to read out. There is a long natural history to the intermediate space, which has made it a challenge to study. Clearly an unmet need for our patients. We know that TACE is not curative and patients will eventually progress. I’ve always thought of this as if patients don’t die of their liver disease, if their cirrhosis isn’t that bad, eventually their tumor will come back, and it will either migrate them to advanced disease or sometimes even patients get recurrent locoregional treatments. Every time we do that, there is the cost of liver function, and that will impact what they get as far as systemic treatments. If we can’t get patients to first-line systemic treatment, we’ll never get them to second- or third-line or beyond, which is the evolving paradigm.

Transcript Edited for Clarity