Multimodality Management of Advanced Liver Cancer - Episode 3

Hepatocellular Carcinoma: Antiangiogenic Therapy Options


Ghassan K. Abou-Alfa, MD, MBA: We’ll move on to another part, which we should definitely spend some time on, the whole concept of the antiangiogenic as well as the TKIs [tyrosine kinase inhibitors]. I’ll start by saying that the whole story, if you recall, started with sorafenib. At that time, the understanding was that actually it was an anti-RAF; later on it was acknowledged to be a rather soft, not necessarily the strongest, antiangiogenic, but there definitely was an antiangiogenic component.

Later on in the game, other trials came on board after a lot of effort in other studies that were sadly all negative, until we came to this new era in the last 3 years, as I mentioned in the beginning, and we have the new drug called lenvatinib. Let’s ask Tim. Tell us, what’s lenvatinib?

Tim F. Greten, MD: Lenvatinib is another multi-tyrosine kinase inhibitor that was initially was used in other cancers and then tested also in HCC [hepatocellular carcinoma]. It probably it has a stronger vascular component or anti-vascular component, I should say, than sorafenib.

Ghassan K. Abou-Alfa, MD, MBA: Fair. Mike, lenvatinib, anything intriguing in regard to the response that we can talk about, especially compared to the sorafenib?

Michael A. Morse, MD, MHS, FACP: Well, in the REFLECT trial, there was a higher response rate. Now, it’s important in reviewing the literature to realize that both modified RECIST [Response Evaluation Criteria in Solid Tumors] and RECIST are used in different clinical trials. The top line data used modified RECIST, and there was about a 42% response rate based on that, which is certainly something we were not expecting from sorafenib. There can be responses but not quite as often.

Ghassan K. Abou-Alfa, MD, MBA: Fair enough. It’s good that at least we have 2 choices of therapy now, being sorafenib and lenvatinib in first-line therapy. But then to go back to the sorafenib for a second, Catherine, it came a little bit of a surprise first, but now we are getting a better understanding. Regarding regorafenib with the conditional prior sorafenib exposure and tolerance, tell us a little bit more about that story with the RESORCE study.

Catherine Frenette, MD, FAST, AGAF: The RESORCE trial was the regorafenib in second-line, and it was specifically studied in patients who had previously tolerated sorafenib, really trying to ensure that tolerability and the ability of the patients to tolerate that second-line TKI. The patients had to have tolerated sorafenib, at least 400 mg a day for at least 20 of the last 28 days. And then they were enrolled and randomized to regorafenib versus placebo. And we did see an improvement in overall survival in that study, and there was the very interesting publication of survival from the start of sorafenib to death was 26 months with that combination. So really a breakthrough in terms of the survival that we can expect with systemic therapy. I think it really emphasized the need to maintain liver function in these patients, so that they can receive multiple lines of therapy.

Ghassan K. Abou-Alfa, MD, MBA: By all means. Now we have at least the theoretical thought that probably the resistance to sorafenib is actually led by certain activation of VEGF, and that probably it’s a better target, and IGF [insulin-like growth factor], which are better targets for regorafenib than just for sorafenib. With this said, we’ll go back to Riccardo. You have a lot of experience, actually, you led a lot of efforts in regard to sorafenib in combination with the chemoembolization. Tell us a little bit more about the idea of putting a TKI with embolization. What are your thoughts on that?

Riccardo Lencioni, MD, FSIR, EBIR: Well, one of the issues with chemoembolization is in reality, the creation of hypoxia in the tumor microenvironment is good because, of course, one of the mechanisms is ischemia. However, on the other end, this is known to upregulate several negators involved in angiogenesis, such as hypoxia-inducible factor 1-alpha and VEGF. So the idea to look for a synergistic effect from chemoembolization plus a drug that would be able to mitigate or prevent this neoangiogenic switch, which clearly is eventful in facilitating progression, was investigated in several studies. Clearly, many of them looked at the combination of TACE [transarterial chemoembolization] and sorafenib versus TACE alone but also investigating other drugs, including brivanib, orantinib. Unfortunately, the bottom line is that what looked like a nice mechanism based on preclinical data didn’t really result in a meaningful effect. Therefore, this combination was not really having such an impact in the clinical management of HCC.

Ghassan K. Abou-Alfa, MD, MBA: We’ll hold that thought because you’re bringing up a very important point. As you suggested, you are the first actually to do a combination of the TACE plus sorafenib, and there are many other efforts. And as you said, they were negative. But we’ll hold that thought because definitely we’re going to come back to it in regard to other potential combinations. Before we go there, let’s go back to the use of TKIs and especially in second-line. Tim, cabozantinib, tell us more.

Tim F. Greten, MD: Cabozantinib is a very interesting drug because it’s a c-Met inhibitor. I don’t want to bore you with all the details, but there was a lot of interest because there were some data—a lot of preclinical data but also data from biopsy—that c-Met plays an important role. There are certain groups that may respond better than others. Now in the end, we have to say this all never really played out. We had all the science, but in the end, it’s basically shown to work in the second line as an effective drug. And it’s really the first non-sorafenib-like agent, because regorafenib and sorafenib are very similar drugs. It is another TKI shown to be very effective in the second-line setting.

Ghassan K. Abou-Alfa, MD, MBA: I like what you said. Interestingly, historically, before the advent of the checkpoint inhibitors, all that we were busy with was c-Met because hepatocyte growth factor, which is a receptor for c-Met, made a lot of sense in the liver. You’re right that it would have been, and it is actually, a very highly potential target. Back to you, Mike. However, there were anti-c-Met inhibitors like, for example, tivantinib, but they didn’t make it, while cabozantinib did. Your thoughts?

Michael A. Morse, MD, MHS, FACP: Tivantinib is more narrowly Met focused. And I think the question is how much of a component does Met play here. I think the additional targeting of AXL is now getting a lot of attention. It’s not really a target that we thought much about in the past, but given that, cabozantinib does target it. And AXL has a number of activities, some of which do synergize well with the immune system and modulating the immune system. AXL downregulation in some preclinical models increases the immune response and increases autoimmunity against the tumor. I think that’s probably the issue here, that these drugs that have more broad targeting seem to be the ones that are reaching the milestone of clinical utility.

Ghassan K. Abou-Alfa, MD, MBA: I totally agree with you. We know retrospectively the tivantinib decision was to move on only with a patient with high c-Met. And they decided for themselves that a 3 to 4+, 50% expression on the immuno-stain of c-Met positivity would imply that the patient would be eligible for the study. The only thing that we did with the cabozantinib is we allowed all patients to come on, as Mike is suggesting.

Transcript Edited for Clarity