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Emerging Multikinase Inhibitors in HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, UCLA; Laura M. Kulik, MD, Northwestern University Feinberg School of Medicine; R. Kate Kelley, MD, University of California-San Francisco; Riad Salem, MD, Northwestern University Feinberg School of Medicine
Published: Tuesday, Mar 28, 2017



Transcript:

Ghassan K. Abou-Alfa, MD:
There is still a lot going on in regard to antiangiogenics. Let’s talk about 2 multikinases—one of them is lenvatinib in first-line, and the other is ramucirumab, especially in the high elevated alpha-fetoprotein. Can you tell us about both, Richard?

Richard S. Finn, MD: Yes. Lenvatinib is a multi-targeted kinase inhibitor, not too dissimilar from sorafenib in its kinase profile—a very potent VEGF inhibitor. It has shown significant activity in thyroid cancer, where it has an indication, and, now, there are recent data in renal cancer as well.

Many years ago, a phase III study was launched comparing sorafenib to lenvatinib in the frontline setting. This was an open-label study and it was driven like many of the studies in frontline cancer—based on a relatively small phase II experience. About 35 to 40 patients had a very provocative overall survival in the 15- to 17-month range, which is not a number we’ve seen in frontline, in general. It was somewhat of a mixed population of patients, but, needless to say, it justified further exploration. We should know, in the near future, the results of that frontline study.

You also alluded to the study with ramucirumab. Different from the molecules we’ve talked about so far today, ramucirumab is a monoclonal antibody to the VEGF receptor. It has had proven activity in gastric cancer, colon cancer, and also lung cancer. And the question of its role in liver cancer was based on some early phase II data—again, a small, single-agent experience even before the sorafenib approval—that had an interesting frontline survival of around 15 months. Needless to say, a second-line, large placebo-controlled study was conducted, and that actually was a negative study. There was no benefit to ramucirumab over placebo in that phase III study. However, there was a pretty strong biomarker effort to try to identify a group of patients that benefit. It has been demonstrated that those patients, who had a baseline elevated alpha fetoprotein in their serum of greater than 400, were the group of patients who did get a survival benefit. Interestingly, for those patients who had an AFP less than 400, placebo—and those that got ramucirumab—had a median survival of around 11 months. The curves completely overlapped. However, in those patients who had a high baseline AFP, again, similar to the MET story, high AFP is a poor prognostic factor. But it also identified a group of patients—it wasn’t a small group, it was about 100 patients per arm—that received a survival advantage with the addition of ramucirumab.

With that data in hand, there has been a very strong commitment to pursuing that data in another phase III study. This study is ongoing, and for patients who progress on frontline therapy with sorafenib, they are being randomized to placebo or ramucirumab intravenously only if they have a high AFP. That is an inclusion criteria. Again, a smarter way, maybe, of developing drugs in liver cancer, which is still to be proven, may be in selecting a group of patients who you think have a greater chance of benefit from receiving treatment.

Transcript Edited for Clarity

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Transcript:

Ghassan K. Abou-Alfa, MD:
There is still a lot going on in regard to antiangiogenics. Let’s talk about 2 multikinases—one of them is lenvatinib in first-line, and the other is ramucirumab, especially in the high elevated alpha-fetoprotein. Can you tell us about both, Richard?

Richard S. Finn, MD: Yes. Lenvatinib is a multi-targeted kinase inhibitor, not too dissimilar from sorafenib in its kinase profile—a very potent VEGF inhibitor. It has shown significant activity in thyroid cancer, where it has an indication, and, now, there are recent data in renal cancer as well.

Many years ago, a phase III study was launched comparing sorafenib to lenvatinib in the frontline setting. This was an open-label study and it was driven like many of the studies in frontline cancer—based on a relatively small phase II experience. About 35 to 40 patients had a very provocative overall survival in the 15- to 17-month range, which is not a number we’ve seen in frontline, in general. It was somewhat of a mixed population of patients, but, needless to say, it justified further exploration. We should know, in the near future, the results of that frontline study.

You also alluded to the study with ramucirumab. Different from the molecules we’ve talked about so far today, ramucirumab is a monoclonal antibody to the VEGF receptor. It has had proven activity in gastric cancer, colon cancer, and also lung cancer. And the question of its role in liver cancer was based on some early phase II data—again, a small, single-agent experience even before the sorafenib approval—that had an interesting frontline survival of around 15 months. Needless to say, a second-line, large placebo-controlled study was conducted, and that actually was a negative study. There was no benefit to ramucirumab over placebo in that phase III study. However, there was a pretty strong biomarker effort to try to identify a group of patients that benefit. It has been demonstrated that those patients, who had a baseline elevated alpha fetoprotein in their serum of greater than 400, were the group of patients who did get a survival benefit. Interestingly, for those patients who had an AFP less than 400, placebo—and those that got ramucirumab—had a median survival of around 11 months. The curves completely overlapped. However, in those patients who had a high baseline AFP, again, similar to the MET story, high AFP is a poor prognostic factor. But it also identified a group of patients—it wasn’t a small group, it was about 100 patients per arm—that received a survival advantage with the addition of ramucirumab.

With that data in hand, there has been a very strong commitment to pursuing that data in another phase III study. This study is ongoing, and for patients who progress on frontline therapy with sorafenib, they are being randomized to placebo or ramucirumab intravenously only if they have a high AFP. That is an inclusion criteria. Again, a smarter way, maybe, of developing drugs in liver cancer, which is still to be proven, may be in selecting a group of patients who you think have a greater chance of benefit from receiving treatment.

Transcript Edited for Clarity
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