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Advances in Systemic Therapy for HCC

Panelists:Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, Geffen School of Medicine; Riccardo Lencioni, MD, Sylvester Comprehensive Cancer Center; Amit Singal, MD, UT Southwestern Medical Center
Published: Monday, Jul 11, 2016


Transcript:

Ghassan K. Abou-Alfa, MD:
Richard, I’ll go back to you now. No doubt we spoke about that kind of lull, but they’re still ongoing. Tell me a little bit more. What’s happening in the c-Met world?

Richard Finn, MD: So, c-Met—or the hepatocyte growth factor receptor—is felt to play an important role in liver regeneration, in normal liver biology. And as a receptor tyrosine kinase—like EGFR, like HER2, or like FGFR—it is implicated as being an oncogene. C-Met inhibitors have been around for a while, both kinase inhibitors and antibodies. They’ve been pursued in gastric cancer—in lung cancer first—and have failed. However, the story of liver cancer is still ongoing, and it’s an exciting area, largely because if you look at how the other drugs were developed, the c-Met inhibitor—at least tivantinib—has been developed initially in the second-line setting on a randomized phase II study, which was generally negative: tivantinib versus placebo.

But, retrospectively, they went back and saw that patients who had elevated c-Met expression by immunohistochemistry actually had an improvement in OS; it was a small number. They found that patients who had high c-Met expression actually had a worse prognosis, and there were data presented at the GI ASCO meeting also supporting that.

There’s been the idea that c-Met expression, or upregulation of c-Met, plays a role in sorafenib resistance. And, therefore, a very large randomized phase III study has been completed, and the results are awaited. That is now taking tissue biopsy and enrolling patients that only have elevated c-Met expression and then randomizing them to tivantinib or placebo. The results are awaited. This is a very important study because it would be the first biomarker, predictive marker–therapy in liver cancer, should the study be positive.

Ghassan K. Abou-Alfa, MD: Well, I have to say that, here, I’m not taking a bet, but it’s fascinating. No doubt we agree that there is a prognostic value probably for c-Met—which needs still to be deciphered as part of phase III trials—but this is where tivantinib actually has been only offered, for patients with more than 50% IHC 3+ to 4+ c-Met expression. While in the other study of cabozantinib, we took a different approach, where pretty much we’re treating everybody because of the multikinase component of the drug. Time will tell, but, obviously, these are very two valuable studies that are really ongoing. Other things that are ongoing, ADI-PEG 20—which is the arginine deamination formulated with polyethylene glycol and depriving the cells of arginine—and there is regorafenib, which is pretty much a multikinase inhibitor, as well, with a great study still ongoing in the second-line setting. But I would like to really finish up by talking about what we all talk about—the elephant in the room—immunotherapy.

Transcript Edited for Clarity
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Transcript:

Ghassan K. Abou-Alfa, MD:
Richard, I’ll go back to you now. No doubt we spoke about that kind of lull, but they’re still ongoing. Tell me a little bit more. What’s happening in the c-Met world?

Richard Finn, MD: So, c-Met—or the hepatocyte growth factor receptor—is felt to play an important role in liver regeneration, in normal liver biology. And as a receptor tyrosine kinase—like EGFR, like HER2, or like FGFR—it is implicated as being an oncogene. C-Met inhibitors have been around for a while, both kinase inhibitors and antibodies. They’ve been pursued in gastric cancer—in lung cancer first—and have failed. However, the story of liver cancer is still ongoing, and it’s an exciting area, largely because if you look at how the other drugs were developed, the c-Met inhibitor—at least tivantinib—has been developed initially in the second-line setting on a randomized phase II study, which was generally negative: tivantinib versus placebo.

But, retrospectively, they went back and saw that patients who had elevated c-Met expression by immunohistochemistry actually had an improvement in OS; it was a small number. They found that patients who had high c-Met expression actually had a worse prognosis, and there were data presented at the GI ASCO meeting also supporting that.

There’s been the idea that c-Met expression, or upregulation of c-Met, plays a role in sorafenib resistance. And, therefore, a very large randomized phase III study has been completed, and the results are awaited. That is now taking tissue biopsy and enrolling patients that only have elevated c-Met expression and then randomizing them to tivantinib or placebo. The results are awaited. This is a very important study because it would be the first biomarker, predictive marker–therapy in liver cancer, should the study be positive.

Ghassan K. Abou-Alfa, MD: Well, I have to say that, here, I’m not taking a bet, but it’s fascinating. No doubt we agree that there is a prognostic value probably for c-Met—which needs still to be deciphered as part of phase III trials—but this is where tivantinib actually has been only offered, for patients with more than 50% IHC 3+ to 4+ c-Met expression. While in the other study of cabozantinib, we took a different approach, where pretty much we’re treating everybody because of the multikinase component of the drug. Time will tell, but, obviously, these are very two valuable studies that are really ongoing. Other things that are ongoing, ADI-PEG 20—which is the arginine deamination formulated with polyethylene glycol and depriving the cells of arginine—and there is regorafenib, which is pretty much a multikinase inhibitor, as well, with a great study still ongoing in the second-line setting. But I would like to really finish up by talking about what we all talk about—the elephant in the room—immunotherapy.

Transcript Edited for Clarity
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