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Emerging c-MET 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: Thursday, Mar 23, 2017



Transcript:

Ghassan K. Abou-Alfa, MD:
No doubt that with regorafenib, we’re not laying in our arms and being comfortable. But there’s a lot going on in regard to the field, and this, again, by the way, is good news for the patients before anybody else. With this, I would like to go over a few drugs. Tell us where things are going. There are 2 c-MET inhibitors still awaiting reporting. Let’s start with the tivantinib from Richard’s standpoint.

Richard S. Finn, MD: To your previous question about individualizing treatment, the clinical study with tivantinib is probably the first biomarker-directed study in advanced HCC, as far as identifying a predictive marker. Tivantinib is an oral, small molecule, non-ATP competitive inhibitor of c-MET—c-MET being the hepatocyte growth factor receptor. It has a long history of data suggesting it’s important in driving the development of liver cancer. It’s not a far stretch considering its ligand is hepatocyte growth factor. And what was interesting about the development of tivantinib is they did a randomized phase II study versus placebo in second-line, which, by and large, was a negative study showing that tivantinib really did not improve survival significantly over placebo.

However, retrospectively in a preplanned analysis, they looked at patients who had high c-MET expression in their tumor by immunohistochemistry. And in those patients who were defined as c-MET low, again, there was no benefit to tivantinib. But in a subset that had high c-MET expression, not only did the control group do very poorly—so high c-MET was a poor prognostic factor—but it also predicted for benefit to tivantinib. Meaning, if you’re high c-MET and you got tivantinib, you did better than the placebo group that was high c-MET. So that was the basis for a confirmatory study.

The randomized, placebo-controlled METIV-HCC study was a phase III study randomizing patients 2:1 between tivantinib or placebo for patients who had a biopsy specimen that showed that they had high c-MET expression. The results of this study are eagerly awaited. It has completed accrual, and I think we should hear about those results shortly. If positive, it will be the first new generation type of study in liver cancer where, like in other diseases, we’re using a biomarker to select patients to get treated.

Ghassan K. Abou-Alfa, MD: I’m definitely voicing a very important appeal for biopsies and checking on the markers and what have we. And here we go: we are both involved in cabozantinib and we are not necessarily keen on that c-MET expression as being a driver for. Tell us about the cabozantinib story.

R. Kate Kelley, MD: Cabozantinib is another multikinase inhibitor that is now approved for use in thyroid cancer as well as renal cell carcinoma. And its principle targets, like sorafenib and regorafenib and its other family members, include VEGFR2 and VEGFR3. But it also has some unique targets including c-MET and several others like RET and AXL. In other tumor types, the expression of c-MET in tumor tissue in paraffin blocks or tumor that’s been collected prior to the start of a study hasn’t really shown a clear relationship with response. That’s in renal cell or in thyroid cancer; in liver cancer, we don’t know yet. But the principle is that there are multiple ways that this drug is potentially inhibiting growth and that c-MET alone may not be the only expression required.

The phase II data of cabozantinib, where a little over 40 patients were treated in a phase II study, they showed pretty encouraging overall survival greater than 11 months in greater than first-line patients—so largely in a second-line population. So that’s prompted a multinational ongoing randomized phase III trial, which we’re hoping will report sometime in the next year or 2, as well and potentially give us another interesting agent to add to the mix here for liver cancer.

Ghassan K. Abou-Alfa, MD: Fascinating that we have, here on the table, 2 drugs, which really are both multikinases with c-MET. One of them is going in a population with 50% 3 to 4+ expression of c-MET while the other, being cabozantinib, is going across the board, understood as being a multikinase with, of course, an interest in c-MET, but not necessarily putting a mark in regard to how much expression. Time will tell. This is really just the fascinating part about what we do day-to-day.

Transcript Edited for Clarity

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Transcript:

Ghassan K. Abou-Alfa, MD:
No doubt that with regorafenib, we’re not laying in our arms and being comfortable. But there’s a lot going on in regard to the field, and this, again, by the way, is good news for the patients before anybody else. With this, I would like to go over a few drugs. Tell us where things are going. There are 2 c-MET inhibitors still awaiting reporting. Let’s start with the tivantinib from Richard’s standpoint.

Richard S. Finn, MD: To your previous question about individualizing treatment, the clinical study with tivantinib is probably the first biomarker-directed study in advanced HCC, as far as identifying a predictive marker. Tivantinib is an oral, small molecule, non-ATP competitive inhibitor of c-MET—c-MET being the hepatocyte growth factor receptor. It has a long history of data suggesting it’s important in driving the development of liver cancer. It’s not a far stretch considering its ligand is hepatocyte growth factor. And what was interesting about the development of tivantinib is they did a randomized phase II study versus placebo in second-line, which, by and large, was a negative study showing that tivantinib really did not improve survival significantly over placebo.

However, retrospectively in a preplanned analysis, they looked at patients who had high c-MET expression in their tumor by immunohistochemistry. And in those patients who were defined as c-MET low, again, there was no benefit to tivantinib. But in a subset that had high c-MET expression, not only did the control group do very poorly—so high c-MET was a poor prognostic factor—but it also predicted for benefit to tivantinib. Meaning, if you’re high c-MET and you got tivantinib, you did better than the placebo group that was high c-MET. So that was the basis for a confirmatory study.

The randomized, placebo-controlled METIV-HCC study was a phase III study randomizing patients 2:1 between tivantinib or placebo for patients who had a biopsy specimen that showed that they had high c-MET expression. The results of this study are eagerly awaited. It has completed accrual, and I think we should hear about those results shortly. If positive, it will be the first new generation type of study in liver cancer where, like in other diseases, we’re using a biomarker to select patients to get treated.

Ghassan K. Abou-Alfa, MD: I’m definitely voicing a very important appeal for biopsies and checking on the markers and what have we. And here we go: we are both involved in cabozantinib and we are not necessarily keen on that c-MET expression as being a driver for. Tell us about the cabozantinib story.

R. Kate Kelley, MD: Cabozantinib is another multikinase inhibitor that is now approved for use in thyroid cancer as well as renal cell carcinoma. And its principle targets, like sorafenib and regorafenib and its other family members, include VEGFR2 and VEGFR3. But it also has some unique targets including c-MET and several others like RET and AXL. In other tumor types, the expression of c-MET in tumor tissue in paraffin blocks or tumor that’s been collected prior to the start of a study hasn’t really shown a clear relationship with response. That’s in renal cell or in thyroid cancer; in liver cancer, we don’t know yet. But the principle is that there are multiple ways that this drug is potentially inhibiting growth and that c-MET alone may not be the only expression required.

The phase II data of cabozantinib, where a little over 40 patients were treated in a phase II study, they showed pretty encouraging overall survival greater than 11 months in greater than first-line patients—so largely in a second-line population. So that’s prompted a multinational ongoing randomized phase III trial, which we’re hoping will report sometime in the next year or 2, as well and potentially give us another interesting agent to add to the mix here for liver cancer.

Ghassan K. Abou-Alfa, MD: Fascinating that we have, here on the table, 2 drugs, which really are both multikinases with c-MET. One of them is going in a population with 50% 3 to 4+ expression of c-MET while the other, being cabozantinib, is going across the board, understood as being a multikinase with, of course, an interest in c-MET, but not necessarily putting a mark in regard to how much expression. Time will tell. This is really just the fascinating part about what we do day-to-day.

Transcript Edited for Clarity
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