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Clinical Rationale for Cabozantinib in HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, Geffen School of Medicine at UCLA; Masatoshi Kudo, MD, PhD, Kindai University Faculty of Medicine; Arndt Vogel, MD, Hannover Medical School
Published: Tuesday, Oct 02, 2018



Transcript: 

Ghassan K. Abou-Alfa, MD: Richard, you mentioned that already, of course, it’s nice to have options. But there are way too many. So, if anything, I do remember that tivantinib—which is another multi-TKI with c-MET inhibition, similar to the cabozantinib—was in a phase III trial, but it was negative. Why was the tivantinib negative, and why was the cabozantinib positive?

Richard S. Finn, MD: Well, they are different molecules. Cabozantinib, I think, has probably a little broader kinase profile. I think the main question for us is, is c-MET an important target in liver cancer? The data that drove the tivantinib study were retrospective look. It was an all-comer study in the second-line setting. And when they looked at c-MET expression by immunohistochemistry, those patients had a worse prognosis, and they did better with tivantinib. And that was the basis for the phase III study, and that phase III study attempted to use a biomarker, immunohistochemistry, and it failed.

And one of the biggest failures is that the control arm did much better than anyone expected. And I think it raises the question of at least measuring c-MET by immunohistochemistry—is that a meaningful measurement? We know that there are genomic changes in c-MET in liver cancer that are amplified, and maybe that’s the group that’s really c-MET driven and should be selected for targeting. But I think that we can say that by immunohistochemistry, that does not hold up as a robust biomarker for response. Why was this study positive versus the other? I think the biggest thing is the molecule. I think the molecule is different, and they didn’t focus on a false biomarker.

Ghassan K. Abou-Alfa, MD: I totally agree. If anything, really, my humble contribution to this study—which was really in great collaboration and really came with the same thoughts with the sponsor—is that we clearly understood that what was interpreted as being c-MET activation, which was measured in the tivantinib study at 50%, 3+ to 4+ expression on the immunostaining, would not be a requirement to get on the study. Tivantinib required that, so they really just took highly selected patients with high c-MET expression, whereas in the cabozantinib study, it was for all-comers. And this is really an important component, which, of course, was further solidified by exactly what Dr. Finn was saying: the high value and the broad aspect of that multi-TKI, and we’re definitely very impressed about the positive results of that drug. I would like to ask, Masatoshi—any experience or any perception in regard to cabozantinib from Japan?

Masatoshi Kudo, MD, PhD: With cabozantinib, unfortunately, Japan cannot join the global study. The company did not invite…

Ghassan K. Abou-Alfa, MD: Don’t worry.

Richard S. Finn, MD: Don’t take it personally.

Masatoshi Kudo, MD, PhD: But the Japanese company has a license now, and it’s now about to start a bridging phase II study. So, after finishing that trial, then I believe that we can use it—use cabozantinib.

Ghassan K. Abou-Alfa, MD: That’s great. It’s good to be excited about it—that’s great. Last point. This is fascinating: If anything, we have sorafenib; we have also lenvatinib, which we’re waiting for the approval; we have the regorafenib already FDA approved; nivolumab, with conditional approval in the United States at least for now; and we have cabozantinib. This is really moving from 1 drug to 5 drugs in literally barely 1 year. That’s really quite impressive. And, with this said, as we already heard from Rich, as well, there’s more to come. And the question is, the ramucirumab—we don’t have the data yet, but what’s the story with the high AFP and why, out of nothing, there is a press release saying this is a positive study? What’s your expectation or thoughts?

Arndt Vogel, MD: So, I think the ramucirumab data are also very interesting. The REACH study, which looked at the efficacy of ramucirumab in HCC in the second-line setting, was a negative trial. But they did a retrospective analysis, and they have found that in patients with high AFP levels, the cutoff was 400 ng/mL. But they had a poor survival on the placebo arm, 4.2 months, and when they were treated with ramucirumab, it was improved to 7.8 months—so, clearly a significant improvement. On the other hand, patients with a lower AFP level had a good median overall survival of around 1 year, and this was not further improved by ramucirumab. Based on these data, they started the REACH-2 study.

We have now a press release indicating that ramucirumab is significantly better than placebo in this group of patients with a high AFP value. But what we also have thought already is that the control arm in this REACH-2 study was much better compared with the REACH-1 study. And there are already some indications that the median AFP level was lower in the control arm of the REACH-2 study. So, I think we really need to have a further discussion on the value of AFP. And what I think is really clear is that it’s a highly prognostic marker, most likely not just in second-line therapy but also in first-line therapy. And maybe we really need to look more in detail at the efficacy of all these different drugs in this high-AFP-level patient group, so we can decide which drug might be the best possible drug.

Ghassan K. Abou-Alfa, MD: Well, of course, and we’ll wait for that data. And, of course, this was a nice reminder of the nice data that we heard from Dr. Kudo in regard to lenvatinib, as well.

Transcript Edited for Clarity 

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Transcript: 

Ghassan K. Abou-Alfa, MD: Richard, you mentioned that already, of course, it’s nice to have options. But there are way too many. So, if anything, I do remember that tivantinib—which is another multi-TKI with c-MET inhibition, similar to the cabozantinib—was in a phase III trial, but it was negative. Why was the tivantinib negative, and why was the cabozantinib positive?

Richard S. Finn, MD: Well, they are different molecules. Cabozantinib, I think, has probably a little broader kinase profile. I think the main question for us is, is c-MET an important target in liver cancer? The data that drove the tivantinib study were retrospective look. It was an all-comer study in the second-line setting. And when they looked at c-MET expression by immunohistochemistry, those patients had a worse prognosis, and they did better with tivantinib. And that was the basis for the phase III study, and that phase III study attempted to use a biomarker, immunohistochemistry, and it failed.

And one of the biggest failures is that the control arm did much better than anyone expected. And I think it raises the question of at least measuring c-MET by immunohistochemistry—is that a meaningful measurement? We know that there are genomic changes in c-MET in liver cancer that are amplified, and maybe that’s the group that’s really c-MET driven and should be selected for targeting. But I think that we can say that by immunohistochemistry, that does not hold up as a robust biomarker for response. Why was this study positive versus the other? I think the biggest thing is the molecule. I think the molecule is different, and they didn’t focus on a false biomarker.

Ghassan K. Abou-Alfa, MD: I totally agree. If anything, really, my humble contribution to this study—which was really in great collaboration and really came with the same thoughts with the sponsor—is that we clearly understood that what was interpreted as being c-MET activation, which was measured in the tivantinib study at 50%, 3+ to 4+ expression on the immunostaining, would not be a requirement to get on the study. Tivantinib required that, so they really just took highly selected patients with high c-MET expression, whereas in the cabozantinib study, it was for all-comers. And this is really an important component, which, of course, was further solidified by exactly what Dr. Finn was saying: the high value and the broad aspect of that multi-TKI, and we’re definitely very impressed about the positive results of that drug. I would like to ask, Masatoshi—any experience or any perception in regard to cabozantinib from Japan?

Masatoshi Kudo, MD, PhD: With cabozantinib, unfortunately, Japan cannot join the global study. The company did not invite…

Ghassan K. Abou-Alfa, MD: Don’t worry.

Richard S. Finn, MD: Don’t take it personally.

Masatoshi Kudo, MD, PhD: But the Japanese company has a license now, and it’s now about to start a bridging phase II study. So, after finishing that trial, then I believe that we can use it—use cabozantinib.

Ghassan K. Abou-Alfa, MD: That’s great. It’s good to be excited about it—that’s great. Last point. This is fascinating: If anything, we have sorafenib; we have also lenvatinib, which we’re waiting for the approval; we have the regorafenib already FDA approved; nivolumab, with conditional approval in the United States at least for now; and we have cabozantinib. This is really moving from 1 drug to 5 drugs in literally barely 1 year. That’s really quite impressive. And, with this said, as we already heard from Rich, as well, there’s more to come. And the question is, the ramucirumab—we don’t have the data yet, but what’s the story with the high AFP and why, out of nothing, there is a press release saying this is a positive study? What’s your expectation or thoughts?

Arndt Vogel, MD: So, I think the ramucirumab data are also very interesting. The REACH study, which looked at the efficacy of ramucirumab in HCC in the second-line setting, was a negative trial. But they did a retrospective analysis, and they have found that in patients with high AFP levels, the cutoff was 400 ng/mL. But they had a poor survival on the placebo arm, 4.2 months, and when they were treated with ramucirumab, it was improved to 7.8 months—so, clearly a significant improvement. On the other hand, patients with a lower AFP level had a good median overall survival of around 1 year, and this was not further improved by ramucirumab. Based on these data, they started the REACH-2 study.

We have now a press release indicating that ramucirumab is significantly better than placebo in this group of patients with a high AFP value. But what we also have thought already is that the control arm in this REACH-2 study was much better compared with the REACH-1 study. And there are already some indications that the median AFP level was lower in the control arm of the REACH-2 study. So, I think we really need to have a further discussion on the value of AFP. And what I think is really clear is that it’s a highly prognostic marker, most likely not just in second-line therapy but also in first-line therapy. And maybe we really need to look more in detail at the efficacy of all these different drugs in this high-AFP-level patient group, so we can decide which drug might be the best possible drug.

Ghassan K. Abou-Alfa, MD: Well, of course, and we’ll wait for that data. And, of course, this was a nice reminder of the nice data that we heard from Dr. Kudo in regard to lenvatinib, as well.

Transcript Edited for Clarity 
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