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Ramucirumab After Progression in Advanced HCC

Panelists: Ghassan K. Abou-Alfa, MD, Weill Cornell Medical College; Peter Galle, MD, PhD Johannes Gutenberg University, Mainz; Riad Salem, MD, Northwestern University; Amit Singal, MD UT Southwestern Medical Center
Published: Monday, Jan 07, 2019



Transcript: 

Ghassan K. Abou-Alfa, MD: We already spoke about sorafenib. We spoke about regorafenib. We spoke about lenvatinib. We spoke about cabozantinib. We already have talked about 4 drugs. By the way, 3 are already FDA approved—sorafenib, regorafenib, and lenvatinib. Cabozantinib, of course, is going through the FDA approval process. We’ll see where it’s going to end up, but, of course, we see positive data with positive outcomes, as published in the New England Journal of Medicine. Interestingly, on top of those 4 drugs, there’s a fifth one—a TKI [tyrosine kinase inhibitor]—that was really brought into more attention at the last ASCO [American Society of Clinical Oncology] annual meeting—ramucirumab. Peter, if I recall, there was a negative study with ramucirumab. Then we know about REACH-2. Tell us the difference.

Peter Galle, MD, PhD: So ramucirumab is an antibody that interferes with the antiangiogenic pathway. It had been originally tested in the REACH trial. It was well tolerated and there was a trend for an improved overall survival for those receiving ramucirumab. However, the hazard ratio was not sufficient. In the subgroup analysis, it became apparent that those patients who had a high AFP level, specifically above 400, were benefitting more. This was not a prespecified endpoint. Therefore, REACH was clearly a negative trial. What was very interesting is that that information was then used. A second trial was set up. That’s unusual. Typically, those negative trials end the story of a drug. Here, it didn’t. There was an enrichment for patients with an AFP above 400, and it was a positive trial.

There were a couple of differences though, which is interesting. Asking for high AFP results in a different group of patients than if you take it at random. Investigators probably pushed their patients slowly over the limit of 400, and, therefore, there were some unexpected outcomes, for example, in the placebo-treated group. This group actually lived longer, resulting in not as high of an objective difference in overall survival between ramucirumab-treated and placebo-treated patients, as expected. Nevertheless, we saw a hazard ratio of 0.7-something. This was clearly a positive trial, which is nice. It’s the first trial that we have where a biomarker can be used to stratify, and it is relatively well tolerated. It’s not yet approved but is being added to our armamentarium for the second-line setting.

Ghassan K. Abou-Alfa, MD: I totally agree. To be fair, before we carry on with the discussion, the ramucirumab data was simply presented as an abstract. We have yet to see the manuscript to understand more details. Riad, is AFP really a marker for the disease?

Riad Salem, MD: Undoubtedly, we use it. It’s clearly something that I think most of us believe is a biomarker for more aggressive disease. We all fight it, but I think we all use it to follow patients. We can’t use it in studies and we can’t quantify it, but yet, we all use it.

Regarding the positive aspects of REACH-2, aside from what Peter was listing, if you notice, most of the studies that are positive—your study, Ghassan’s, etcetera—the overall survival delta is in the 3-month range. Now you’ve got a positive study, but it’s in the 1.5-month range. And so, I ask whether that is a factor for you now, statistically, by trial design? It’s positive. It’s well tolerated, and it’s a biomarker. This is fantastic. And now you’re in the 1.5-month range in terms of survival benefit. How do you digest that? Is that important to you? Is it just a positive trial, hence it should be used.? Is the magnitude of the delta worth it? I ask because I don’t know, and I ask because I’m curious about how you interpret that, in terms of what is the lowest end of the survival difference that matters to you?

Ghassan K. Abou-Alfa, MD: Absolutely, these are important points. There are many perspectives. We are dissecting an abstract report. What are your thoughts on that REACH-2 study?

Amit Singal, MD: We had talked about AFP being a prognostic biomarker. We have several studies showing that to be true. We know that in terms of the mechanism of action, AFP tends to be higher, in regard to VEGF activation. And so, in terms of the mechanism of action, in terms of this drug, it may actually provide some biological rationale.

In terms of AFP being a biomarker, my issue is that when you take a look across all trials, those high-AFP patients tend to do worse. And when you take a look at the subgroup of patients who have high AFP, all of these other therapies tend to have very similar hazard ratios. So while it’s a biomarker, my concern is that it’s not a specific biomarker that shows that ramucirumab is going to work better than the other therapies. So it doesn’t necessarily help me in terms of treatment decision making. When I think of a biomarker, I think of a biomarker that will say, “This drug works better than drug Y.” I don’t think we’re there yet.

Ghassan K. Abou-Alfa, MD: No, I totally agree. One of the arguments that’s given for REACH-2 is that at the end of the day, maybe these patients, because of the high AFP level, saw that it worked fair anyway, and that’s why the magnitude of the improvement is limited. But on the other hand, while this argument is there, I would say that we’re hearing from everybody that we’re still kind of perplexed about where to put it.
There’s still a lot to learn from this. When the manuscript comes out, we’ll hopefully learn a bit more about that. And, of course, we’ll use it accordingly and will apply it accordingly based on the interpretation at that time.

Transcript Edited for Clarity 

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Transcript: 

Ghassan K. Abou-Alfa, MD: We already spoke about sorafenib. We spoke about regorafenib. We spoke about lenvatinib. We spoke about cabozantinib. We already have talked about 4 drugs. By the way, 3 are already FDA approved—sorafenib, regorafenib, and lenvatinib. Cabozantinib, of course, is going through the FDA approval process. We’ll see where it’s going to end up, but, of course, we see positive data with positive outcomes, as published in the New England Journal of Medicine. Interestingly, on top of those 4 drugs, there’s a fifth one—a TKI [tyrosine kinase inhibitor]—that was really brought into more attention at the last ASCO [American Society of Clinical Oncology] annual meeting—ramucirumab. Peter, if I recall, there was a negative study with ramucirumab. Then we know about REACH-2. Tell us the difference.

Peter Galle, MD, PhD: So ramucirumab is an antibody that interferes with the antiangiogenic pathway. It had been originally tested in the REACH trial. It was well tolerated and there was a trend for an improved overall survival for those receiving ramucirumab. However, the hazard ratio was not sufficient. In the subgroup analysis, it became apparent that those patients who had a high AFP level, specifically above 400, were benefitting more. This was not a prespecified endpoint. Therefore, REACH was clearly a negative trial. What was very interesting is that that information was then used. A second trial was set up. That’s unusual. Typically, those negative trials end the story of a drug. Here, it didn’t. There was an enrichment for patients with an AFP above 400, and it was a positive trial.

There were a couple of differences though, which is interesting. Asking for high AFP results in a different group of patients than if you take it at random. Investigators probably pushed their patients slowly over the limit of 400, and, therefore, there were some unexpected outcomes, for example, in the placebo-treated group. This group actually lived longer, resulting in not as high of an objective difference in overall survival between ramucirumab-treated and placebo-treated patients, as expected. Nevertheless, we saw a hazard ratio of 0.7-something. This was clearly a positive trial, which is nice. It’s the first trial that we have where a biomarker can be used to stratify, and it is relatively well tolerated. It’s not yet approved but is being added to our armamentarium for the second-line setting.

Ghassan K. Abou-Alfa, MD: I totally agree. To be fair, before we carry on with the discussion, the ramucirumab data was simply presented as an abstract. We have yet to see the manuscript to understand more details. Riad, is AFP really a marker for the disease?

Riad Salem, MD: Undoubtedly, we use it. It’s clearly something that I think most of us believe is a biomarker for more aggressive disease. We all fight it, but I think we all use it to follow patients. We can’t use it in studies and we can’t quantify it, but yet, we all use it.

Regarding the positive aspects of REACH-2, aside from what Peter was listing, if you notice, most of the studies that are positive—your study, Ghassan’s, etcetera—the overall survival delta is in the 3-month range. Now you’ve got a positive study, but it’s in the 1.5-month range. And so, I ask whether that is a factor for you now, statistically, by trial design? It’s positive. It’s well tolerated, and it’s a biomarker. This is fantastic. And now you’re in the 1.5-month range in terms of survival benefit. How do you digest that? Is that important to you? Is it just a positive trial, hence it should be used.? Is the magnitude of the delta worth it? I ask because I don’t know, and I ask because I’m curious about how you interpret that, in terms of what is the lowest end of the survival difference that matters to you?

Ghassan K. Abou-Alfa, MD: Absolutely, these are important points. There are many perspectives. We are dissecting an abstract report. What are your thoughts on that REACH-2 study?

Amit Singal, MD: We had talked about AFP being a prognostic biomarker. We have several studies showing that to be true. We know that in terms of the mechanism of action, AFP tends to be higher, in regard to VEGF activation. And so, in terms of the mechanism of action, in terms of this drug, it may actually provide some biological rationale.

In terms of AFP being a biomarker, my issue is that when you take a look across all trials, those high-AFP patients tend to do worse. And when you take a look at the subgroup of patients who have high AFP, all of these other therapies tend to have very similar hazard ratios. So while it’s a biomarker, my concern is that it’s not a specific biomarker that shows that ramucirumab is going to work better than the other therapies. So it doesn’t necessarily help me in terms of treatment decision making. When I think of a biomarker, I think of a biomarker that will say, “This drug works better than drug Y.” I don’t think we’re there yet.

Ghassan K. Abou-Alfa, MD: No, I totally agree. One of the arguments that’s given for REACH-2 is that at the end of the day, maybe these patients, because of the high AFP level, saw that it worked fair anyway, and that’s why the magnitude of the improvement is limited. But on the other hand, while this argument is there, I would say that we’re hearing from everybody that we’re still kind of perplexed about where to put it.
There’s still a lot to learn from this. When the manuscript comes out, we’ll hopefully learn a bit more about that. And, of course, we’ll use it accordingly and will apply it accordingly based on the interpretation at that time.

Transcript Edited for Clarity 
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