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Frontline Clinical Trials in Liver Cancer

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Anthony El-Khoueiry, MD, University of Southern California Norris Comprehensive Cancer Center; Catherine Frenette, MD, Scripps Green Hospital; A. Ruth He, MD, PhD, Georgetown University Medical Center; Riccardo Lencioni, MD, Sylvester Comprehensive Cancer Center
Published: Tuesday, Feb 27, 2018



Transcript: 

Ghassan K. Abou-Alfa, MD: I’ll go back to Catherine. We heard at the last ASCO, which was barely a year ago, that a new drug called lenvatinib was actually tested against sorafenib in a phase III trial. And the study was posted. Tell us more.

Catherine Frenette, MD: Lenvatinib is another tyrosine kinase inhibitor. It was tested, as you said, head-to-head in frontline therapy in patients with advanced HCC. It was powered as a non-inferiority trial. And as you said, it was a positive trial.

Interestingly, with the lenvatinib data, we actually found that there was a fair response rate with lenvatinib, over 20% of patients—1 in 4 patients had partial response. They also had a prolonged time-to-progression, as well as a prolonged progression-free survival. And those 3 things were actually statistically significantly superior to sorafenib.

Now interestingly, even though they had a better response rate and better time-to-progression and progression-free survival, that didn’t translate to a statistically significant prolonged overall survival of lenvatinib compared with sorafenib. So, as Anthony had stated earlier, the progression-free-survival doesn’t necessarily correlate to overall survival. But this does add another frontline option for our patients at this time.

Ghassan K. Abou-Alfa, MD: That’s great. And if anything, you know the targets of lenvatinib, including the FGF added to the PDGF and VGFR. It’s very important, probably that’s why there were certain nuances, as we agreed. It really showed that lenvatinib, after all, has a certain plus compared to the sorafenib, despite, at the end of the day, the overall survival was similar between the 2 studies. And now, Ruth, lenvatinib already is on the market for other indications, and next year will probably be FDA approved. But how would you choose between lenvatinib and sorafenib?

A. Ruth He, MD, PhD: That’s a very difficult question.

Ghassan K. Abou-Alfa, MD: That’s why I asked you.

A. Ruth He, MD, PhD: In this circumstance, usually we would look at the side effect profile and try to pick each one therapy based on the toxicity profile. But really, I believe the landscape for HCC treatment is shifting. I suspect we will have more frontline therapy options to choose and eventually, hopefully, we’ll come up with a strategy on how to pick those therapy. Currently, there’s standard strategy on how to pick either one.

Ghassan K. Abou-Alfa, MD: I might agree with you in regard to the potential for the side effects playing a role in regard to the choice. But interestingly, there are other things that can play a role as well, which is, as I was just alluding to, the actually targets that you’re going after. We didn’t really bring this up except in the beginning about remembering the etiology—and we spoke about the hepatitis B versus hepatitis C—we didn’t touch on the alpha-fetoprotein level. And I think these kinds of things might actually get the map that you are aspiring for, which will make you choose one drug versus the other. That’s totally fair.

But Anthony, to take you back to the checkpoint inhibitors, as we said, the nivolumab approval is pending to be confirmed the phase III trial in the first-line setting, which is nivolumab versus sorafenib. Tell us more about that study.

Anthony El-Khoueiry, MD: So, CheckMate-459 is actually a frontline randomized phase III study. These are previously untreated patients with advanced hepatocellular cancer—Child-Pugh A—who will be randomized to nivolumab versus the current standard of care, sorafenib. And the primary endpoint of that study is overall survival.

As far as I know, the accrual is complete and we are pending results on that study. It’s important also to note that checkpoint inhibitors are being evaluated in the phase III setting in second-line. So, that’s a phase III study of pembrolizumab versus best supportive care, also post sorafenib. That’s also I think near completion, or still accruing. But these 2 large phase III studies will provide more confidence in the early data that we’ve seen with nivolumab.

Ghassan K. Abou-Alfa, MD: Absolutely it will, and no question that so far, I’m seeing that the cutoff is between checkpoint inhibitor first, followed by TKIs, or TKI first followed by checkpoint inhibitors other than the choice of which checkpoint inhibitors to use. And, if anything, my understanding is that there is another pretty intense study that’s looking into checkpoint inhibitors, but specifically in the combination of anti–CTLA-4 and the anti–PD-L1, which I believe is called the HIMALAYA, which is combining durvalumab and tremelimumab. Can you first explain to all of us what is the synergy about combining the anti–CTLA-4 and anti–PD-L1 together? Where does this go into in regard to the immune system?

Anthony El-Khoueiry, MD: Right. What we alluded to at the beginning of the conversation is that the cancer has multiple ways by which it hides from the immune system. So, there are many immune suppressive mechanisms. The checkpoints, which are like the breaks for the T cells, are expressed on the surface of tumor cells but also on the surface of T cells and on other cells, including PD-L1, CTLA-4, and others. There are also other surface markers that are more like agonists. They’re like the gas pedals—like OX40, for example.

We now have a large number of drugs that target these various checkpoints, or agonists, to stimulate the immune system. So, the idea of combining anti–PD-L1 with anti–CTLA-4 started in other tumor types. Actually, it started in melanoma and has now evolved into other diseases. In HCC specifically, you mentioned the HIMALAYA trial, which is a phase III randomized trial of 3 arms: previously untreated patients who would be randomized to durvalumab, which is the anti-PD-L1 antibody, versus durvalumab and tremelimumab, anti–PD-L1 plus anti–CTLA-4, versus sorafenib, the current standard of care.

There is already a phase I study that was presented with the combination of durvalumab and tremelimumab, and that showed a response rate of 18%. Incidentally, something was culled out in that phase I study, that patients with no viral infection and no hepatitis B or C had a response rate of 30%. Again, we don’t know if this is a factor of just numbers or that it’s truly a difference between etiologies, because so far, we see responses across all etiologies with the checkpoint inhibitor, so we will see.

The last thing I would add is there are also important approaches that are evolving, and you may come back to in the future, that are stimulating the immune system from different angles. Because there are other cellular components and there are other cytokines that have an immune suppressive role and combining those also with checkpoint inhibitors is important in the future.

Ghassan K. Abou-Alfa, MD: Of course, I totally agree.

Transcript Edited for Clarity 

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Transcript: 

Ghassan K. Abou-Alfa, MD: I’ll go back to Catherine. We heard at the last ASCO, which was barely a year ago, that a new drug called lenvatinib was actually tested against sorafenib in a phase III trial. And the study was posted. Tell us more.

Catherine Frenette, MD: Lenvatinib is another tyrosine kinase inhibitor. It was tested, as you said, head-to-head in frontline therapy in patients with advanced HCC. It was powered as a non-inferiority trial. And as you said, it was a positive trial.

Interestingly, with the lenvatinib data, we actually found that there was a fair response rate with lenvatinib, over 20% of patients—1 in 4 patients had partial response. They also had a prolonged time-to-progression, as well as a prolonged progression-free survival. And those 3 things were actually statistically significantly superior to sorafenib.

Now interestingly, even though they had a better response rate and better time-to-progression and progression-free survival, that didn’t translate to a statistically significant prolonged overall survival of lenvatinib compared with sorafenib. So, as Anthony had stated earlier, the progression-free-survival doesn’t necessarily correlate to overall survival. But this does add another frontline option for our patients at this time.

Ghassan K. Abou-Alfa, MD: That’s great. And if anything, you know the targets of lenvatinib, including the FGF added to the PDGF and VGFR. It’s very important, probably that’s why there were certain nuances, as we agreed. It really showed that lenvatinib, after all, has a certain plus compared to the sorafenib, despite, at the end of the day, the overall survival was similar between the 2 studies. And now, Ruth, lenvatinib already is on the market for other indications, and next year will probably be FDA approved. But how would you choose between lenvatinib and sorafenib?

A. Ruth He, MD, PhD: That’s a very difficult question.

Ghassan K. Abou-Alfa, MD: That’s why I asked you.

A. Ruth He, MD, PhD: In this circumstance, usually we would look at the side effect profile and try to pick each one therapy based on the toxicity profile. But really, I believe the landscape for HCC treatment is shifting. I suspect we will have more frontline therapy options to choose and eventually, hopefully, we’ll come up with a strategy on how to pick those therapy. Currently, there’s standard strategy on how to pick either one.

Ghassan K. Abou-Alfa, MD: I might agree with you in regard to the potential for the side effects playing a role in regard to the choice. But interestingly, there are other things that can play a role as well, which is, as I was just alluding to, the actually targets that you’re going after. We didn’t really bring this up except in the beginning about remembering the etiology—and we spoke about the hepatitis B versus hepatitis C—we didn’t touch on the alpha-fetoprotein level. And I think these kinds of things might actually get the map that you are aspiring for, which will make you choose one drug versus the other. That’s totally fair.

But Anthony, to take you back to the checkpoint inhibitors, as we said, the nivolumab approval is pending to be confirmed the phase III trial in the first-line setting, which is nivolumab versus sorafenib. Tell us more about that study.

Anthony El-Khoueiry, MD: So, CheckMate-459 is actually a frontline randomized phase III study. These are previously untreated patients with advanced hepatocellular cancer—Child-Pugh A—who will be randomized to nivolumab versus the current standard of care, sorafenib. And the primary endpoint of that study is overall survival.

As far as I know, the accrual is complete and we are pending results on that study. It’s important also to note that checkpoint inhibitors are being evaluated in the phase III setting in second-line. So, that’s a phase III study of pembrolizumab versus best supportive care, also post sorafenib. That’s also I think near completion, or still accruing. But these 2 large phase III studies will provide more confidence in the early data that we’ve seen with nivolumab.

Ghassan K. Abou-Alfa, MD: Absolutely it will, and no question that so far, I’m seeing that the cutoff is between checkpoint inhibitor first, followed by TKIs, or TKI first followed by checkpoint inhibitors other than the choice of which checkpoint inhibitors to use. And, if anything, my understanding is that there is another pretty intense study that’s looking into checkpoint inhibitors, but specifically in the combination of anti–CTLA-4 and the anti–PD-L1, which I believe is called the HIMALAYA, which is combining durvalumab and tremelimumab. Can you first explain to all of us what is the synergy about combining the anti–CTLA-4 and anti–PD-L1 together? Where does this go into in regard to the immune system?

Anthony El-Khoueiry, MD: Right. What we alluded to at the beginning of the conversation is that the cancer has multiple ways by which it hides from the immune system. So, there are many immune suppressive mechanisms. The checkpoints, which are like the breaks for the T cells, are expressed on the surface of tumor cells but also on the surface of T cells and on other cells, including PD-L1, CTLA-4, and others. There are also other surface markers that are more like agonists. They’re like the gas pedals—like OX40, for example.

We now have a large number of drugs that target these various checkpoints, or agonists, to stimulate the immune system. So, the idea of combining anti–PD-L1 with anti–CTLA-4 started in other tumor types. Actually, it started in melanoma and has now evolved into other diseases. In HCC specifically, you mentioned the HIMALAYA trial, which is a phase III randomized trial of 3 arms: previously untreated patients who would be randomized to durvalumab, which is the anti-PD-L1 antibody, versus durvalumab and tremelimumab, anti–PD-L1 plus anti–CTLA-4, versus sorafenib, the current standard of care.

There is already a phase I study that was presented with the combination of durvalumab and tremelimumab, and that showed a response rate of 18%. Incidentally, something was culled out in that phase I study, that patients with no viral infection and no hepatitis B or C had a response rate of 30%. Again, we don’t know if this is a factor of just numbers or that it’s truly a difference between etiologies, because so far, we see responses across all etiologies with the checkpoint inhibitor, so we will see.

The last thing I would add is there are also important approaches that are evolving, and you may come back to in the future, that are stimulating the immune system from different angles. Because there are other cellular components and there are other cytokines that have an immune suppressive role and combining those also with checkpoint inhibitors is important in the future.

Ghassan K. Abou-Alfa, MD: Of course, I totally agree.

Transcript Edited for Clarity 
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