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Emerging Novel Combinations 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: Wednesday, Jan 09, 2019



Transcript: 

Ghassan K. Abou-Alfa, MD: We are really not done, with regard to checkpoint inhibitors. We have really focused quite a bit on anti–PD-1 [programmed cell death protein 1] therapy. There is also anti-CTLA4 therapy, and now we have a new study, the HIMALAYA study, which I’m honored to chair, but I would love to hear your thoughts on it.

Amit Singal, MD: Yes. For those who don’t know, the HIMALAYA trial is evaluating single-agent immunotherapy versus dual agents. It looks at combining PD-1 and CTLA4. To Peter’s point, it’s not just single-agent immunotherapy. It’s really looking at doublets, triplets, etc, in terms of seeing if we can take that 15% and improve response rates with PD-1 and CTLA4. Can we lengthen the survival? And so, the HIMALAYA trial is evaluating this combination as dual agents versus a single agent versus sorafenib. I think that there’s a lot of hope that this will boost these response rates and the survival even further. So we’ll see what they show.

Ghassan K. Abou-Alfa, MD: Absolutely. The HIMALAYA study is really dependent on the fact that a lot of the anti-CTLA4 activity will happen at the lymph node levels. And then the activation of the immune system, at this point, will come to the antitumor effect of the tumor, per se, followed by the anti–PD-1, where the combination might really play a major role. The HIMALAYA study is a very large study looking at 2 variants of the combination of the durvalumab and tremelimumab versus single-agent durvalumab as the standard of care. So we’ll see where this take us. Riad, I am not trying to steal the show here from all of the great stuff in interventional radiology. At the ASCO [American Society of Clinical Oncology] Annual Meeting, there was a poster presented on the combination of atezolizumab plus bevacizumab with a response rate of close to 70%.

Riad Salem, MD: Yes. I’ve done my homework. I’ve read the abstract, and that’s, unfortunately, as you know, the source of some of this data. About 30 or so patients were reported and only about 20 or 21…

Ghassan K. Abou-Alfa, MD: Yes, I think there were about 53 patients, and they reported on 23. Exactly.

Riad Salem, MD: Yes, 23 of them were valuable, and of those, there was about a 70% response rate. So again, one has to wonder what happened to those other ones? Maybe it’s not follow-up? There could be many reasons. Having said that, again, I think what’s exciting about this is the message that I hear regarding this response rate. That’s the common theme. People are seeing very high response rates, and they want to combine these.

My history with treating with bevacizumab has been less than impressive, with adverse events that were unacceptable. So it’s interesting to see sort of a reintroduction of bevacizumab in this field. But the team from Yale has reported on this, and again, they are very excited about the response rates. Again, this is just an abstract forum.

Ghassan K. Abou-Alfa, MD: So let’s talk a little about the science. Peter, is there any scientific argument for why a combination of a TKI [tyrosine kinase inhibitor] and a checkpoint inhibitor will make sense?

Peter Galle, MD, PhD: With this particular combination, antiangiogenesis with a monoclonal antibody and immune-oncology makes more sense than you would believe at first glance. The point is that antiangiogenesis has dramatically changed in our scientific understanding. Initially, we felt that this shut off the blood supply and that the tumor had no nutrients.

Then we learned it’s above shutting off blood supply. It’s normalizing vasculature. So the vessels become normalized. Now we understand that it’s actually interfering with the immune system. Aspects such as antigen representation and endothelial function in the immune system are also addressed by antiangiogenesis. So we are altering, in a complex way, the micromilieu of the tumor. The other thing is, you cannot predict. These are 2 substances: bevacizumab and atezolizumab. As a single agent, both have been relatively unremarkable. They have not been very active. In combination, these are the best results we have ever seen, on a small scale.
So I think there is a rationale. It’s a complex change of the tumor micromilieu, and that is increasingly coming to attention as the backbone of future treatment.

Ghassan K. Abou-Alfa, MD: Fair enough. Amit, tell us a little about that data that Riad mentioned on atezolizumab plus bevacizumab. The response rates were actually based on about half of the patients on the study. Tell us what your thoughts are.

Amit Singal, MD: Yes. They required people to have 16 weeks of assessment before they reported in. And so you really end up with half of the sample, in terms of taking a look at these response rates. You have to wonder if the response rates in the other patients who weren’t included in the abstract are just as promising or if this is a very select group of patients. Like all of these other abstracts, in an early form the data are promising. The FDA is giving this breakthrough therapy designation in the United States, so this really pushes this forward. And now IMbrave150 is ongoing. But I think that it’s too early to say that this is going to be it. At the end of the day, this is a select subgroup of a relatively small number of patients. I think we have to wait for larger data.

Riad Salem, MD: In fact, could I add 1 thing to what Amit is saying? One of the observations I’ve made with these anti-VEGF inhibitors is a transient reduction in flow in the tumor. You call a response because it’s less vascular, but once discontinued, in a month, 6 weeks, that very same area is reperfused and revascularized. So I do think this area is prime for studying the response concept. In this case, regarding vascularity, there can be transient changes. I’ve seen patients stop using sorafenib. All of a sudden, the vascularity is back within 4 weeks. But yet we call something response and necrosis, meaning it’s dead. But then it’s alive 4 weeks later. This is very important.

Peter Galle, MD, PhD: If I may add to that, Riad, this is extremely important. What was promising, though, was that the assessment in the combination was done by RECIST [Response Evaluation Criteria In Solid Tumors] 1.1 but not by modified. So they were trying to pay attention to this temporary lack of perfusion, which was not meaningful in terms of response.

Ghassan K. Abou-Alfa, MD: So if anything, we are hearing quite a bit about this. Clearly we can see the excitement. If anything, looking at the combination of a TKI and a checkpoint inhibitor, we really don’t have the full understanding of that. We have notions, and we heard them from both sides of the table.

On the other hand, as Amit mentioned, if we could not assess that specific patient, we can’t include that in the interpretation of the results. This is definitely a bit debatable. Nonetheless, this is still a disease in need of new therapies. I think the advent of this combination and several endless numbers of combinations is important. This is already in a phase III trial, but we have lenvatinib plus pembrolizumab, nivolumab plus sorafenib, etc, etc.

There are different options evolving. We should not forget about the PHOCUS study that Peter and I are involved in, which really is trying to look into the vaccinia virus intratumoral injection that really has its own first direct cell lysis.

No. 2 is in an immunogenic effect added to an antivascular effect added to a combination with sorafenib. This is in addition to the other advent, which was already approved in the European markets. Here we see a certain frequency of wavelength through a better-operated machine. Patients put this over their tongue, and it will ultimately destroy the tumor.

And now there’s already chit-chat and debate about combining it with X, Y, or Z. There’s quite a bit going on, which is really fascinating. We remain very positive about the potential opportunities for patients over here.

Transcript Edited for Clarity 

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Transcript: 

Ghassan K. Abou-Alfa, MD: We are really not done, with regard to checkpoint inhibitors. We have really focused quite a bit on anti–PD-1 [programmed cell death protein 1] therapy. There is also anti-CTLA4 therapy, and now we have a new study, the HIMALAYA study, which I’m honored to chair, but I would love to hear your thoughts on it.

Amit Singal, MD: Yes. For those who don’t know, the HIMALAYA trial is evaluating single-agent immunotherapy versus dual agents. It looks at combining PD-1 and CTLA4. To Peter’s point, it’s not just single-agent immunotherapy. It’s really looking at doublets, triplets, etc, in terms of seeing if we can take that 15% and improve response rates with PD-1 and CTLA4. Can we lengthen the survival? And so, the HIMALAYA trial is evaluating this combination as dual agents versus a single agent versus sorafenib. I think that there’s a lot of hope that this will boost these response rates and the survival even further. So we’ll see what they show.

Ghassan K. Abou-Alfa, MD: Absolutely. The HIMALAYA study is really dependent on the fact that a lot of the anti-CTLA4 activity will happen at the lymph node levels. And then the activation of the immune system, at this point, will come to the antitumor effect of the tumor, per se, followed by the anti–PD-1, where the combination might really play a major role. The HIMALAYA study is a very large study looking at 2 variants of the combination of the durvalumab and tremelimumab versus single-agent durvalumab as the standard of care. So we’ll see where this take us. Riad, I am not trying to steal the show here from all of the great stuff in interventional radiology. At the ASCO [American Society of Clinical Oncology] Annual Meeting, there was a poster presented on the combination of atezolizumab plus bevacizumab with a response rate of close to 70%.

Riad Salem, MD: Yes. I’ve done my homework. I’ve read the abstract, and that’s, unfortunately, as you know, the source of some of this data. About 30 or so patients were reported and only about 20 or 21…

Ghassan K. Abou-Alfa, MD: Yes, I think there were about 53 patients, and they reported on 23. Exactly.

Riad Salem, MD: Yes, 23 of them were valuable, and of those, there was about a 70% response rate. So again, one has to wonder what happened to those other ones? Maybe it’s not follow-up? There could be many reasons. Having said that, again, I think what’s exciting about this is the message that I hear regarding this response rate. That’s the common theme. People are seeing very high response rates, and they want to combine these.

My history with treating with bevacizumab has been less than impressive, with adverse events that were unacceptable. So it’s interesting to see sort of a reintroduction of bevacizumab in this field. But the team from Yale has reported on this, and again, they are very excited about the response rates. Again, this is just an abstract forum.

Ghassan K. Abou-Alfa, MD: So let’s talk a little about the science. Peter, is there any scientific argument for why a combination of a TKI [tyrosine kinase inhibitor] and a checkpoint inhibitor will make sense?

Peter Galle, MD, PhD: With this particular combination, antiangiogenesis with a monoclonal antibody and immune-oncology makes more sense than you would believe at first glance. The point is that antiangiogenesis has dramatically changed in our scientific understanding. Initially, we felt that this shut off the blood supply and that the tumor had no nutrients.

Then we learned it’s above shutting off blood supply. It’s normalizing vasculature. So the vessels become normalized. Now we understand that it’s actually interfering with the immune system. Aspects such as antigen representation and endothelial function in the immune system are also addressed by antiangiogenesis. So we are altering, in a complex way, the micromilieu of the tumor. The other thing is, you cannot predict. These are 2 substances: bevacizumab and atezolizumab. As a single agent, both have been relatively unremarkable. They have not been very active. In combination, these are the best results we have ever seen, on a small scale.
So I think there is a rationale. It’s a complex change of the tumor micromilieu, and that is increasingly coming to attention as the backbone of future treatment.

Ghassan K. Abou-Alfa, MD: Fair enough. Amit, tell us a little about that data that Riad mentioned on atezolizumab plus bevacizumab. The response rates were actually based on about half of the patients on the study. Tell us what your thoughts are.

Amit Singal, MD: Yes. They required people to have 16 weeks of assessment before they reported in. And so you really end up with half of the sample, in terms of taking a look at these response rates. You have to wonder if the response rates in the other patients who weren’t included in the abstract are just as promising or if this is a very select group of patients. Like all of these other abstracts, in an early form the data are promising. The FDA is giving this breakthrough therapy designation in the United States, so this really pushes this forward. And now IMbrave150 is ongoing. But I think that it’s too early to say that this is going to be it. At the end of the day, this is a select subgroup of a relatively small number of patients. I think we have to wait for larger data.

Riad Salem, MD: In fact, could I add 1 thing to what Amit is saying? One of the observations I’ve made with these anti-VEGF inhibitors is a transient reduction in flow in the tumor. You call a response because it’s less vascular, but once discontinued, in a month, 6 weeks, that very same area is reperfused and revascularized. So I do think this area is prime for studying the response concept. In this case, regarding vascularity, there can be transient changes. I’ve seen patients stop using sorafenib. All of a sudden, the vascularity is back within 4 weeks. But yet we call something response and necrosis, meaning it’s dead. But then it’s alive 4 weeks later. This is very important.

Peter Galle, MD, PhD: If I may add to that, Riad, this is extremely important. What was promising, though, was that the assessment in the combination was done by RECIST [Response Evaluation Criteria In Solid Tumors] 1.1 but not by modified. So they were trying to pay attention to this temporary lack of perfusion, which was not meaningful in terms of response.

Ghassan K. Abou-Alfa, MD: So if anything, we are hearing quite a bit about this. Clearly we can see the excitement. If anything, looking at the combination of a TKI and a checkpoint inhibitor, we really don’t have the full understanding of that. We have notions, and we heard them from both sides of the table.

On the other hand, as Amit mentioned, if we could not assess that specific patient, we can’t include that in the interpretation of the results. This is definitely a bit debatable. Nonetheless, this is still a disease in need of new therapies. I think the advent of this combination and several endless numbers of combinations is important. This is already in a phase III trial, but we have lenvatinib plus pembrolizumab, nivolumab plus sorafenib, etc, etc.

There are different options evolving. We should not forget about the PHOCUS study that Peter and I are involved in, which really is trying to look into the vaccinia virus intratumoral injection that really has its own first direct cell lysis.

No. 2 is in an immunogenic effect added to an antivascular effect added to a combination with sorafenib. This is in addition to the other advent, which was already approved in the European markets. Here we see a certain frequency of wavelength through a better-operated machine. Patients put this over their tongue, and it will ultimately destroy the tumor.

And now there’s already chit-chat and debate about combining it with X, Y, or Z. There’s quite a bit going on, which is really fascinating. We remain very positive about the potential opportunities for patients over here.

Transcript Edited for Clarity 
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