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Interplay Between Angiogenesis and Immunity

Panelists:Johanna C. Bendell, MD, Sarah Cannon Research Institute; Edward Garon, MD, Jonsson Comprehensive Cancer Center at UCLA; Roy Herbst, MD, Yale School of Medicine; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Manish Shah, MD, Weill Cornell Medical College; Mark Socinski, MD, University of Pittsburgh
Published: Thursday, May 05, 2016


Transcript:

Mark A. Socinski, MD:
Roy, I want to ask you, obviously I always call 2015 the year of immunotherapy in lung cancer. It was a banner year for us in lung cancer. But there’s an increasing interest in this interplay between angiogenesis and immunotherapy. I wonder if we could get your thoughts on that.

Roy S. Herbst, MD, PhD: Right. So, certainly I would agree with the others that angiogenesis clearly plays a role in all the tumor types we’re discussing. How much of a role varies. There’s never been a really good marker for angiogenesis, and it’s a redundant process. There are many mechanisms. But it’s receiving a new life in combination studies, because with immunotherapy now being the molecule of the year— a big focus at ASCO last year—this year, the question is, how can we make immunotherapy better? And one thought is that in order for checkpoint inhibitors to function, you both have to have a checkpoint in play and have the ability to inhibit that.

You also have to have T-cells, tumor infiltrating lymphocytes in the tumor. And one thing that’s been found in a number of studies, and in some that we’ve done, is that when you look at biopsies of patients who are not responding to some of these immunotherapies, you see that the T-cells don’t get to the tumor. They’re either not there at all or you can oftentimes see a rim of cells that are not getting there. So, one thought—and it’s based on some very early preclinical data… It is very hard to do these models, as you can imagine. You need to study a mouse by its very nature that’s growing a tumor. You make it immune incompetent and then you want to test the immune system. But there are data that are beginning to emerge that some of these antiangiogenic agents can actually help get the T-cells to the tumor, whether it’s through the matrix metalloproteinase inhibitors that might help breakdown the collagenase and get the T-cells in, or some of the anti-angiogenic agents like VEGF inhibitors. The same way they used to improve drug delivery by relieving vascular tension within a tumor. It’s very exciting now to think that we can now use some of these agents in combination with immune checkpoint inhibitors.

And there are trials ongoing right now, that several of us are participating in, that I think will have very nice data, one way or the other, to tell us if this is worth doing in the future.

Mark A. Socinski, MD: Yes. And, Dr. Bendell, you recently published a trial looking at combination therapy.

Johanna Bendell, MD: Yes, this is on behalf of many investigators who have been looking at a PD-L1 inhibitor, which is a different type of checkpoint inhibitor, in combination with bevacizumab. And that initial data have been published, an abstract for a presentation where we’ve looked at clinical safety about trying to combine these two together. Will we see something that we weren’t expecting? And certainly what we’ve seen is that you can give these agents safely together, and there’s certainly early clinical data. So, it’s just suggesting that there may be benefits to doing this. And I know that Dr. Herbst is running a study that’s looking at this, as well using other agents, too.

Roy S. Herbst, MD, PhD: Right. And we’ve been very impressed by the bevacizumab combinations with the drug atezolizumab, formerly known as MPDL3288. But, we are seeing, again, it’s hard to tell from single-arm trials if they’re randomized. Certainly in renal cancer it makes a lot of sense. That’s a tumor that’s driven by VEGF, but certainly in lung cancer and certainly in GI malignancies.

So, I think it’s very compelling. And we’re running a trial now, and several others are involved looking at pembrolizumab, which is a PD-1 inhibitor, plus the ramucirumab, in three tumor types—lung, gastric, and bladder—in sort of broad genitourinary cancers. And again, it’s still early. The first thing you have to do is look at combined toxicities. Can you give it? But, I think that it’s a very compelling thought, because when you look at why patients are resistant to immune therapies it is because you’re not getting the T-cells to the tumor.

Mark A. Socinski, MD: Right. Yelena, you have some.

Yelena Y. Janjigian, MD: Sure. Along the combination strategy lines and outside of VEGF-R2, HER-2 is one of the sort of biggest targets in gastric. And what makes VEGF inhibition appealing is that, by and large, it’s a very well tolerated intervention. Patients do well. Although there is some risk associated with hypertension and bleeding, it’s very manageable. And so you can build on that strategy by combinations of therapies. We have a trial starting now to explore a combination of VEGF-R2 inhibition with HER2 based on our preclinical data showing strong synergy, and the duration of response would be higher. Again, because you’re getting it, you could see it as a drug delivery system, as well, improving permeation.

Mark A. Socinski, MD: But Roy, I’m just thinking about this. Is there any reason to suspect toxicities would be an issue with combining these drugs, knowing what we know about each drug independently?

Roy S. Herbst, MD, PhD: Not offhand, but you never know.

Mark A. Socinski, MD: You have to do the studies, right?

Roy S. Herbst, MD, PhD: Right. And of course you know in lung cancer we’ve always been worried about issues with bleeding with these inhibitors. With the immune therapies, we worry most about pneumonitis, and could there be some combined activity? Perhaps. And, again, I guess it also depends on whether you’re using a small molecule to inhibit angiogenesis or an antibody. There could be some interactions. I think what I’m very excited about is here we have data on how anti-angiogenic therapies work. We’ve known that for a long time. We have reasons that are beginning to emerge as to why immune therapies are either not an active—so primary resistance—or acquired resistance that might develop. That’s actually a huge area, Mark, the fact that people are getting immune therapies and they benefit, and then they stop benefitting.

Now, a few years into this, we’re starting to all see that. So, we’re looking for combinations that are going to be tolerated that can perhaps overcome that resistance. Right now it’s a bit of speculation, some preclinical data. But certainly, there are trials that are important to do. The one thing that we’re trying to do at our place at Smilow Cancer Hospital at Yale is try to include biopsies. I’m sure the others are doing the same thing. So, really understand why these things are working or not.

Mark A. Socinski, MD: Repeat biopsies?

Roy S. Herbst, MD, PhD: Repeat biopsies. So, if in fact our hypothesis is true, that we are getting more T-cells into the tumor, let’s prove that. And you actually don’t have to prove that in the COMMA trials. We can just look at trials where people get into the agents. Like with the big phase III trial that you ran, Eddie, you could perhaps find some of the samples from that study and try to understand that, and see before and after – did the tumor infiltrating lymphocytes change in some way both in quantity and character?

Johanna Bendell, MD: One thing I would like to say really quickly is in terms of safety signals. So, certainly we haven’t seen anything in combination with the anti-angiogenic antibodies and the immune therapies. But I think Roy brought up a very important point. The small molecule tyrosine kinase inhibitors have a very different toxicity profile and may have some overlap. For instance, there could be potential liver toxicities with the small molecule tyrosine kinase inhibitors that might interact with potential hepatotoxicity from immune agents. So, I think that outside of a clinical trial I wouldn’t put those two...

Roy S. Herbst, MD, PhD: Right. I was alluding to that. You know we will present at a meeting at some point soon but, yes, small molecules—not always specific—they can have on- and off-target toxicities. And I do think the experiment has to be done. I would not do this; I would not try this at home.

Mark A. Socinski, MD: Right. So, Manish, your perspective on this area?

Manish Shah, MD: I agree with what’s been said already. I think that the nice thing about anti-angiogenic therapy is that they have broad activity. They can augment chemotherapy. They can affect the immune infiltrate and improve the activity of checkpoint inhibitors. They have multiple effects that are beneficial from an anticancer standpoint. One thing I wanted to come back to with regard to what Eddie said in lung cancer and the approval of ramucirumab in the second-line setting...So, in colon cancer it’s been demonstrated that continued anti-angiogenic blockade from first- to second-line therapy is beneficial. That was based on the TML study and another study as well. And are there data like that in lung cancer?

Edward Garon, MD: So, the data is not necessarily specifically on continued therapy. There were a percentage of patients who were on the REVEL trial who had received prior angiogenesis inhibition with bevacizumab. And so that is a group that was included and that group was evaluated, although it was only a subset of the trial. So, we don’t necessarily have analogous trials where large numbers of patients were treated with an angiogenesis inhibitor in the front-line setting and then evaluated subsequently in a rigorous fashion.

Manish Shah, MD: In colon cancer, the hazard ratio issue is about 0.8. So, there is about a 20% benefit with continuing anti-angiogenic therapy. And that gets to the preclinical data that others know about with regard to, once you’ve stopped the blockade, you get a sprouting effect of the neo-angiogenesis, and that may sort of increase the tumor growth. So, I think that’s a very interesting concept as well.

Mark A. Socinski, MD: Yes, that actually leads into the next question I was going to ask.

Transcript Edited for Clarity
Slider Left
Slider Right


Transcript:

Mark A. Socinski, MD:
Roy, I want to ask you, obviously I always call 2015 the year of immunotherapy in lung cancer. It was a banner year for us in lung cancer. But there’s an increasing interest in this interplay between angiogenesis and immunotherapy. I wonder if we could get your thoughts on that.

Roy S. Herbst, MD, PhD: Right. So, certainly I would agree with the others that angiogenesis clearly plays a role in all the tumor types we’re discussing. How much of a role varies. There’s never been a really good marker for angiogenesis, and it’s a redundant process. There are many mechanisms. But it’s receiving a new life in combination studies, because with immunotherapy now being the molecule of the year— a big focus at ASCO last year—this year, the question is, how can we make immunotherapy better? And one thought is that in order for checkpoint inhibitors to function, you both have to have a checkpoint in play and have the ability to inhibit that.

You also have to have T-cells, tumor infiltrating lymphocytes in the tumor. And one thing that’s been found in a number of studies, and in some that we’ve done, is that when you look at biopsies of patients who are not responding to some of these immunotherapies, you see that the T-cells don’t get to the tumor. They’re either not there at all or you can oftentimes see a rim of cells that are not getting there. So, one thought—and it’s based on some very early preclinical data… It is very hard to do these models, as you can imagine. You need to study a mouse by its very nature that’s growing a tumor. You make it immune incompetent and then you want to test the immune system. But there are data that are beginning to emerge that some of these antiangiogenic agents can actually help get the T-cells to the tumor, whether it’s through the matrix metalloproteinase inhibitors that might help breakdown the collagenase and get the T-cells in, or some of the anti-angiogenic agents like VEGF inhibitors. The same way they used to improve drug delivery by relieving vascular tension within a tumor. It’s very exciting now to think that we can now use some of these agents in combination with immune checkpoint inhibitors.

And there are trials ongoing right now, that several of us are participating in, that I think will have very nice data, one way or the other, to tell us if this is worth doing in the future.

Mark A. Socinski, MD: Yes. And, Dr. Bendell, you recently published a trial looking at combination therapy.

Johanna Bendell, MD: Yes, this is on behalf of many investigators who have been looking at a PD-L1 inhibitor, which is a different type of checkpoint inhibitor, in combination with bevacizumab. And that initial data have been published, an abstract for a presentation where we’ve looked at clinical safety about trying to combine these two together. Will we see something that we weren’t expecting? And certainly what we’ve seen is that you can give these agents safely together, and there’s certainly early clinical data. So, it’s just suggesting that there may be benefits to doing this. And I know that Dr. Herbst is running a study that’s looking at this, as well using other agents, too.

Roy S. Herbst, MD, PhD: Right. And we’ve been very impressed by the bevacizumab combinations with the drug atezolizumab, formerly known as MPDL3288. But, we are seeing, again, it’s hard to tell from single-arm trials if they’re randomized. Certainly in renal cancer it makes a lot of sense. That’s a tumor that’s driven by VEGF, but certainly in lung cancer and certainly in GI malignancies.

So, I think it’s very compelling. And we’re running a trial now, and several others are involved looking at pembrolizumab, which is a PD-1 inhibitor, plus the ramucirumab, in three tumor types—lung, gastric, and bladder—in sort of broad genitourinary cancers. And again, it’s still early. The first thing you have to do is look at combined toxicities. Can you give it? But, I think that it’s a very compelling thought, because when you look at why patients are resistant to immune therapies it is because you’re not getting the T-cells to the tumor.

Mark A. Socinski, MD: Right. Yelena, you have some.

Yelena Y. Janjigian, MD: Sure. Along the combination strategy lines and outside of VEGF-R2, HER-2 is one of the sort of biggest targets in gastric. And what makes VEGF inhibition appealing is that, by and large, it’s a very well tolerated intervention. Patients do well. Although there is some risk associated with hypertension and bleeding, it’s very manageable. And so you can build on that strategy by combinations of therapies. We have a trial starting now to explore a combination of VEGF-R2 inhibition with HER2 based on our preclinical data showing strong synergy, and the duration of response would be higher. Again, because you’re getting it, you could see it as a drug delivery system, as well, improving permeation.

Mark A. Socinski, MD: But Roy, I’m just thinking about this. Is there any reason to suspect toxicities would be an issue with combining these drugs, knowing what we know about each drug independently?

Roy S. Herbst, MD, PhD: Not offhand, but you never know.

Mark A. Socinski, MD: You have to do the studies, right?

Roy S. Herbst, MD, PhD: Right. And of course you know in lung cancer we’ve always been worried about issues with bleeding with these inhibitors. With the immune therapies, we worry most about pneumonitis, and could there be some combined activity? Perhaps. And, again, I guess it also depends on whether you’re using a small molecule to inhibit angiogenesis or an antibody. There could be some interactions. I think what I’m very excited about is here we have data on how anti-angiogenic therapies work. We’ve known that for a long time. We have reasons that are beginning to emerge as to why immune therapies are either not an active—so primary resistance—or acquired resistance that might develop. That’s actually a huge area, Mark, the fact that people are getting immune therapies and they benefit, and then they stop benefitting.

Now, a few years into this, we’re starting to all see that. So, we’re looking for combinations that are going to be tolerated that can perhaps overcome that resistance. Right now it’s a bit of speculation, some preclinical data. But certainly, there are trials that are important to do. The one thing that we’re trying to do at our place at Smilow Cancer Hospital at Yale is try to include biopsies. I’m sure the others are doing the same thing. So, really understand why these things are working or not.

Mark A. Socinski, MD: Repeat biopsies?

Roy S. Herbst, MD, PhD: Repeat biopsies. So, if in fact our hypothesis is true, that we are getting more T-cells into the tumor, let’s prove that. And you actually don’t have to prove that in the COMMA trials. We can just look at trials where people get into the agents. Like with the big phase III trial that you ran, Eddie, you could perhaps find some of the samples from that study and try to understand that, and see before and after – did the tumor infiltrating lymphocytes change in some way both in quantity and character?

Johanna Bendell, MD: One thing I would like to say really quickly is in terms of safety signals. So, certainly we haven’t seen anything in combination with the anti-angiogenic antibodies and the immune therapies. But I think Roy brought up a very important point. The small molecule tyrosine kinase inhibitors have a very different toxicity profile and may have some overlap. For instance, there could be potential liver toxicities with the small molecule tyrosine kinase inhibitors that might interact with potential hepatotoxicity from immune agents. So, I think that outside of a clinical trial I wouldn’t put those two...

Roy S. Herbst, MD, PhD: Right. I was alluding to that. You know we will present at a meeting at some point soon but, yes, small molecules—not always specific—they can have on- and off-target toxicities. And I do think the experiment has to be done. I would not do this; I would not try this at home.

Mark A. Socinski, MD: Right. So, Manish, your perspective on this area?

Manish Shah, MD: I agree with what’s been said already. I think that the nice thing about anti-angiogenic therapy is that they have broad activity. They can augment chemotherapy. They can affect the immune infiltrate and improve the activity of checkpoint inhibitors. They have multiple effects that are beneficial from an anticancer standpoint. One thing I wanted to come back to with regard to what Eddie said in lung cancer and the approval of ramucirumab in the second-line setting...So, in colon cancer it’s been demonstrated that continued anti-angiogenic blockade from first- to second-line therapy is beneficial. That was based on the TML study and another study as well. And are there data like that in lung cancer?

Edward Garon, MD: So, the data is not necessarily specifically on continued therapy. There were a percentage of patients who were on the REVEL trial who had received prior angiogenesis inhibition with bevacizumab. And so that is a group that was included and that group was evaluated, although it was only a subset of the trial. So, we don’t necessarily have analogous trials where large numbers of patients were treated with an angiogenesis inhibitor in the front-line setting and then evaluated subsequently in a rigorous fashion.

Manish Shah, MD: In colon cancer, the hazard ratio issue is about 0.8. So, there is about a 20% benefit with continuing anti-angiogenic therapy. And that gets to the preclinical data that others know about with regard to, once you’ve stopped the blockade, you get a sprouting effect of the neo-angiogenesis, and that may sort of increase the tumor growth. So, I think that’s a very interesting concept as well.

Mark A. Socinski, MD: Yes, that actually leads into the next question I was going to ask.

Transcript Edited for Clarity
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