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Promising Immunotherapy Agents for NSCLC

Panelists: Everett Vokes, MD, University of Chicago Medicine and Biological Sciences; Roy Herbst, MD, PhD, Yale Cancer Center; Fred Hirsch, MD, PhD, University of Colorado School of Medicine; Suresh Ramalingam, MD, Winship Cancer Institute Emory University; Naiyer Rizvi, MD, Columbia University Medical Center
Published Online: Thursday, Oct 12, 2017



Transcript: 

Everett Vokes, MD: Roy, I’d like to turn to you, again, a little bit, as somebody who’s been involved in investigational therapies throughout your career. What are new, promising single agents (immunotherapy agents), and what combinations excite you as we go forward?

Roy Herbst, MD, PhD: Sure. We want to combine, and combine in a rational way. This field is wide open. In fact, if you look at some of the data, I think there are well over 900 trials, ongoing, in the immunotherapy space. I have a slide that I use when I lecture on trials in lung cancer (about combinations of PD-1 and PD-L1), and I’m ready to make a second slide. The number is getting larger. So, there are many things moving forward.

But, of course, I think first you have ask, what’s the target? Is it present in the tumor? Or, what are you modulating? And you need to do very good careful phase I work. The way I like to think about it is, you know you have agents that can, if you look at a T cell, just focus on the T cell. They can either stimulate a T cell or are checkpoints that inhibit a T cell. So, you can imagine you could make antibodies or molecules to target both. Certainly, we’ve been working on PD-1, PD-L1—that’s a given. CTLA4, I think that’s very much in play right now. The data in melanoma are quite compelling.

Most of the trials are looking rather positive. Some, marginal. In lung cancer, we just don’t have the phase III data yet. I think, in the next year, we’ll have data from the MYSTIC trial, which I’m sure Naiyer can update us on. And we’ll see data from the CheckMate-227 trial. We know that the MYSTIC trial didn’t hit its interim analysis in progression-free survival, but it still has an overall survival, which is, of course, the ultimate endpoint, pending. So, that makes a lot of sense.

Other checkpoints to think about are LAG-3 and KIM-3. At the European Society for Medical Oncology (ESMO) 2017 Congress, there were so many groups presenting their molecules to target those other checkpoints. Then, you think about something called 4-1BB—that’s on the other end. That puts the gas on. Certainly, if you use that, you’d want to release the brake. So, that’s one of the checkpoints, but those agents are moving forward well.

Then you name it. There are targets. There are vaccines trying to stimulate neoantigens. There are personalized vaccines that are ongoing in lung cancer. There are specific antibodies. What’s that? That’s an antibody that might target an antigen on the tumor, but it also targets CD3, which is going to bring in T cells. Those are ongoing. There are early targets that are being studied.

And then there are things that are working on the immune microenvironment—adenosine and CD73 and CSF1R and looking at macrophages. A macrophage is involved in inflammation. And really, we could talk all day. And then, finally, VEGF. I think one thing that’s very interesting is, looking back at the old ECOG trial, bevacizumab plus chemotherapy. Now there are some data that I think do suggest that angiogenesis plus immune therapy does have some potential with surgery. Why? Because angiogenesis inhibitors increase blood flow to tumors, so you get more T cells in the tumor. There’s also an effect of inhibiting VEGF on improving the presentation of an antigen to the T cells with the dendritic cell mechanism.

So, I think we’re going see more of those, either with bevacizumab or with ramucirumab—ramucirumab/pembrolizumab, for example. There are so many agents. What we need to do, as investigators, is have these trials available for our patients, but also always ask, what’s the rationale for it? Are we obtaining tissue? And in that, I would recommend fresh tissue whenever possible. But tumor plasma is important to really analyze. I think we’ll slowly move forward in this way. Lung-MAP’s testing this, as we’ve talked about, and certainly other single-arm or multi-arm trials are coming from different groups.

Transcript Edited for Clarity 

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Transcript: 

Everett Vokes, MD: Roy, I’d like to turn to you, again, a little bit, as somebody who’s been involved in investigational therapies throughout your career. What are new, promising single agents (immunotherapy agents), and what combinations excite you as we go forward?

Roy Herbst, MD, PhD: Sure. We want to combine, and combine in a rational way. This field is wide open. In fact, if you look at some of the data, I think there are well over 900 trials, ongoing, in the immunotherapy space. I have a slide that I use when I lecture on trials in lung cancer (about combinations of PD-1 and PD-L1), and I’m ready to make a second slide. The number is getting larger. So, there are many things moving forward.

But, of course, I think first you have ask, what’s the target? Is it present in the tumor? Or, what are you modulating? And you need to do very good careful phase I work. The way I like to think about it is, you know you have agents that can, if you look at a T cell, just focus on the T cell. They can either stimulate a T cell or are checkpoints that inhibit a T cell. So, you can imagine you could make antibodies or molecules to target both. Certainly, we’ve been working on PD-1, PD-L1—that’s a given. CTLA4, I think that’s very much in play right now. The data in melanoma are quite compelling.

Most of the trials are looking rather positive. Some, marginal. In lung cancer, we just don’t have the phase III data yet. I think, in the next year, we’ll have data from the MYSTIC trial, which I’m sure Naiyer can update us on. And we’ll see data from the CheckMate-227 trial. We know that the MYSTIC trial didn’t hit its interim analysis in progression-free survival, but it still has an overall survival, which is, of course, the ultimate endpoint, pending. So, that makes a lot of sense.

Other checkpoints to think about are LAG-3 and KIM-3. At the European Society for Medical Oncology (ESMO) 2017 Congress, there were so many groups presenting their molecules to target those other checkpoints. Then, you think about something called 4-1BB—that’s on the other end. That puts the gas on. Certainly, if you use that, you’d want to release the brake. So, that’s one of the checkpoints, but those agents are moving forward well.

Then you name it. There are targets. There are vaccines trying to stimulate neoantigens. There are personalized vaccines that are ongoing in lung cancer. There are specific antibodies. What’s that? That’s an antibody that might target an antigen on the tumor, but it also targets CD3, which is going to bring in T cells. Those are ongoing. There are early targets that are being studied.

And then there are things that are working on the immune microenvironment—adenosine and CD73 and CSF1R and looking at macrophages. A macrophage is involved in inflammation. And really, we could talk all day. And then, finally, VEGF. I think one thing that’s very interesting is, looking back at the old ECOG trial, bevacizumab plus chemotherapy. Now there are some data that I think do suggest that angiogenesis plus immune therapy does have some potential with surgery. Why? Because angiogenesis inhibitors increase blood flow to tumors, so you get more T cells in the tumor. There’s also an effect of inhibiting VEGF on improving the presentation of an antigen to the T cells with the dendritic cell mechanism.

So, I think we’re going see more of those, either with bevacizumab or with ramucirumab—ramucirumab/pembrolizumab, for example. There are so many agents. What we need to do, as investigators, is have these trials available for our patients, but also always ask, what’s the rationale for it? Are we obtaining tissue? And in that, I would recommend fresh tissue whenever possible. But tumor plasma is important to really analyze. I think we’ll slowly move forward in this way. Lung-MAP’s testing this, as we’ve talked about, and certainly other single-arm or multi-arm trials are coming from different groups.

Transcript Edited for Clarity 
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