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NSCLC: Mechanisms of Resistance to Antiangiogenic Therapy

Insights From: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; Ronald J. Scheff, MD, Weill Cornell Medical College; Ann Tsao, MD, MD Anderson Cancer Center
Published: Thursday, May 03, 2018



Transcript: 

Ronald J. Scheff, MD: I don’t know that we know these specific mechanisms of resistance to anti-angiogenesis therapy. We do know that, as with all the drugs that we use in non–small cell lung cancer, resistance does occur and is problematic. I think what’s interesting and important is that we know from the REVEL trial that in patients whose disease is resistant to antiangiogenesis therapy in the first-line setting, typically using bevacizumab, those patients may respond to ramucirumab in the second-line. And there are differences in the antibodies. Bevacizumab targets VEGF and ramucirumab targets VEGF receptor 2.

Benjamin P. Levy, MD: We don’t have a very clear picture of what’s truly in play in terms of mechanisms of resistance for antiangiogenic strategies. Similarly, we don’t have a real clear picture for mechanisms of resistance for immunotherapy. I think we’re still trying to learn what’s really going on when patients’ tumors progress either on an antiangiogenic drug or even immunotherapy. There have been some data looking at continuing antiangiogenic drugs beyond progression. So, there was a trial called the AvaALL trial that evaluated continuing bevacizumab beyond progression and adding it to subsequent lines of therapy, even in the setting of progression, compared to just adding a subsequent line of therapy.

In that trial, unfortunately, we did not see any benefit in terms of overall survival. So, I think what we can glean from this is that when patients’ tumors are progressing on an antiangiogenic drug, if you’re ready to make a therapeutic switch and you think the patient needs a therapeutic switch, there’s no role for continuing the antiangiogenic drug. I think you just need to switch, and we just don’t know what’s really happening mechanistically in that tumor in terms of its resistant patterns. This is certainly an area of preclinical research and trying to better understand scientifically what’s happening to the tumor.

Ann Tsao, MD: Our current frontline regimen allows bevacizumab in the frontline setting, which is a monoclonal antibody to the ligand VEGF. So, it takes VEGF out of circulation. It’s possible that going to a salvage therapy using a VEGF receptor tyrosine kinase inhibitor, or monoclonal antibody, could potentially be beneficial for our patients by switching up the mechanism by targeting the receptor instead of the ligand. So, this is an area of research that needs to be pursued further, but in clinical practice, we do see that there are patients who benefit from this.

Transcript Edited for Clarity 
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Transcript: 

Ronald J. Scheff, MD: I don’t know that we know these specific mechanisms of resistance to anti-angiogenesis therapy. We do know that, as with all the drugs that we use in non–small cell lung cancer, resistance does occur and is problematic. I think what’s interesting and important is that we know from the REVEL trial that in patients whose disease is resistant to antiangiogenesis therapy in the first-line setting, typically using bevacizumab, those patients may respond to ramucirumab in the second-line. And there are differences in the antibodies. Bevacizumab targets VEGF and ramucirumab targets VEGF receptor 2.

Benjamin P. Levy, MD: We don’t have a very clear picture of what’s truly in play in terms of mechanisms of resistance for antiangiogenic strategies. Similarly, we don’t have a real clear picture for mechanisms of resistance for immunotherapy. I think we’re still trying to learn what’s really going on when patients’ tumors progress either on an antiangiogenic drug or even immunotherapy. There have been some data looking at continuing antiangiogenic drugs beyond progression. So, there was a trial called the AvaALL trial that evaluated continuing bevacizumab beyond progression and adding it to subsequent lines of therapy, even in the setting of progression, compared to just adding a subsequent line of therapy.

In that trial, unfortunately, we did not see any benefit in terms of overall survival. So, I think what we can glean from this is that when patients’ tumors are progressing on an antiangiogenic drug, if you’re ready to make a therapeutic switch and you think the patient needs a therapeutic switch, there’s no role for continuing the antiangiogenic drug. I think you just need to switch, and we just don’t know what’s really happening mechanistically in that tumor in terms of its resistant patterns. This is certainly an area of preclinical research and trying to better understand scientifically what’s happening to the tumor.

Ann Tsao, MD: Our current frontline regimen allows bevacizumab in the frontline setting, which is a monoclonal antibody to the ligand VEGF. So, it takes VEGF out of circulation. It’s possible that going to a salvage therapy using a VEGF receptor tyrosine kinase inhibitor, or monoclonal antibody, could potentially be beneficial for our patients by switching up the mechanism by targeting the receptor instead of the ligand. So, this is an area of research that needs to be pursued further, but in clinical practice, we do see that there are patients who benefit from this.

Transcript Edited for Clarity 
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