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Combination Strategies With VEGF-Targeted Therapy in NSCLC

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: Monday, May 07, 2018



Transcript: 

Benjamin P. Levy, MD: The future is bright for antiangiogenic drugs. We now see that adding antiangiogenic drugs to chemotherapy and immunotherapy in a 4-drug regimen has led to meaningful improvements in survival from the IMpower150 trial. Looking forward, I see 2 real areas that may bear fruit. One is adding antiangiogenic drugs to targeted therapy, and we’ve seen with adding bevacizumab to erlotinib that there’s an improvement in response rate and progression-free survival. We’re still waiting for the overall survival from that data. There are ongoing trials adding bevacizumab to alectinib, an ALK-directed therapy. So, I think in the genotype world, there is some scientific rationale of adding an antiangiogenic drug to a targeted therapy, and we’ll have to see where the clinical data set out.

The other area is adding antiangiogenic drugs to immunotherapy, and, of course, this was looked at in the 4-drug regimen from IMpower150. But there are ongoing trials with ramucirumab being added to pembrolizumab and ramucirumab being added to other immunotherapies. Bevacizumab is being added as well. And there’s a lot of preclinical rationale to do this. We know that VEGF fosters an immunosuppressive environment, and if we can target VEGF all along giving immunotherapy, there may be some real synergy here. The VEGF targeting may allow for a more less-immunosuppressive environment, which may allow the immunotherapy to work better. I think there’s a lot of promise. I look forward to the data with combination strategies looking at antiangiogenic drugs with checkpoint inhibitors.

Ronald J. Scheff, MD: Checkpoint inhibitors are a new category of anti-cancer treatment that is very exciting and very important, making use of T cells in the immune system to attack cancer cells. It turns out that the VEGF pathway, the angiogenesis pathway, is involved in immunosuppression. So, the VEGF pathways lead to elaboration of factors that will inhibit T cells and will increase Treg cells, and so by inhibiting the VEGF pathway, we’re actually enhancing the immune effect against the tumor. So, it makes sense that using these drugs together should be studied because the checkpoint inhibitors help the immune system attack the cancer. And by fighting the angiogenesis pathways, we can also enhance the body’s immune response to cancer cells.

Ann Tsao, MD: One of the most important studies that will be coming out this year will be the IMpower150 trial. And this is a trial looking at carboplatin/paclitaxel/bevacizumab with atezolizumab. That is one of the arms. They then compared it with carboplatin/Taxol (paclitaxel)/atezolizumab and then also carboplatin/paclitaxel/bevacizumab. Now in a press release that has come out recently, they have reported that progression-free survival is significantly better with the quadruplet regimen. So, there is clearly some benefit here, and we’ll have to choose our patients and figure out who are the ones that will benefit the most from a quadruplet frontline regimen.

Obviously, one of the clearest pathways for it in terms of research would be looking at combining checkpoint inhibitors with antiangiogenics. And the thought of this is that if you target both the immune system with your checkpoint inhibitors, and then also the vascular pathway with your antiangiogenic inhibitors, you may get a synergistic benefit. And indeed, we’ve seen with the IMpower150 that this may definitely be the case.

Ronald J. Scheff, MD: There’s an important trial from Japan that was published in Lancet Oncology in 2014 in which patients with non–small cell lung cancer that was EGFR-mutated were randomized to receive erlotinib in frontline treatment versus erlotinib plus bevacizumab. And the data from that trial are very important because it shows an impressive progression-free survival advantage with the addition of bevacizumab to erlotinib. We’re still waiting for overall survival data, which should be available in the near future, but particularly if overall survival turns out to be enhanced by the addition of bevacizumab, this, in my view, could possibly become the new standard of care in treating EGFR-mutated non–small cell lung cancer. Again, right now we have improved progression-free survival, based on this clinical trial, with the addition of bevacizumab to erlotinib. So, it’s an important and exciting avenue of research right now.

Transcript Edited for Clarity 
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Transcript: 

Benjamin P. Levy, MD: The future is bright for antiangiogenic drugs. We now see that adding antiangiogenic drugs to chemotherapy and immunotherapy in a 4-drug regimen has led to meaningful improvements in survival from the IMpower150 trial. Looking forward, I see 2 real areas that may bear fruit. One is adding antiangiogenic drugs to targeted therapy, and we’ve seen with adding bevacizumab to erlotinib that there’s an improvement in response rate and progression-free survival. We’re still waiting for the overall survival from that data. There are ongoing trials adding bevacizumab to alectinib, an ALK-directed therapy. So, I think in the genotype world, there is some scientific rationale of adding an antiangiogenic drug to a targeted therapy, and we’ll have to see where the clinical data set out.

The other area is adding antiangiogenic drugs to immunotherapy, and, of course, this was looked at in the 4-drug regimen from IMpower150. But there are ongoing trials with ramucirumab being added to pembrolizumab and ramucirumab being added to other immunotherapies. Bevacizumab is being added as well. And there’s a lot of preclinical rationale to do this. We know that VEGF fosters an immunosuppressive environment, and if we can target VEGF all along giving immunotherapy, there may be some real synergy here. The VEGF targeting may allow for a more less-immunosuppressive environment, which may allow the immunotherapy to work better. I think there’s a lot of promise. I look forward to the data with combination strategies looking at antiangiogenic drugs with checkpoint inhibitors.

Ronald J. Scheff, MD: Checkpoint inhibitors are a new category of anti-cancer treatment that is very exciting and very important, making use of T cells in the immune system to attack cancer cells. It turns out that the VEGF pathway, the angiogenesis pathway, is involved in immunosuppression. So, the VEGF pathways lead to elaboration of factors that will inhibit T cells and will increase Treg cells, and so by inhibiting the VEGF pathway, we’re actually enhancing the immune effect against the tumor. So, it makes sense that using these drugs together should be studied because the checkpoint inhibitors help the immune system attack the cancer. And by fighting the angiogenesis pathways, we can also enhance the body’s immune response to cancer cells.

Ann Tsao, MD: One of the most important studies that will be coming out this year will be the IMpower150 trial. And this is a trial looking at carboplatin/paclitaxel/bevacizumab with atezolizumab. That is one of the arms. They then compared it with carboplatin/Taxol (paclitaxel)/atezolizumab and then also carboplatin/paclitaxel/bevacizumab. Now in a press release that has come out recently, they have reported that progression-free survival is significantly better with the quadruplet regimen. So, there is clearly some benefit here, and we’ll have to choose our patients and figure out who are the ones that will benefit the most from a quadruplet frontline regimen.

Obviously, one of the clearest pathways for it in terms of research would be looking at combining checkpoint inhibitors with antiangiogenics. And the thought of this is that if you target both the immune system with your checkpoint inhibitors, and then also the vascular pathway with your antiangiogenic inhibitors, you may get a synergistic benefit. And indeed, we’ve seen with the IMpower150 that this may definitely be the case.

Ronald J. Scheff, MD: There’s an important trial from Japan that was published in Lancet Oncology in 2014 in which patients with non–small cell lung cancer that was EGFR-mutated were randomized to receive erlotinib in frontline treatment versus erlotinib plus bevacizumab. And the data from that trial are very important because it shows an impressive progression-free survival advantage with the addition of bevacizumab to erlotinib. We’re still waiting for overall survival data, which should be available in the near future, but particularly if overall survival turns out to be enhanced by the addition of bevacizumab, this, in my view, could possibly become the new standard of care in treating EGFR-mutated non–small cell lung cancer. Again, right now we have improved progression-free survival, based on this clinical trial, with the addition of bevacizumab to erlotinib. So, it’s an important and exciting avenue of research right now.

Transcript Edited for Clarity 
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