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Blocking VEGFR2 vs VEGFA or VEGFB in Lung Cancer

Insights From: Joachim G. Aerts, MD, PhD, Erasmus Medical Center Cancer Institute; Enriqueta Felip, MD, PhD, Vall d’Hebron University Hospital; Marina Garassino, MD, National Cancer Institute of Milan; Roy Herbst, MD, Yale School of Medicine
Published: Wednesday, Dec 28, 2016


Transcript:

Enriqueta Felip, MD, PhD:
In the situation of bevacizumab in first line, the development has been in only nonsquamous histology due to the fact that the phase II trials show hemoptysis in patients with squamous cell carcinoma. In the case of nintedanib, in the randomized trial comparing nintedanib plus the docetaxel or nintedanib plus placebo, there are differences in overall survival for the subgroup of adenocarcinoma, but not for the subgroup of squamous cell carcinoma. This is different in the REVEL trial, the ramucirumab trial. Both subgroups benefited from the addition of ramucirumab, nonsquamous and squamous. And, the toxicity was no different between the two histology subgroups.

Marina Garassino, MD: Both of the strategies are active to control non–small cell lung cancer. However, they are different. One strategy is binding the ligand; the other strategy is binding the receptor. We have one clinical aspect that can explain the situation. That is that ramucirumab is the only drug active both in squamous and in nonsquamous. And we know that VEGFR2 maybe is the key receptor for all of the process of angiogenesis. So, maybe targeting the VEGF receptor 2 can be a more active strategy, but it’s only an idea. There are no clear data on that.

Joachim G. Aerts, MD, PhD: Ramucirumab blocks the VEGFR2 receptor. While, for instance, bevacizumab works on circulating VEGF. You block it at the cellular level with ramucirumab. And, we don’t know exactly what are the differences, but we see differences in how it works and how it can also be affective beyond its effect on the tumor cells. So, let’s look at myeloid cells. The immunosuppressive cells, which can also become endothelial cells, also have this receptor on their surface. Besides the effect directly on tumor growth, or tumor cells, or the endothelial cells, it also has an effect on the immune system. Ramucirumab is a VEGFR-2 blocker, it blocks the receptor there. And, we have to keep in mind, that all different kinds of VEGF antiangiogenic agents all have a different way of acting on the endothelial cells, but also on other cells. So, these VEGFR-2 receptors, for instance, also present on immune cells. It could be that by blocking this, they also have an effect on the immunosuppressive cells. And besides the effect on the blood vessels, or on the endothelial cells, you also have an effect on the immune system with this agent.

Roy Herbst MD, PhD: Ramucirumab is a VEGFR2 inhibitor, so it works on the receptor as opposed to bevacizumab and other agents that trap the circulating ligand. Sure, I think it can work differently because now it’s blocking the receptor activation at the tumor cell. It might have a direct effect on the tumor cell, a more direct effect because of its mechanism working on that receptor, both on the tumor cell and the endothelial cell. It can work on the receptor in both, so I think you could hypothesize that a VEGFR2 antibody is having an effect both on the tumor and the microenvironment, and could be more potent. One thing I always worried about, and many worry about, with the VEGF trap approach, binding at the ligand, is that you might not have as complete an inhibition as well.

Transcript Edited for Clarity
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Transcript:

Enriqueta Felip, MD, PhD:
In the situation of bevacizumab in first line, the development has been in only nonsquamous histology due to the fact that the phase II trials show hemoptysis in patients with squamous cell carcinoma. In the case of nintedanib, in the randomized trial comparing nintedanib plus the docetaxel or nintedanib plus placebo, there are differences in overall survival for the subgroup of adenocarcinoma, but not for the subgroup of squamous cell carcinoma. This is different in the REVEL trial, the ramucirumab trial. Both subgroups benefited from the addition of ramucirumab, nonsquamous and squamous. And, the toxicity was no different between the two histology subgroups.

Marina Garassino, MD: Both of the strategies are active to control non–small cell lung cancer. However, they are different. One strategy is binding the ligand; the other strategy is binding the receptor. We have one clinical aspect that can explain the situation. That is that ramucirumab is the only drug active both in squamous and in nonsquamous. And we know that VEGFR2 maybe is the key receptor for all of the process of angiogenesis. So, maybe targeting the VEGF receptor 2 can be a more active strategy, but it’s only an idea. There are no clear data on that.

Joachim G. Aerts, MD, PhD: Ramucirumab blocks the VEGFR2 receptor. While, for instance, bevacizumab works on circulating VEGF. You block it at the cellular level with ramucirumab. And, we don’t know exactly what are the differences, but we see differences in how it works and how it can also be affective beyond its effect on the tumor cells. So, let’s look at myeloid cells. The immunosuppressive cells, which can also become endothelial cells, also have this receptor on their surface. Besides the effect directly on tumor growth, or tumor cells, or the endothelial cells, it also has an effect on the immune system. Ramucirumab is a VEGFR-2 blocker, it blocks the receptor there. And, we have to keep in mind, that all different kinds of VEGF antiangiogenic agents all have a different way of acting on the endothelial cells, but also on other cells. So, these VEGFR-2 receptors, for instance, also present on immune cells. It could be that by blocking this, they also have an effect on the immunosuppressive cells. And besides the effect on the blood vessels, or on the endothelial cells, you also have an effect on the immune system with this agent.

Roy Herbst MD, PhD: Ramucirumab is a VEGFR2 inhibitor, so it works on the receptor as opposed to bevacizumab and other agents that trap the circulating ligand. Sure, I think it can work differently because now it’s blocking the receptor activation at the tumor cell. It might have a direct effect on the tumor cell, a more direct effect because of its mechanism working on that receptor, both on the tumor cell and the endothelial cell. It can work on the receptor in both, so I think you could hypothesize that a VEGFR2 antibody is having an effect both on the tumor and the microenvironment, and could be more potent. One thing I always worried about, and many worry about, with the VEGF trap approach, binding at the ligand, is that you might not have as complete an inhibition as well.

Transcript Edited for Clarity
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