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Resistance to Antiangiogenic Therapy 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, Jan 04, 2017


Transcript:

Marina Garassino, MD:
Saying what the main mechanisms of resistance to antiangiogenics are is a controversial issue. There are several theories, but it is very different, for example, from EGFR mutations in which T790M is clearly a mechanism of the resistance. For antiangiogenics, we know that we have a mechanism of intrinsic resistance because we can see a lot of patients not responding immediately to the first line of therapy. So, in this case, we have intrinsic resistance. But, we have also mechanism of acquired resistance. In the two cases with the different mechanisms, we have an overexpression of some factors; for example, the overexpression of the receptor of VEGF, in particular, VEGF-A. We can also have the overexpression of PDGF, and we can have also the overexpression of FGF. For acquired resistance, we have also other mechanisms, such as the recruitment of progenitors of vascular cells, such as BMDC (bone marrow-derived cells). And we can also recruit some pericytes.

Roy S. Herbst, MD, PhD: When you ask about resistance to antiangiogenic therapy, it’s both primary and acquired. Primary would be a lot of patients don’t benefit from it, so it might be that the tumor isn’t even driven by VEGF. Maybe VEGF is not being made by the tumor or it’s not co-opting and bringing the vessels in. There might be other mechanisms of angiogenesis and other inhibitors required other than blocking VEGF-A. Why would resistance develop? I guess resistance could develop if the tumor learned how to bring blood vessels in, in the absence of this factor if there were other pathways involved. But I think the bigger problem is just primary resistance, primary effect. I’m not as worried about secondary resistance. This field is good, but it’s not great as far as the biology and understanding of it, the biomarkers and the understanding of it. So, we know that these agents have some effect. The effect is reasonable, but it’s not a home run. It’s just a very solid improvement in standard of care. That’s why I think we need to look at these VEGF inhibitors and think, how can we make them even more valuable in our lung cancer treatment, combining them perhaps with immunotherapy or other targeted therapies.

Marina Garassino, MD: We have controversial data on the use of continuing antiangiogenics because we don’t have a very large, randomized, controlled trial on the issue. So, continuing to target angiogenesis can be a good strategy because we see that the subgroup analysis of trials—in particular, the REVEL trial—15% of patients were already treated with bevacizumab. When they progressed, they were treated with ramucirumab, and the same goes for nintedanib also, if the proportion of patients was less. I think that we have also to consider that in other diseases, such as colorectal cancer, we have several data that show that targeting angiogenesis for all the disease of the patients can be feasible and useful. In lung cancer, this is something that can be done, but we need to have more studies that confirm the data.

Enriqueta Felip, MD, PhD: From a biological point of view, it makes sense to inhibit angiogenesis in first line, second line, and in all lines of the disease. Angiogenesis is a hallmark of cancer. In the studies, for example, analyzing ramucirumab or nintedanib, patients previously treated with bevacizumab were allowed to be included. And these patients also benefited from the addition of a second-line antiangiogenic drug. So, there is some rationale to maintain that inhibition of angiogenesis throughout the disease evolution.

Joachim G. Aerts, MD, PhD: While we know now that these different antiangiogenic agents all have a different working mechanism, one of the interesting theoretical concepts could be that you also sequence your treatment of these antiangiogenic agents. You could imagine that when patients are progressing after bevacizumab, there could be a response to ramucirumab or another agent just based on the fact that they have a different kind of working mechanism. And that’s, for now, as far as my knowledge is, only theoretical. I don’t know of any clinical data on that, but I think it’s an interesting concept, which you can look at.

Transcript Edited for Clarity
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Transcript:

Marina Garassino, MD:
Saying what the main mechanisms of resistance to antiangiogenics are is a controversial issue. There are several theories, but it is very different, for example, from EGFR mutations in which T790M is clearly a mechanism of the resistance. For antiangiogenics, we know that we have a mechanism of intrinsic resistance because we can see a lot of patients not responding immediately to the first line of therapy. So, in this case, we have intrinsic resistance. But, we have also mechanism of acquired resistance. In the two cases with the different mechanisms, we have an overexpression of some factors; for example, the overexpression of the receptor of VEGF, in particular, VEGF-A. We can also have the overexpression of PDGF, and we can have also the overexpression of FGF. For acquired resistance, we have also other mechanisms, such as the recruitment of progenitors of vascular cells, such as BMDC (bone marrow-derived cells). And we can also recruit some pericytes.

Roy S. Herbst, MD, PhD: When you ask about resistance to antiangiogenic therapy, it’s both primary and acquired. Primary would be a lot of patients don’t benefit from it, so it might be that the tumor isn’t even driven by VEGF. Maybe VEGF is not being made by the tumor or it’s not co-opting and bringing the vessels in. There might be other mechanisms of angiogenesis and other inhibitors required other than blocking VEGF-A. Why would resistance develop? I guess resistance could develop if the tumor learned how to bring blood vessels in, in the absence of this factor if there were other pathways involved. But I think the bigger problem is just primary resistance, primary effect. I’m not as worried about secondary resistance. This field is good, but it’s not great as far as the biology and understanding of it, the biomarkers and the understanding of it. So, we know that these agents have some effect. The effect is reasonable, but it’s not a home run. It’s just a very solid improvement in standard of care. That’s why I think we need to look at these VEGF inhibitors and think, how can we make them even more valuable in our lung cancer treatment, combining them perhaps with immunotherapy or other targeted therapies.

Marina Garassino, MD: We have controversial data on the use of continuing antiangiogenics because we don’t have a very large, randomized, controlled trial on the issue. So, continuing to target angiogenesis can be a good strategy because we see that the subgroup analysis of trials—in particular, the REVEL trial—15% of patients were already treated with bevacizumab. When they progressed, they were treated with ramucirumab, and the same goes for nintedanib also, if the proportion of patients was less. I think that we have also to consider that in other diseases, such as colorectal cancer, we have several data that show that targeting angiogenesis for all the disease of the patients can be feasible and useful. In lung cancer, this is something that can be done, but we need to have more studies that confirm the data.

Enriqueta Felip, MD, PhD: From a biological point of view, it makes sense to inhibit angiogenesis in first line, second line, and in all lines of the disease. Angiogenesis is a hallmark of cancer. In the studies, for example, analyzing ramucirumab or nintedanib, patients previously treated with bevacizumab were allowed to be included. And these patients also benefited from the addition of a second-line antiangiogenic drug. So, there is some rationale to maintain that inhibition of angiogenesis throughout the disease evolution.

Joachim G. Aerts, MD, PhD: While we know now that these different antiangiogenic agents all have a different working mechanism, one of the interesting theoretical concepts could be that you also sequence your treatment of these antiangiogenic agents. You could imagine that when patients are progressing after bevacizumab, there could be a response to ramucirumab or another agent just based on the fact that they have a different kind of working mechanism. And that’s, for now, as far as my knowledge is, only theoretical. I don’t know of any clinical data on that, but I think it’s an interesting concept, which you can look at.

Transcript Edited for Clarity
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