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Differentiating Among Anti-VEGF Therapies in Lung Adenocarcinoma

Insights From:Anders Mellemgaard, MD, Herlev University Hospital; Sanjay Popat, PhD, FRCP, The Royal Marsden Hospital;Martin Reck, MD, PhD, Hospital Grosshansdorf
Published: Monday, Nov 28, 2016


Transcript:

Sanjay Popat, PhD:
In the second-line setting of advanced non–small cell lung cancer in the nonsquamous population, there’s a clear biological rationale for targeting angiogenesis. We know it’s a critical factor in tumor growth progression and poor survival. We know in the first-line setting that using VEGF-directed therapy, such as bevacizumab, can have an advantage. And we know now from trial data that targeting angiogenesis in the second-line setting can also give survival benefits.

In the second-line setting, there are three potential antiangiogenic agents: ramucirumab, nintedanib, and bevacizumab. Bevacizumab is a classic antiangiogenic compound. It’s a monoclonal antibody, which is targeted against the growth factor VEGF-A. Ramucirumab is another monoclonal antibody, but rather than targeting the growth factor, it targets the VEGF-R2 receptor, which is the main receptor that binds to VEGF-A.

Nintedanib works in a totally different way. This is a tyrosine kinase inhibitor that acts on the kinase associated with a number of different receptors associated with angiogenesis. Specifically, it inhibits VEGF-R1, 2, and 3; FGR-1, 2, and 3; and PDGF alpha and beta. All of these are important in the complex process that is known as antiangiogenesis.

When targeting multiple angiogenic pathways, you’re giving a broader hit. The process of angiogenesis is really quite complex, specifically in tumors. It could be very context-dependent. So, there are different pathways that can come into force at different time points in the tumor’s growth. Targeting all of these different pathways through one particular therapeutic approach, such as nintedanib, can, therefore, have good biological rationale.

The three agents—bevacizumab, ramucirumab, and nintedanib—have been used in different populations. Bevacizumab has really been evaluated in the first-line setting, particularly in the nonsquamous population, because of safety concerns in the squamous population during development. Ramucirumab has been evaluated in the second-line setting and seems to be active with a survival advantage both in adenocarcinomas and in squamous. Nintedanib has been licensed for use in Europe for adenocarcinomas. There is a survival benefit in that population, which is underpinned by a progression-free survival benefit.

Martin Reck, MD, PhD: Antiangiogenesis has become a very attractive instrument for the treatment of patients with advanced non–small cell lung cancer. And the first antiangiogenic agent that has been approved in treatment of each of the patients with advanced non-squamous, non–small cell cancer was bevacizumab. However, we do see that in most patients, there is a resistance following treatment with bevacizumab after a couple of months.

We haven’t really understood the mechanisms of resistance following treatment with bevacizumab. We have some data that there is a dynamic change of the pathways of angiogenesis that are activating following treatment with bevacizumab. So, it makes sense to change the way to impact angiogenesis like it’s done by nintedanib, because nintedanib is interfering with various pathways that are associated with tumor-related angiogenesis. We have looked for the efficacy of nintedanib, in particular following treatment with bevacizumab. We had a cohort of patients pretreated with bevacizumab that received nintedanib at time of progression, and we have seen a consistent signal of efficacy for these patients who have been pretreated with bevacizumab. So, for practical considerations, even if a patient has received prior treatment with bevacizumab, they also would be an appropriate candidate for the combination of nintedanib and docetaxel, for example.

Talking about the optimum sequence of antiangiogenic approaches, currently we have, I would say, the clinical avenue. This is the first-line efficacy that we have seen for bevacizumab followed by a differential antiangiogenic approach utilized by ramucirumab and nintedanib. Whether we are going to see additional trials looking at other sequences, I am in doubt, because currently there is so much going on in the field of immunotherapy that people are not really interested in novel antiangiogenic sequences. However, what we can say is that a sequence of different antiangiogenic approaches is efficacious and is something that is real for practical considerations.

Transcript Edited for Clarity
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Transcript:

Sanjay Popat, PhD:
In the second-line setting of advanced non–small cell lung cancer in the nonsquamous population, there’s a clear biological rationale for targeting angiogenesis. We know it’s a critical factor in tumor growth progression and poor survival. We know in the first-line setting that using VEGF-directed therapy, such as bevacizumab, can have an advantage. And we know now from trial data that targeting angiogenesis in the second-line setting can also give survival benefits.

In the second-line setting, there are three potential antiangiogenic agents: ramucirumab, nintedanib, and bevacizumab. Bevacizumab is a classic antiangiogenic compound. It’s a monoclonal antibody, which is targeted against the growth factor VEGF-A. Ramucirumab is another monoclonal antibody, but rather than targeting the growth factor, it targets the VEGF-R2 receptor, which is the main receptor that binds to VEGF-A.

Nintedanib works in a totally different way. This is a tyrosine kinase inhibitor that acts on the kinase associated with a number of different receptors associated with angiogenesis. Specifically, it inhibits VEGF-R1, 2, and 3; FGR-1, 2, and 3; and PDGF alpha and beta. All of these are important in the complex process that is known as antiangiogenesis.

When targeting multiple angiogenic pathways, you’re giving a broader hit. The process of angiogenesis is really quite complex, specifically in tumors. It could be very context-dependent. So, there are different pathways that can come into force at different time points in the tumor’s growth. Targeting all of these different pathways through one particular therapeutic approach, such as nintedanib, can, therefore, have good biological rationale.

The three agents—bevacizumab, ramucirumab, and nintedanib—have been used in different populations. Bevacizumab has really been evaluated in the first-line setting, particularly in the nonsquamous population, because of safety concerns in the squamous population during development. Ramucirumab has been evaluated in the second-line setting and seems to be active with a survival advantage both in adenocarcinomas and in squamous. Nintedanib has been licensed for use in Europe for adenocarcinomas. There is a survival benefit in that population, which is underpinned by a progression-free survival benefit.

Martin Reck, MD, PhD: Antiangiogenesis has become a very attractive instrument for the treatment of patients with advanced non–small cell lung cancer. And the first antiangiogenic agent that has been approved in treatment of each of the patients with advanced non-squamous, non–small cell cancer was bevacizumab. However, we do see that in most patients, there is a resistance following treatment with bevacizumab after a couple of months.

We haven’t really understood the mechanisms of resistance following treatment with bevacizumab. We have some data that there is a dynamic change of the pathways of angiogenesis that are activating following treatment with bevacizumab. So, it makes sense to change the way to impact angiogenesis like it’s done by nintedanib, because nintedanib is interfering with various pathways that are associated with tumor-related angiogenesis. We have looked for the efficacy of nintedanib, in particular following treatment with bevacizumab. We had a cohort of patients pretreated with bevacizumab that received nintedanib at time of progression, and we have seen a consistent signal of efficacy for these patients who have been pretreated with bevacizumab. So, for practical considerations, even if a patient has received prior treatment with bevacizumab, they also would be an appropriate candidate for the combination of nintedanib and docetaxel, for example.

Talking about the optimum sequence of antiangiogenic approaches, currently we have, I would say, the clinical avenue. This is the first-line efficacy that we have seen for bevacizumab followed by a differential antiangiogenic approach utilized by ramucirumab and nintedanib. Whether we are going to see additional trials looking at other sequences, I am in doubt, because currently there is so much going on in the field of immunotherapy that people are not really interested in novel antiangiogenic sequences. However, what we can say is that a sequence of different antiangiogenic approaches is efficacious and is something that is real for practical considerations.

Transcript Edited for Clarity
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