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Mechanisms of Anti-angiogenic 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: Friday, Dec 16, 2016


Transcript:

Marina Garassino, MD:
Ramucirumab is the only drug approved for non–small cell lung cancer independent by histology. So, it is now approved for the treatment of advanced non–small cell lung cancer in second line with docetaxel. And, different from the other 2 antiangiogenics, ramucirumab also works in the squamous histology. Bevacizumab, and also, nintedanib, work only in adenocarcinoma histology.

Enriqueta Felip, MD, PhD: The mechanism of action is different for bevacizumab and ramucirumab. Both drugs are inhibiting angiogenesis. However, bevacizumab is inhibiting the vascular endothelial growth factor. Ramucirumab is a monoclonal antibody inhibiting the vascular endothelial growth factor receptor. This is the main difference between the 2 drugs. So, one inhibits the ligand; ramucirumab inhibits the receptor.

Marina Garassino, MD: It’s quite difficult to say who are the perfect patients to have this kind of drug. I think that it is important to discuss with each patient all the possibilities. Two years ago, we had no possibilities for this kind of patient, now we have the possibility to choose among many treatments. So, we also have to discuss with the patient, if they want, alopecia and all the side effects of docetaxel. But, we have to clearly explain to the patient so that, maybe, in this way, they can achieve all the possibilities of treatment. The most important toxicity is neutropenia, and I think that all oncologists are very able to treat the neutropenia. And so, I think this is not something that will stop us from using the combination drug.

Joachim G. Aerts, MD, PhD: Well, ramucirumab was approved based on a very large second-line trial in which patients who were getting progressive disease after chemotherapy, both squamous and nonsquamous cell lung cancer patients, were treated with docetaxel or docetaxel in combination with ramucirumab. And the trial was powered for OS as an endpoint, and it reached a statistical endpoint by increasing the median overall survival from 9 months to 10.5 months. So, this was a statistically significant improvement. The interesting thing was that it was both in the squamous and nonsquamous.

And, regarding the toxicities, we know the main toxicity was the neutropenia, which is known when we used docetaxel and was slightly increased in the combination arm. And the other toxicity related to the ramucirumab was, so to say, the class effect. So, we know that patients are getting more hypertension, more thromboembolic events related to the VGF blockade.

Regarding these class effects for toxicity, one thing that was not more observed in the ramucirumab arm was pulmonary hemorrhage. So, there were no more hemorrhage events in the patients in the combination arm than in the monotherapy arm. To wrap up on the trial, this was the first second-line trial showing an activity of anti-angiogenic agents in both histological subtypes, showing a small but a significant increase in overall survival, and with an acceptable toxicity.

Roy S. Herbst, MD, PhD: Oh, I’m very excited about using ramucirumab. Ramucirumab was approved in combination with docetaxel in a trial versus docetaxel alone. Even though it’s an inhibitor of VEGF receptor 2, VEGFR2, it was studied both in squamous and nonsquamous lung cancer. Actually, I was impressed by the trial. The hazard ratio was around 0.8, so it wasn’t the best result one would have wanted, but it clearly has improvement over docetaxel alone with very few additional side effects. So, for someone in whom I’m going to use docetaxel in lung cancer, I would use it with ramucirumab. I also think ramucirumab is going to have a very important role in lung cancer, as you start combining it with other agents, including immunotherapies. One thing, that I’m very interested in, is why for certain immunotherapies when we treat patients, the T cells don’t make it into the tumor. I’m betting that one way we can enhance delivery of T cells to the tumor and trafficking them will be through the VEGFR2 receptor, and inhibiting that. I think we’ll start seeing trials, and actually I’m already leading a phase I trial of ramucirumab plus pembrolizumab in this disease. So, this drug is approved, it’s being used in lung cancer, and now it’s part of several exciting research trials, as we speak.

Transcript Edited for Clarity
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Transcript:

Marina Garassino, MD:
Ramucirumab is the only drug approved for non–small cell lung cancer independent by histology. So, it is now approved for the treatment of advanced non–small cell lung cancer in second line with docetaxel. And, different from the other 2 antiangiogenics, ramucirumab also works in the squamous histology. Bevacizumab, and also, nintedanib, work only in adenocarcinoma histology.

Enriqueta Felip, MD, PhD: The mechanism of action is different for bevacizumab and ramucirumab. Both drugs are inhibiting angiogenesis. However, bevacizumab is inhibiting the vascular endothelial growth factor. Ramucirumab is a monoclonal antibody inhibiting the vascular endothelial growth factor receptor. This is the main difference between the 2 drugs. So, one inhibits the ligand; ramucirumab inhibits the receptor.

Marina Garassino, MD: It’s quite difficult to say who are the perfect patients to have this kind of drug. I think that it is important to discuss with each patient all the possibilities. Two years ago, we had no possibilities for this kind of patient, now we have the possibility to choose among many treatments. So, we also have to discuss with the patient, if they want, alopecia and all the side effects of docetaxel. But, we have to clearly explain to the patient so that, maybe, in this way, they can achieve all the possibilities of treatment. The most important toxicity is neutropenia, and I think that all oncologists are very able to treat the neutropenia. And so, I think this is not something that will stop us from using the combination drug.

Joachim G. Aerts, MD, PhD: Well, ramucirumab was approved based on a very large second-line trial in which patients who were getting progressive disease after chemotherapy, both squamous and nonsquamous cell lung cancer patients, were treated with docetaxel or docetaxel in combination with ramucirumab. And the trial was powered for OS as an endpoint, and it reached a statistical endpoint by increasing the median overall survival from 9 months to 10.5 months. So, this was a statistically significant improvement. The interesting thing was that it was both in the squamous and nonsquamous.

And, regarding the toxicities, we know the main toxicity was the neutropenia, which is known when we used docetaxel and was slightly increased in the combination arm. And the other toxicity related to the ramucirumab was, so to say, the class effect. So, we know that patients are getting more hypertension, more thromboembolic events related to the VGF blockade.

Regarding these class effects for toxicity, one thing that was not more observed in the ramucirumab arm was pulmonary hemorrhage. So, there were no more hemorrhage events in the patients in the combination arm than in the monotherapy arm. To wrap up on the trial, this was the first second-line trial showing an activity of anti-angiogenic agents in both histological subtypes, showing a small but a significant increase in overall survival, and with an acceptable toxicity.

Roy S. Herbst, MD, PhD: Oh, I’m very excited about using ramucirumab. Ramucirumab was approved in combination with docetaxel in a trial versus docetaxel alone. Even though it’s an inhibitor of VEGF receptor 2, VEGFR2, it was studied both in squamous and nonsquamous lung cancer. Actually, I was impressed by the trial. The hazard ratio was around 0.8, so it wasn’t the best result one would have wanted, but it clearly has improvement over docetaxel alone with very few additional side effects. So, for someone in whom I’m going to use docetaxel in lung cancer, I would use it with ramucirumab. I also think ramucirumab is going to have a very important role in lung cancer, as you start combining it with other agents, including immunotherapies. One thing, that I’m very interested in, is why for certain immunotherapies when we treat patients, the T cells don’t make it into the tumor. I’m betting that one way we can enhance delivery of T cells to the tumor and trafficking them will be through the VEGFR2 receptor, and inhibiting that. I think we’ll start seeing trials, and actually I’m already leading a phase I trial of ramucirumab plus pembrolizumab in this disease. So, this drug is approved, it’s being used in lung cancer, and now it’s part of several exciting research trials, as we speak.

Transcript Edited for Clarity
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