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Lung Adenocarcinoma: Patient Selection With Ramucirumab vs Nintedanib

Insights From:Anders Mellemgaard, MD, Herlev University Hospital; Sanjay Popat, PhD, FRCP, The Royal Marsden Hospital;Martin Reck, MD, PhD, Hospital Grosshansdorf
Published: Wednesday, Nov 30, 2016


Transcript:

Martin Reck, MD, PhD:
In the second-line treatment of patients with adenocarcinoma or with pretreated non–small cell lung cancer, we now have two positive trials, after decades of negative trials, showing a superior efficacy for the combination of docetaxel and an antiangiogenic compound, which has been nintedanib or ramucirumab. It’s difficult to compare both of these trials, one with another, because you cannot perform any cross-trial comparisons. However, there are some differences that may be important for clinical practice. Number-one is histology.

In the REVEL trial, the combination of ramucirumab and docetaxel has been investigated in patients with pretreated non–small cell lung cancer regardless of histology. And the improved efficacy has been observed across all histologies. So, we have a progression-free survival signal and we have an overall survival signal. For patients with squamous cell histology, we preferably may use the combination of docetaxel and ramucirumab if we do not use an immunotherapy like nivolumab.

The story is a little bit different in patients with adenocarcinoma. There, we do have the data for the combination of docetaxel and nintedanib, as well as docetaxel and ramucirumab. However, we have a very good rational for the combination of docetaxel and nintedanib in this group of patients with fast progressing tumors and who never responded to first-line chemotherapy.

From a practical point of view, there are some additional differences. Ramucirumab is an IV drug, nintedanib is an oral drug. This may impact the treatment decision and may also impact the convenience of the patient. Another factor is the tolerability profile. In both trials, in general, we have observed the toxicity profile that is associated with docetaxel. For the REVEL trial, the side effect, which predominantly was associated with the combination of ramucirumab and docetaxel, has been myelotoxicity. And for nintedanib, we have seen a little bit more GI toxicity, like diarrhea, and a transient elevation of the liver enzymes. So, these are also some specific factors that may influence the treatment decision.

Sanjay Popat, PhD: Both nintedanib and ramucirumab can potentially be given combined with docetaxel in patients in the second-line setting with non–small cell lung cancer, patients for whom to use which drugs is very much a decision-making process between the oncologist and the patient. Nintedanib, for example, is only licensed for adenocarcinomas in combination with docetaxel, with no survival advantage seen in the squamous population. Ramucirumab, for example, is licensed for use both in squamous and nonsquamous. Therefore, histology is less of an issue when considering ramucirumab. Ramucirumab is given intravenously, and docetaxel is given orally, and these methods of administration may have some benefits for the healthcare system that one works in and also for patient preference, as well. The toxicity of these compounds is different, as well, and so this needs to be borne in mind when making decisions about combining agents together for the particular patient in front of you.

Anders Mellemgaard, MD: We have very similar studies showing a positive effect of antiangiogenic agents, both with ramucirumab and with nintedanib. And the trials that looked at this are designed in the same way. So, I think they can be compared in many ways. Of course, they’re not a direct comparison. But if we have the choice between these two different compounds, one thing that would be important to look at would be to acknowledge the difference in toxicity with these two treatments.

Ramucirumab increases the hematologic toxicity of docetaxel. So, we see an increased risk of leucopenia and febrile neutropenia, which are a concern because these are serious adverse events, side effects. It also is often costly because it makes the patients stay in the hospital rather than being treated as an outpatient.

Nintedanib, on the other hand, has other adverse events. And diarrhea is an issue here that we need to be able to manage. We also, in some patients, do see elevated liver enzymes that we should be observant of. We should adjust treatment if we observe significant elevation in liver enzymes.

Martin Reck, MD, PhD: We have seen some new results in patients with pretreated non–small cell lung cancer. In particular, now we have randomized trials showing the superior efficacy of immunotherapies and the PD-1 antibodies, like nivolumab and pembrolizumab. And we also have seen the efficacy of combinations of antiangiogenic compounds and chemotherapies in this group of pretreated patients. It’s difficult to compare one treatment with another. It’s a completely different mode of action. However, we have got some points of interest that may guide us for future clinical trials. So, what we have seen in the nivolumab trial in pretreated patients with nonsquamous histology has been a crossing of the overall survival curve, which means there have been some patients not really benefiting from this treatment. We have to figure out who are these patients and how can we improve the treatment efficacy in this group of patients.

On the other hand, when we look at the trial on the combination of docetaxel and nintedanib, we have seen this superior efficacy, in particular, in this prognostic group of patients with fast progressing tumors, in this group of patients with refractory diseases who never responded to first-line chemotherapy. So, these are some observations in the particular trials, and I think it would be of great interest to explore in future trials whether, for example, a combination might be feasible.

Transcript Edited for Clarity
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Transcript:

Martin Reck, MD, PhD:
In the second-line treatment of patients with adenocarcinoma or with pretreated non–small cell lung cancer, we now have two positive trials, after decades of negative trials, showing a superior efficacy for the combination of docetaxel and an antiangiogenic compound, which has been nintedanib or ramucirumab. It’s difficult to compare both of these trials, one with another, because you cannot perform any cross-trial comparisons. However, there are some differences that may be important for clinical practice. Number-one is histology.

In the REVEL trial, the combination of ramucirumab and docetaxel has been investigated in patients with pretreated non–small cell lung cancer regardless of histology. And the improved efficacy has been observed across all histologies. So, we have a progression-free survival signal and we have an overall survival signal. For patients with squamous cell histology, we preferably may use the combination of docetaxel and ramucirumab if we do not use an immunotherapy like nivolumab.

The story is a little bit different in patients with adenocarcinoma. There, we do have the data for the combination of docetaxel and nintedanib, as well as docetaxel and ramucirumab. However, we have a very good rational for the combination of docetaxel and nintedanib in this group of patients with fast progressing tumors and who never responded to first-line chemotherapy.

From a practical point of view, there are some additional differences. Ramucirumab is an IV drug, nintedanib is an oral drug. This may impact the treatment decision and may also impact the convenience of the patient. Another factor is the tolerability profile. In both trials, in general, we have observed the toxicity profile that is associated with docetaxel. For the REVEL trial, the side effect, which predominantly was associated with the combination of ramucirumab and docetaxel, has been myelotoxicity. And for nintedanib, we have seen a little bit more GI toxicity, like diarrhea, and a transient elevation of the liver enzymes. So, these are also some specific factors that may influence the treatment decision.

Sanjay Popat, PhD: Both nintedanib and ramucirumab can potentially be given combined with docetaxel in patients in the second-line setting with non–small cell lung cancer, patients for whom to use which drugs is very much a decision-making process between the oncologist and the patient. Nintedanib, for example, is only licensed for adenocarcinomas in combination with docetaxel, with no survival advantage seen in the squamous population. Ramucirumab, for example, is licensed for use both in squamous and nonsquamous. Therefore, histology is less of an issue when considering ramucirumab. Ramucirumab is given intravenously, and docetaxel is given orally, and these methods of administration may have some benefits for the healthcare system that one works in and also for patient preference, as well. The toxicity of these compounds is different, as well, and so this needs to be borne in mind when making decisions about combining agents together for the particular patient in front of you.

Anders Mellemgaard, MD: We have very similar studies showing a positive effect of antiangiogenic agents, both with ramucirumab and with nintedanib. And the trials that looked at this are designed in the same way. So, I think they can be compared in many ways. Of course, they’re not a direct comparison. But if we have the choice between these two different compounds, one thing that would be important to look at would be to acknowledge the difference in toxicity with these two treatments.

Ramucirumab increases the hematologic toxicity of docetaxel. So, we see an increased risk of leucopenia and febrile neutropenia, which are a concern because these are serious adverse events, side effects. It also is often costly because it makes the patients stay in the hospital rather than being treated as an outpatient.

Nintedanib, on the other hand, has other adverse events. And diarrhea is an issue here that we need to be able to manage. We also, in some patients, do see elevated liver enzymes that we should be observant of. We should adjust treatment if we observe significant elevation in liver enzymes.

Martin Reck, MD, PhD: We have seen some new results in patients with pretreated non–small cell lung cancer. In particular, now we have randomized trials showing the superior efficacy of immunotherapies and the PD-1 antibodies, like nivolumab and pembrolizumab. And we also have seen the efficacy of combinations of antiangiogenic compounds and chemotherapies in this group of pretreated patients. It’s difficult to compare one treatment with another. It’s a completely different mode of action. However, we have got some points of interest that may guide us for future clinical trials. So, what we have seen in the nivolumab trial in pretreated patients with nonsquamous histology has been a crossing of the overall survival curve, which means there have been some patients not really benefiting from this treatment. We have to figure out who are these patients and how can we improve the treatment efficacy in this group of patients.

On the other hand, when we look at the trial on the combination of docetaxel and nintedanib, we have seen this superior efficacy, in particular, in this prognostic group of patients with fast progressing tumors, in this group of patients with refractory diseases who never responded to first-line chemotherapy. So, these are some observations in the particular trials, and I think it would be of great interest to explore in future trials whether, for example, a combination might be feasible.

Transcript Edited for Clarity
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