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Practical Implications of the LUME-Lung 1 Findings

Insights From:Anders Mellemgaard, MD, Herlev University Hospital; Sanjay Popat, PhD, FRCP, The Royal Marsden Hospital;Martin Reck, MD, PhD, Hospital Grosshansdorf
Published: Monday, Dec 05, 2016


Transcript:

Martin Reck, MD, PhD:
The LUME-Lung 1 trial was a very large prospective randomized placebo-controlled phase 3 trial investigating the combination of docetaxel/nintedanib compared to docetaxel alone and placebo in more than 1200 patients with pretreated advanced non–small cell lung cancer. The primary endpoint of LUME-Lung 1 was progression-free survival assessed by independent central radio-electric review, and its secondary endpoints consisted of overall survival response, tolerability, and quality of life.

As the key result, we have seen a significant improvement in progression-free survival, independent from histology, in favor of the combination of nintedanib and docetaxel. Looking at the secondary endpoints, we have also seen a significant improvement in overall survival in patients with advanced adenocarcinoma. Furthermore, we have got the very interesting result that there has been a pronounced efficacy of this combination in patients with fast-progressing adenocarcinoma and in refractory patients who never responded to first-line chemotherapy.

With regard of tolerability, predominantly, we have seen the toxicity associated with docetaxel, and the characteristic adverse events (AEs) of nintedanib have been GI effects, like diarrhea, or a transient elevation of liver enzymes. Looking at the characteristic AEs caused by the antiangiogenic nature of the compound, we haven’t seen any relevant increase in bleeding events or any relevant increase in severe hypertension events. So, overall, this is a new option that we have for pretreated patients with advanced adenocarcinoma.

Sanjay Popat, PhD, FRCP: The therapeutic decision making for patients in the second-line setting, when combining nintedanib with docetaxel, comes from analysis of the LUME-Lung 1 study. Here, subset analysis has demonstrated that the greatest benefit seems to be in the population of patients progressing within 9 months while starting first-line therapy, where the survival advantage is associated with a hazard ratio of about 0.7. And in that group of patients, one would certainly want to consider the combination of nintedanib and docetaxel because that is the group with a bigger survival benefit.

A large survival advantage is also seen in patients who have progression as their best response to first-line chemotherapy, and that can be up to 30% of patients we treat in real life. So, that seems to represent an ideal population of patients with whom to combine nintedanib with docetaxel.

Anders Mellemgaard, MD: Even though there is an effect in all adenocarcinoma patients with these compounds, it’s clear that this effect is bigger in patients who have a shorter interval. And it’s illustrating something about the tumor biology. It’s also something that we haven’t previously paid too much attention to. But it is important, when we try to figure out the right treatment, that we look at the individual patient history and try to find out, is this a short interval or is it a longer interval? That would, with the information that we have now, be important in terms of selection of the right drug.

The exact cutoff, what is a short interval and what’s a longer interval, is difficult because this is a continuum. We frequently talk about 9 months between the start of first- and start of second-line therapy, not because 9 months is a particularly important time point, but rather because below 9 months is where we see the biggest effect of nintedanib. That’s been, at least partly, replicated in the study of ramucirumab.

In both the study of ramucirumab and the study of nintedanib, we did see that patients who had a shorter interval appeared to have a bigger effect of the treatment. So, probably both these two drugs are better for patients with a short interval. But a particular finding in the nintedanib study was the patients who progressed on first-line treatment. They are patients with particularly aggressive tumor biology who actually responded very well to a nintedanib treatment. And that exact finding was not replicated in the REVEL trial that looked at ramucirumab. Even though it appears that there are differences, these two drugs are not totally identical.

Martin Reck, MD, PhD: Nintedanib has shown its efficacy in pretreated patients with adenocarcinoma. Currently, it is explored in several indications. For thoracic tumors, we have seen quite interesting data on patients with advanced pleural mesothelioma. So, we have a positive sign in a randomized phase II trial. This is now going to be confirmed in a randomized phase III trial. We are also working on this issue of tolerability.

We are performing a phase I trial exploring the efficacy of weekly docetaxel in combination with nintedanib in order to improve the tolerability by maintaining the efficacy of this combination. And from my personal perspective, I would be very excited to see a trial combining nintedanib with an immune therapy, because we have seen that VEGF, or angiogenesis, is a very strong immunosuppressive factor. To use an antiangiogenic compound and a checkpoint inhibitor really might increase the efficacy of the immune therapy.

Transcript Edited for Clarity
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Transcript:

Martin Reck, MD, PhD:
The LUME-Lung 1 trial was a very large prospective randomized placebo-controlled phase 3 trial investigating the combination of docetaxel/nintedanib compared to docetaxel alone and placebo in more than 1200 patients with pretreated advanced non–small cell lung cancer. The primary endpoint of LUME-Lung 1 was progression-free survival assessed by independent central radio-electric review, and its secondary endpoints consisted of overall survival response, tolerability, and quality of life.

As the key result, we have seen a significant improvement in progression-free survival, independent from histology, in favor of the combination of nintedanib and docetaxel. Looking at the secondary endpoints, we have also seen a significant improvement in overall survival in patients with advanced adenocarcinoma. Furthermore, we have got the very interesting result that there has been a pronounced efficacy of this combination in patients with fast-progressing adenocarcinoma and in refractory patients who never responded to first-line chemotherapy.

With regard of tolerability, predominantly, we have seen the toxicity associated with docetaxel, and the characteristic adverse events (AEs) of nintedanib have been GI effects, like diarrhea, or a transient elevation of liver enzymes. Looking at the characteristic AEs caused by the antiangiogenic nature of the compound, we haven’t seen any relevant increase in bleeding events or any relevant increase in severe hypertension events. So, overall, this is a new option that we have for pretreated patients with advanced adenocarcinoma.

Sanjay Popat, PhD, FRCP: The therapeutic decision making for patients in the second-line setting, when combining nintedanib with docetaxel, comes from analysis of the LUME-Lung 1 study. Here, subset analysis has demonstrated that the greatest benefit seems to be in the population of patients progressing within 9 months while starting first-line therapy, where the survival advantage is associated with a hazard ratio of about 0.7. And in that group of patients, one would certainly want to consider the combination of nintedanib and docetaxel because that is the group with a bigger survival benefit.

A large survival advantage is also seen in patients who have progression as their best response to first-line chemotherapy, and that can be up to 30% of patients we treat in real life. So, that seems to represent an ideal population of patients with whom to combine nintedanib with docetaxel.

Anders Mellemgaard, MD: Even though there is an effect in all adenocarcinoma patients with these compounds, it’s clear that this effect is bigger in patients who have a shorter interval. And it’s illustrating something about the tumor biology. It’s also something that we haven’t previously paid too much attention to. But it is important, when we try to figure out the right treatment, that we look at the individual patient history and try to find out, is this a short interval or is it a longer interval? That would, with the information that we have now, be important in terms of selection of the right drug.

The exact cutoff, what is a short interval and what’s a longer interval, is difficult because this is a continuum. We frequently talk about 9 months between the start of first- and start of second-line therapy, not because 9 months is a particularly important time point, but rather because below 9 months is where we see the biggest effect of nintedanib. That’s been, at least partly, replicated in the study of ramucirumab.

In both the study of ramucirumab and the study of nintedanib, we did see that patients who had a shorter interval appeared to have a bigger effect of the treatment. So, probably both these two drugs are better for patients with a short interval. But a particular finding in the nintedanib study was the patients who progressed on first-line treatment. They are patients with particularly aggressive tumor biology who actually responded very well to a nintedanib treatment. And that exact finding was not replicated in the REVEL trial that looked at ramucirumab. Even though it appears that there are differences, these two drugs are not totally identical.

Martin Reck, MD, PhD: Nintedanib has shown its efficacy in pretreated patients with adenocarcinoma. Currently, it is explored in several indications. For thoracic tumors, we have seen quite interesting data on patients with advanced pleural mesothelioma. So, we have a positive sign in a randomized phase II trial. This is now going to be confirmed in a randomized phase III trial. We are also working on this issue of tolerability.

We are performing a phase I trial exploring the efficacy of weekly docetaxel in combination with nintedanib in order to improve the tolerability by maintaining the efficacy of this combination. And from my personal perspective, I would be very excited to see a trial combining nintedanib with an immune therapy, because we have seen that VEGF, or angiogenesis, is a very strong immunosuppressive factor. To use an antiangiogenic compound and a checkpoint inhibitor really might increase the efficacy of the immune therapy.

Transcript Edited for Clarity
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