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Non-Driver NSCLC: Clinical Decisions in Rapidly Progressing Disease

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 21, 2016


 Transcript:

Martin Reck, MD, PhD:
In the last 2 years, we have seen new data in patients with pretreated non–small cell lung cancer. We have got a lot of information, but we also have seen some problems with the new agents. Nivolumab has been investigated in a large trial, CheckMate-057, compared head-to-head to docetaxel. We have seen a significant improvement in overall survival. This has led to the approval of nivolumab in this group of patients. However, we have to be aware that nivolumab has not been tested against the most efficacious second-line combinations that are available, and this is either a combination of docetaxel and nintedanib, or docetaxel and ramucirumab. And furthermore, we have seen that there has been a crossing in the overall survival curves, which means that, indeed, there have been some patients not really benefitting from this treatment with nivolumab.

On the other hand, the antiangiogenic compound nintedanib has been investigated in a rather large trial, the LUME-Lung 1 trial, in combination with docetaxel compared to docetaxel alone in pretreated patients with advanced non–small cell lung cancer. We have seen a significant improvement in progression-free survival, and this has been the primary endpoint. We also have seen a significant improvement in adenocarcinoma patients, prolonging the overall survival in favor of the combination.

Something that has become very interesting, in particular, in this group of patients with adenocarcinoma, has been the observation that this combination has a pronounced efficacy in poor prognosis patients with pretreated adenocarcinoma. These are patients with fast progressing tumors, who never responded to first-line chemotherapy, and who had progressive disease as best response following first-line chemotherapy. And these are factors that we have to outweigh when we make our selection between the combination of docetaxel and an antiangiogenic compound and immunotherapy.

Sanjay Popat, PhD, FRCP: In patients with rapidly progressing disease in the second-line setting, options include immunotherapy and docetaxel potentially with nintedanib. The LUME-Lung 1 study has demonstrated a preferential activity of docetaxel in combination with nintedanib in patients with adenocarcinoma, in patients whose disease has either relapsed within 9 months of commencing first-line treatment or that has progressed as best response of first-line therapy.

So, for these patients with rapidly progressive disease, combination docetaxel and nintedanib could be an alternative regime for them, and it seems to be better than docetaxel monotherapy. We don’t seem to have these data the same way for combination docetaxel and ramucirumab. In terms of immunotherapy, we know that with nivolumab the extent of benefit of nivolumab is very much contingent on the PD-L1 status. And in patients with either low PD-L1 status or tumors that are rapidly progressive, or patients that are becoming frail, the benefit of immunotherapies such as nivolumab may be minimal. And for those patients, cytotoxic-based chemotherapy with docetaxel, with the addition of perhaps nintedanib, may be an optimal strategy.

Martin Reck, MD, PhD: In the recent trials that have been published for second-line treatment of patients with advanced non–small cell lung cancer—in particular in those trials investigating the efficacy of antiangiogenic agents in combination with chemotherapy—we have seen that there is a pronounced efficacy of these combinations in patients with fast-growing tumors. And this is something new. We haven’t seen this before, and we haven’t assessed this before. But, now, in my clinical practice, I check the carrier of my patients with regard of the interval between the time of the first diagnosis, the time of relapse, and whether I can get some flavor if this is a fast growing tumor or not. And, indeed, this characteristic does impact my decision on my treatment selection.

Anders Mellemgaard, MD: I think one thing that we have become aware of is that the interval from first- to second-line treatment actually tells us something about the biology of the cancer. When selecting a second-line treatment for a patient, a short interval indicates aggressive nature of the tumor, and probably also indicates that this particular tumor is dependent on new vasculature. So, the addition of antiangiogenic treatment makes more sense in tumors that are progressing rapidly. For that reason, I think it’s important to look at this particular factor when selecting a treatment. And we see different outcomes when we look at recent trials.

For example, we see with antiangiogenic agents, such as ramucirumab or nintedanib, the fact that the shorter the interval, the bigger the effect. But, we see the reverse when we look at the checkpoint inhibitors. If there is a good long interval from first to second line, the benefit from immune therapy is bigger.

Transcript Edited for Clarity
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 Transcript:

Martin Reck, MD, PhD:
In the last 2 years, we have seen new data in patients with pretreated non–small cell lung cancer. We have got a lot of information, but we also have seen some problems with the new agents. Nivolumab has been investigated in a large trial, CheckMate-057, compared head-to-head to docetaxel. We have seen a significant improvement in overall survival. This has led to the approval of nivolumab in this group of patients. However, we have to be aware that nivolumab has not been tested against the most efficacious second-line combinations that are available, and this is either a combination of docetaxel and nintedanib, or docetaxel and ramucirumab. And furthermore, we have seen that there has been a crossing in the overall survival curves, which means that, indeed, there have been some patients not really benefitting from this treatment with nivolumab.

On the other hand, the antiangiogenic compound nintedanib has been investigated in a rather large trial, the LUME-Lung 1 trial, in combination with docetaxel compared to docetaxel alone in pretreated patients with advanced non–small cell lung cancer. We have seen a significant improvement in progression-free survival, and this has been the primary endpoint. We also have seen a significant improvement in adenocarcinoma patients, prolonging the overall survival in favor of the combination.

Something that has become very interesting, in particular, in this group of patients with adenocarcinoma, has been the observation that this combination has a pronounced efficacy in poor prognosis patients with pretreated adenocarcinoma. These are patients with fast progressing tumors, who never responded to first-line chemotherapy, and who had progressive disease as best response following first-line chemotherapy. And these are factors that we have to outweigh when we make our selection between the combination of docetaxel and an antiangiogenic compound and immunotherapy.

Sanjay Popat, PhD, FRCP: In patients with rapidly progressing disease in the second-line setting, options include immunotherapy and docetaxel potentially with nintedanib. The LUME-Lung 1 study has demonstrated a preferential activity of docetaxel in combination with nintedanib in patients with adenocarcinoma, in patients whose disease has either relapsed within 9 months of commencing first-line treatment or that has progressed as best response of first-line therapy.

So, for these patients with rapidly progressive disease, combination docetaxel and nintedanib could be an alternative regime for them, and it seems to be better than docetaxel monotherapy. We don’t seem to have these data the same way for combination docetaxel and ramucirumab. In terms of immunotherapy, we know that with nivolumab the extent of benefit of nivolumab is very much contingent on the PD-L1 status. And in patients with either low PD-L1 status or tumors that are rapidly progressive, or patients that are becoming frail, the benefit of immunotherapies such as nivolumab may be minimal. And for those patients, cytotoxic-based chemotherapy with docetaxel, with the addition of perhaps nintedanib, may be an optimal strategy.

Martin Reck, MD, PhD: In the recent trials that have been published for second-line treatment of patients with advanced non–small cell lung cancer—in particular in those trials investigating the efficacy of antiangiogenic agents in combination with chemotherapy—we have seen that there is a pronounced efficacy of these combinations in patients with fast-growing tumors. And this is something new. We haven’t seen this before, and we haven’t assessed this before. But, now, in my clinical practice, I check the carrier of my patients with regard of the interval between the time of the first diagnosis, the time of relapse, and whether I can get some flavor if this is a fast growing tumor or not. And, indeed, this characteristic does impact my decision on my treatment selection.

Anders Mellemgaard, MD: I think one thing that we have become aware of is that the interval from first- to second-line treatment actually tells us something about the biology of the cancer. When selecting a second-line treatment for a patient, a short interval indicates aggressive nature of the tumor, and probably also indicates that this particular tumor is dependent on new vasculature. So, the addition of antiangiogenic treatment makes more sense in tumors that are progressing rapidly. For that reason, I think it’s important to look at this particular factor when selecting a treatment. And we see different outcomes when we look at recent trials.

For example, we see with antiangiogenic agents, such as ramucirumab or nintedanib, the fact that the shorter the interval, the bigger the effect. But, we see the reverse when we look at the checkpoint inhibitors. If there is a good long interval from first to second line, the benefit from immune therapy is bigger.

Transcript Edited for Clarity
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