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Combination Approaches for Second-Line Therapy for NSCLC

Panelists: Everett Vokes, MD, University of Chicago Medicine and Biological Sciences; Roy Herbst, MD, PhD, Yale Cancer Center; Fred Hirsch, MD, PhD, University of Colorado School of Medicine; Suresh Ramalingam, MD, Winship Cancer Institute Emory University; Naiyer Rizvi, MD, Columbia University Medical Center
Published: Tuesday, Oct 03, 2017



Transcript:

Everett Vokes, MD:
We already talked about how long immunotherapy should be given for. Naiyer, is there any reason to assume this would be different for the second-line setting versus the first-line setting?

Naiyer Rizvi, MD: No. I mean, the sort of treatment paradigm is the same.

Everett Vokes, MD: And what about the combination, then, of chemotherapy and of a PD-1 inhibitor, such as pembrolizumab or nivolumab? In the first-line setting, we’ve seen promising data. Is there any similar information in the second-line setting, say, in combining it with a taxane?

Suresh Ramalingam, MD: The key question is, if a patient already got immunotherapy in the first-line setting and they progressed, and you’re searching for a platinum-doublet, should you continue the immunotherapy forward along with the chemotherapy? Or should we just do a clean cut and go in a different direction? We don’t know the answer to the question, but the good news is, the Eastern Cooperative Oncology Group (ECOG) and SWOG investigators (some of Roy’s colleagues) are working on this trial to understand that question, specifically, in a randomized clinical trial. So, we need to start thinking in that direction.

At this point, though, I would say there are some promising approaches in combining chemotherapy with checkpoint inhibition. We saw one trial, at this meeting, for combining nab-paclitaxel with durvalumab, which seemed to have a progression-free survival in the order of about 4.5 to 5 months. There are things that I think will have to be tested further in larger cohorts and randomized settings. I know that the Lung-MAP study that Roy is spearheading with SWOG and other groups is very interested in developing combination approaches in the second-line setting with immunotherapy-based approaches. I think that’s going to provide us with new insight into what combinations will be effective for patients.

Everett Vokes, MD: We have a trial that just started that is slightly based on this kind of thinking—where nivolumab is given as the standard and then the experimental arm is nivolumab plus nab-paclitaxel. So, when looking at the interaction of a PD-1 inhibitor, it’s a little bit similar to what KEYNOTE-021g did, first-line. In that context, Roy, the Lung-MAP study is really the national trial for second-line therapies. It had originally been squamous cell only, but you’re in the process of changing and broadening this, right?

Roy Herbst, MD, PhD: Right. The feeling was, why are drivers only important in squamous cell? Also, it turned out that most of the drugs (the combinations that were being studied) were immunotherapy combinations. So, the new version Lung-MAP, which is just about to launch, will actually have all tumor types allowed. We’re looking, still, at driver targets and armed antibodies against driver targets. Actually, Fred is very involved in the translational aspects of this. But then, we also have to look at immune combinations. The idea would be to look at, you know, and IO-IO (immune-oncology and immune-oncology) combinations.

Now, the good news is, we’re going to have a large final number of patients. All patients are going to have biopsies, so we’ll be able to look and correlate activity with the biopsies. The hardest part of this is finding those combinations that had enough phase I data, that have either preclinical data or data of activity in lung or other tumor types, to move forward. That’s been our challenge.

But actually, we are very excited about a couple of combinations, mostly combinations that are looking at a PD-1 agent plus an agent that might inflame the microenvironment (like an interleukin of some sort or antiangiogenesis inhibitor) in combination with immune therapy. So, we’re very actively working. The nice thing about Lung-MAP, as you know, is all the groups are working together.

Everett Vokes, MD: Yes, and getting along.

Fred Hirsch, MD, PhD: And the view with this infrastructure is that we can actually adopt to the rapid progression in the field. Since we started Lung-MAP, we have been able to modify the Lung-MAP structure and the designs accordingly to what has happened in the field. That has been quite encouraging.

Everett Vokes, MD: Roy, I just want to follow up a little bit on this. You mentioned IO-IO combinations. Why not test IO-chemotherapy combinations for second-line therapy?

Roy Herbst, MD, PhD: That’s a good thought, and that’s being looked at. And I always felt, when I saw the KEYNOTE-021 data, that this might be the place to use these agents. In the frontline setting, we had a group that’s high that can get these drugs alone. But, it might be that in the second-line, that might be exactly where to use it—in patients that are PD-L1 low or totally absent—and to use chemotherapy plus IO. I think that certainly could be an approach. We’re going to have a common control in the Lung-MAP, which will probably be some sort of chemotherapy.

Everett Vokes, MD: Wouldn’t it also allow us to look a little bit at this scientific evolution, then, of PD-L1 expression in a course of getting chemotherapy as opposed to those not getting chemotherapy and seeing how dynamic that biomarker really is?

Roy Herbst, MD, PhD: Yes, I agree. That’s certainly something to think about. There aren’t that many patients who are going to be, as Ram [Suresh] said, in the second-line. Do we keep the drug going or not? I think those are very reasonable approaches, as well.

Transcript Edited for Clarity 

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Transcript:

Everett Vokes, MD:
We already talked about how long immunotherapy should be given for. Naiyer, is there any reason to assume this would be different for the second-line setting versus the first-line setting?

Naiyer Rizvi, MD: No. I mean, the sort of treatment paradigm is the same.

Everett Vokes, MD: And what about the combination, then, of chemotherapy and of a PD-1 inhibitor, such as pembrolizumab or nivolumab? In the first-line setting, we’ve seen promising data. Is there any similar information in the second-line setting, say, in combining it with a taxane?

Suresh Ramalingam, MD: The key question is, if a patient already got immunotherapy in the first-line setting and they progressed, and you’re searching for a platinum-doublet, should you continue the immunotherapy forward along with the chemotherapy? Or should we just do a clean cut and go in a different direction? We don’t know the answer to the question, but the good news is, the Eastern Cooperative Oncology Group (ECOG) and SWOG investigators (some of Roy’s colleagues) are working on this trial to understand that question, specifically, in a randomized clinical trial. So, we need to start thinking in that direction.

At this point, though, I would say there are some promising approaches in combining chemotherapy with checkpoint inhibition. We saw one trial, at this meeting, for combining nab-paclitaxel with durvalumab, which seemed to have a progression-free survival in the order of about 4.5 to 5 months. There are things that I think will have to be tested further in larger cohorts and randomized settings. I know that the Lung-MAP study that Roy is spearheading with SWOG and other groups is very interested in developing combination approaches in the second-line setting with immunotherapy-based approaches. I think that’s going to provide us with new insight into what combinations will be effective for patients.

Everett Vokes, MD: We have a trial that just started that is slightly based on this kind of thinking—where nivolumab is given as the standard and then the experimental arm is nivolumab plus nab-paclitaxel. So, when looking at the interaction of a PD-1 inhibitor, it’s a little bit similar to what KEYNOTE-021g did, first-line. In that context, Roy, the Lung-MAP study is really the national trial for second-line therapies. It had originally been squamous cell only, but you’re in the process of changing and broadening this, right?

Roy Herbst, MD, PhD: Right. The feeling was, why are drivers only important in squamous cell? Also, it turned out that most of the drugs (the combinations that were being studied) were immunotherapy combinations. So, the new version Lung-MAP, which is just about to launch, will actually have all tumor types allowed. We’re looking, still, at driver targets and armed antibodies against driver targets. Actually, Fred is very involved in the translational aspects of this. But then, we also have to look at immune combinations. The idea would be to look at, you know, and IO-IO (immune-oncology and immune-oncology) combinations.

Now, the good news is, we’re going to have a large final number of patients. All patients are going to have biopsies, so we’ll be able to look and correlate activity with the biopsies. The hardest part of this is finding those combinations that had enough phase I data, that have either preclinical data or data of activity in lung or other tumor types, to move forward. That’s been our challenge.

But actually, we are very excited about a couple of combinations, mostly combinations that are looking at a PD-1 agent plus an agent that might inflame the microenvironment (like an interleukin of some sort or antiangiogenesis inhibitor) in combination with immune therapy. So, we’re very actively working. The nice thing about Lung-MAP, as you know, is all the groups are working together.

Everett Vokes, MD: Yes, and getting along.

Fred Hirsch, MD, PhD: And the view with this infrastructure is that we can actually adopt to the rapid progression in the field. Since we started Lung-MAP, we have been able to modify the Lung-MAP structure and the designs accordingly to what has happened in the field. That has been quite encouraging.

Everett Vokes, MD: Roy, I just want to follow up a little bit on this. You mentioned IO-IO combinations. Why not test IO-chemotherapy combinations for second-line therapy?

Roy Herbst, MD, PhD: That’s a good thought, and that’s being looked at. And I always felt, when I saw the KEYNOTE-021 data, that this might be the place to use these agents. In the frontline setting, we had a group that’s high that can get these drugs alone. But, it might be that in the second-line, that might be exactly where to use it—in patients that are PD-L1 low or totally absent—and to use chemotherapy plus IO. I think that certainly could be an approach. We’re going to have a common control in the Lung-MAP, which will probably be some sort of chemotherapy.

Everett Vokes, MD: Wouldn’t it also allow us to look a little bit at this scientific evolution, then, of PD-L1 expression in a course of getting chemotherapy as opposed to those not getting chemotherapy and seeing how dynamic that biomarker really is?

Roy Herbst, MD, PhD: Yes, I agree. That’s certainly something to think about. There aren’t that many patients who are going to be, as Ram [Suresh] said, in the second-line. Do we keep the drug going or not? I think those are very reasonable approaches, as well.

Transcript Edited for Clarity 
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