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Immunotherapy in Stage III NSCLC

Panelists: Mark A. Socinski, MD, AdventHealth Cancer Institute; Paul K. Paik, MD, Memorial Sloan Kettering Cancer Center; Kristin Higgins, MD, Emory Healthcare; Corey J. Langer, MD, Hospital of the University of Pennsylvania; Heather A. Wakelee, MD, Stanford University Medical Center; Ticiana A. Leal, MD, University of Wisconsin School of Medicine and Public Health
Published: Tuesday, Jul 02, 2019

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Transcript: 

Mark A. Socinski, MD: Corey, I want to get your perspective. In the United States, the approval for this is agnostic to PD-L1 [programmed death-ligand 1] status. That is not the case across the ocean, in Europe, where there is some language in the…. If you could just walk us through that analysis that was just done?

Corey J. Langer, MD: There’s a hypothesis-generating subanalysis as part of this trial that analyzed PD-L1 status, and it realized just a bare majority actually had tissue that was sent for PD-L1. A significant minority did not. In this analysis, those who had absolutely no PD-L1 expression, at least in the context of this trial, did not have a survival advantage. If anything, the trend was in the wrong direction.

Mark A. Socinski, MD: But confidence intervals that were quite wide?

Corey J. Langer, MD: Confidence intervals were wide. They overlapped unity. And Europe has taken this to heart. Whether it’s a clinical decision or a financial decision, the approval is restricted to PD-L1–positive disease. I have to confess, I embrace this approach with enthusiasm in anybody who’s PD-L1–positive. I have a certain degree of ambivalence in PD-L1–negative cases. I will still offer it. If the patient and their family are intelligent enough or well versed enough, I’ll actually go over the nuances of the PD-L1 testing.

Mark A. Socinski, MD: So are you and others routinely checking PD-L1 in this setting?

Corey J. Langer, MD: Increasingly, in part because of this trial, and in part because it may inform subsequent therapeutic decisions if they develop disease progression.

Paul K. Paik, MD: I have to agree with Corey. I think he summarized some of the reservations I had initially with the PACIFIC trial. Ultimately, it’s billed as a real-world trial, which, to my years as a scientist, sounds like an uncontrolled trial for at least 50% of it. Notwithstanding that, the overall survival advantage is compelling. But I agree. That subset analysis, for me, based on PD-L1 expression, it’s not that this comes out of the blue. We have, time and again, seen that PD-L1–negative patients don’t derive a lot of benefit from PD-1 [programmed cell death protein 1], PD-L1 checkpoint inhibitors. So this is in the context of that. And there is a risk that there is some harm that might be present. So I think at a minimum, having that discussion with a patient, the context of a negative PD-L1 test, is what I routinely do. And I try to make it as understandable as possible to help navigate through that. It’s also a year of treatments. It’s every 2 weeks. It’s a commitment. For a lot of people, it can be tough.

Heather A. Wakelee, MD: I do want to make sure we talk about the toxicity, too, right?

Mark A. Socinski, MD: Yes.

Heather A. Wakelee, MD: Compared to many of our cytotoxic chemotherapies, certainly immune-based treatments, in general, are pretty well tolerated. But these are not. I’m giving durvalumab, but it’s not without the potential for long-term toxicity. I have never prescribed as much in terms of thyroid replacement hormones until I started giving immune therapy.

Mark A. Socinski, MD: I can agree, yes.

Heather A. Wakelee, MD: Right? And that’s not a toxicity that’s going to resolve, right?

Mark A. Socinski, MD: Right.

Heather A. Wakelee, MD: There are some significant long-term issues, especially if someone has the toxicity and then still has a recurrence of disease, which we know is going to happen—maybe not in the majority, but certainly very close to that. As we look at those survival data and the disease-free survival, it still probably is going to be most of the patients at some point recur although the cure rates are increasing. I think that’s what we’re also enthusiastic about with this trial. I certainly offer durvalumab to my patients who’ve gone through concurrent chemoradiation. But we have to have those discussions and look. And if there are predictors where maybe someone’s not going to benefit, we need to continue to look for that, so that we’re not giving people this long-term risk.

Mark A. Socinski, MD: But you would agree, I think, that there were no surprises? I want to get Kristin’s thoughts. One of the concerns during this trial was immunotherapy, pneumonitis; after radiation, pneumonitis. To your point, the radiation [did not necessarily undergo quality assurance.] And surprisingly, the difference was not alarming. In fact, there was no difference in grade 3 or 4.

Kristin Higgins, MD: That’s exactly right. We did not see high-grade pneumonitis with durvalumab. It is important, however, that you are aware that it could develop. If you are seeing signs of pneumonitis, it is important that you pick up the phone, call your radiation oncologist, and try to figure out if the radiographic changes are in the radiation field to understand if you think it’s driven by radiation versus the durvalumab. Because there certainly would be consequences. And then, it’s of course important to get treatment started for these toxicities if you see them developing.

Mark A. Socinski, MD: So it sounds like we have consensus that, in the appropriate patient, this is a new standard of care.

Corey J. Langer, MD: Absolutely. It was practice-changing. We went 25 years without a single positive trial in this realm. Concurrent chemoradiation was your standard of practice in that entire period.

Mark A. Socinski, MD: So here’s the million-dollar question: What do you do when the patient relapses after a year? Let’s say they relapsed within 6 months of completion of durvalumab? Or what do you do if they relapse 2 years later?

Heather A. Wakelee, MD: I’m going to talk about EGFR again, because, in my practice, of my patients who have come in, many of them, because of the nature of our practice, have had EGFR known mutations and have been treated with the PACIFIC regimen. They got their concurrent chemoradiation. They’ve been on durvalumab. They have relapsed—some of them, but not all of them, of course. But as we would expect, some have. And then, in the setting where someone’s already had exposure to immune therapy, there are separate risks that come into play when you’re then challenging them with EGFR therapy. And so, I’ve actually had some issues where I’ve been concerned about giving osimertinib directly after giving durvalumab or any other immune therapy. We’ve actually gone back to using a bit more of erlotinib in that setting. So that’s just something for people to be aware of. There is some potential increased risk of pneumonitis with osimertinib in combination or directly after immune therapy compared to some of the other TKIs [tyrosine kinase inhibitors].

Now, that’s more in the kind of setting where they’re relapsing during treatment, as opposed to, if it’s been 6 months, I wouldn’t be as worried about that. And if they aren’t going to be getting an EGFR therapy or other targeted treatment, again, looking at the timing; but I’m usually going to give combination chemotherapy plus immune therapy for those patients if they don’t have a driver mutation.

Mark A. Socinski, MD: Corey, your thoughts?

Corey J. Langer, MD: If it’s 6 months or more I’ll usually reinstitute immune therapy with chemotherapy. If it’s during it, I will go with chemotherapy alone, although I think that’s still a testable question as well. And again, it’s histology appropriate. Chemotherapy, even if they’ve previously been exposed to chemotherapy. By definition, these folks have gotten concurrent chemoradiation.

I think the point you’re making about immediately following immunotherapy with a TKI in the EGFR-positive population is something that’s certainly coming out in stage IV disease, and it’s a growing concern in this population. Only 40 or so patients even had an EGFR mutation on the trial. And granted, their PFS [progression-free survival], the hazard ratio is a bit higher. It was still on the right side of 1.

Heather A. Wakelee, MD: Right, which is why we’re treating it.

Corey J. Langer, MD: And regarding the survival, we haven’t even seen the forest plots for that group. So I have offered this regimen to at least the EGFR-mutant patients.

Transcript Edited for Clarity

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Transcript: 

Mark A. Socinski, MD: Corey, I want to get your perspective. In the United States, the approval for this is agnostic to PD-L1 [programmed death-ligand 1] status. That is not the case across the ocean, in Europe, where there is some language in the…. If you could just walk us through that analysis that was just done?

Corey J. Langer, MD: There’s a hypothesis-generating subanalysis as part of this trial that analyzed PD-L1 status, and it realized just a bare majority actually had tissue that was sent for PD-L1. A significant minority did not. In this analysis, those who had absolutely no PD-L1 expression, at least in the context of this trial, did not have a survival advantage. If anything, the trend was in the wrong direction.

Mark A. Socinski, MD: But confidence intervals that were quite wide?

Corey J. Langer, MD: Confidence intervals were wide. They overlapped unity. And Europe has taken this to heart. Whether it’s a clinical decision or a financial decision, the approval is restricted to PD-L1–positive disease. I have to confess, I embrace this approach with enthusiasm in anybody who’s PD-L1–positive. I have a certain degree of ambivalence in PD-L1–negative cases. I will still offer it. If the patient and their family are intelligent enough or well versed enough, I’ll actually go over the nuances of the PD-L1 testing.

Mark A. Socinski, MD: So are you and others routinely checking PD-L1 in this setting?

Corey J. Langer, MD: Increasingly, in part because of this trial, and in part because it may inform subsequent therapeutic decisions if they develop disease progression.

Paul K. Paik, MD: I have to agree with Corey. I think he summarized some of the reservations I had initially with the PACIFIC trial. Ultimately, it’s billed as a real-world trial, which, to my years as a scientist, sounds like an uncontrolled trial for at least 50% of it. Notwithstanding that, the overall survival advantage is compelling. But I agree. That subset analysis, for me, based on PD-L1 expression, it’s not that this comes out of the blue. We have, time and again, seen that PD-L1–negative patients don’t derive a lot of benefit from PD-1 [programmed cell death protein 1], PD-L1 checkpoint inhibitors. So this is in the context of that. And there is a risk that there is some harm that might be present. So I think at a minimum, having that discussion with a patient, the context of a negative PD-L1 test, is what I routinely do. And I try to make it as understandable as possible to help navigate through that. It’s also a year of treatments. It’s every 2 weeks. It’s a commitment. For a lot of people, it can be tough.

Heather A. Wakelee, MD: I do want to make sure we talk about the toxicity, too, right?

Mark A. Socinski, MD: Yes.

Heather A. Wakelee, MD: Compared to many of our cytotoxic chemotherapies, certainly immune-based treatments, in general, are pretty well tolerated. But these are not. I’m giving durvalumab, but it’s not without the potential for long-term toxicity. I have never prescribed as much in terms of thyroid replacement hormones until I started giving immune therapy.

Mark A. Socinski, MD: I can agree, yes.

Heather A. Wakelee, MD: Right? And that’s not a toxicity that’s going to resolve, right?

Mark A. Socinski, MD: Right.

Heather A. Wakelee, MD: There are some significant long-term issues, especially if someone has the toxicity and then still has a recurrence of disease, which we know is going to happen—maybe not in the majority, but certainly very close to that. As we look at those survival data and the disease-free survival, it still probably is going to be most of the patients at some point recur although the cure rates are increasing. I think that’s what we’re also enthusiastic about with this trial. I certainly offer durvalumab to my patients who’ve gone through concurrent chemoradiation. But we have to have those discussions and look. And if there are predictors where maybe someone’s not going to benefit, we need to continue to look for that, so that we’re not giving people this long-term risk.

Mark A. Socinski, MD: But you would agree, I think, that there were no surprises? I want to get Kristin’s thoughts. One of the concerns during this trial was immunotherapy, pneumonitis; after radiation, pneumonitis. To your point, the radiation [did not necessarily undergo quality assurance.] And surprisingly, the difference was not alarming. In fact, there was no difference in grade 3 or 4.

Kristin Higgins, MD: That’s exactly right. We did not see high-grade pneumonitis with durvalumab. It is important, however, that you are aware that it could develop. If you are seeing signs of pneumonitis, it is important that you pick up the phone, call your radiation oncologist, and try to figure out if the radiographic changes are in the radiation field to understand if you think it’s driven by radiation versus the durvalumab. Because there certainly would be consequences. And then, it’s of course important to get treatment started for these toxicities if you see them developing.

Mark A. Socinski, MD: So it sounds like we have consensus that, in the appropriate patient, this is a new standard of care.

Corey J. Langer, MD: Absolutely. It was practice-changing. We went 25 years without a single positive trial in this realm. Concurrent chemoradiation was your standard of practice in that entire period.

Mark A. Socinski, MD: So here’s the million-dollar question: What do you do when the patient relapses after a year? Let’s say they relapsed within 6 months of completion of durvalumab? Or what do you do if they relapse 2 years later?

Heather A. Wakelee, MD: I’m going to talk about EGFR again, because, in my practice, of my patients who have come in, many of them, because of the nature of our practice, have had EGFR known mutations and have been treated with the PACIFIC regimen. They got their concurrent chemoradiation. They’ve been on durvalumab. They have relapsed—some of them, but not all of them, of course. But as we would expect, some have. And then, in the setting where someone’s already had exposure to immune therapy, there are separate risks that come into play when you’re then challenging them with EGFR therapy. And so, I’ve actually had some issues where I’ve been concerned about giving osimertinib directly after giving durvalumab or any other immune therapy. We’ve actually gone back to using a bit more of erlotinib in that setting. So that’s just something for people to be aware of. There is some potential increased risk of pneumonitis with osimertinib in combination or directly after immune therapy compared to some of the other TKIs [tyrosine kinase inhibitors].

Now, that’s more in the kind of setting where they’re relapsing during treatment, as opposed to, if it’s been 6 months, I wouldn’t be as worried about that. And if they aren’t going to be getting an EGFR therapy or other targeted treatment, again, looking at the timing; but I’m usually going to give combination chemotherapy plus immune therapy for those patients if they don’t have a driver mutation.

Mark A. Socinski, MD: Corey, your thoughts?

Corey J. Langer, MD: If it’s 6 months or more I’ll usually reinstitute immune therapy with chemotherapy. If it’s during it, I will go with chemotherapy alone, although I think that’s still a testable question as well. And again, it’s histology appropriate. Chemotherapy, even if they’ve previously been exposed to chemotherapy. By definition, these folks have gotten concurrent chemoradiation.

I think the point you’re making about immediately following immunotherapy with a TKI in the EGFR-positive population is something that’s certainly coming out in stage IV disease, and it’s a growing concern in this population. Only 40 or so patients even had an EGFR mutation on the trial. And granted, their PFS [progression-free survival], the hazard ratio is a bit higher. It was still on the right side of 1.

Heather A. Wakelee, MD: Right, which is why we’re treating it.

Corey J. Langer, MD: And regarding the survival, we haven’t even seen the forest plots for that group. So I have offered this regimen to at least the EGFR-mutant patients.

Transcript Edited for Clarity
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