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Treatment of Unresectable Locally Advanced NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Hossein Borghaei, DO, MS, Fox Chase Cancer Center; Roy S. Herbst, MD, PhD, Yale Cancer Center; Suresh S. Ramalingam, MD, Emory University School of Medicine; Naiyer A. Rizvi, MD, Columbia University Medical Center; Thomas E. Stinchcombe, MD, Duke Cancer Institute
Published: Wednesday, Feb 28, 2018



Transcript: 

Benjamin P. Levy, MD: So, let’s move on. That’s a nice segue, Roy, into the PACIFIC trial. This has obviously been an interesting year, and certainly practice-changing data have emerged with looking at consolidation immunotherapy, post concurrent chemoradiation, for these patients. And so, Naiyer, you want to walk us through the PACIFIC trial, the design and rationale and what we found out from this data?

Naiyer A. Rizvi, MD: Sure. So, the PACIFIC trial was consolidation durvalumab, a PD-L1 antibody after concurrent chemotherapy and radiation therapy for unresectable stage 3 disease. It was a phase III randomized trial, 2:1 to durvalumab every 2 weeks for 1 year or placebo. It was an interesting trial because it was designed at a time where we were first gaining experience with these agents. We were nervous about pneumonitis a few years back. And so, I think it was a bold trial, to give a chemotherapy/RT regimen that induces pneumonitis and then follow that with a PD-L1 antibody that also induces pneumonitis. I think it was definitely a groundbreaking sort of experience.

Nevertheless, the data with this trial were reported out last year and published in the New England Journal of Medicine, and the co-primary and primary endpoints were progression-free survival and overall survival. The trial is not mature enough for overall survival yet, but certainly for progression-free survival there was a difference that was statistically significant. It was a number, I think, much bigger than any of us expected. The PFS went from just under 6 months to close to 18 months, just under 18 months, so about a year improvement in progression-free survival. There was also a significant reduction in distant metastases. There’s actually half the number of brain metastases that developed on the durvalumab consolidation. And I think, also as importantly, we really didn’t find any significant excess of pneumonitis or autoimmune AE, suggesting that this was very tolerable.

Benjamin P. Levy, MD: Yes, and in that data set, one of the things I found interesting was the safety profile. The pneumonitis rate in the durvalumab arm was around 5%, which right after radiation, I would have thought it would have been higher, certainly some biological rationale to believe that. But we didn’t see that. Some of the other interesting parts of that trial were that it benefitted all patients independent of their PD-L1. It didn’t seem to matter. Hoss, you have any comments on that?

Hossein Borghaei, DO, MS: No, I think it was very interesting. The only minor comment I would say is that we have data now for less than 25% or greater than 25% PD-L1 expression, but we technically don’t know what happened to PD-L1 0s, for instance. It’s a minor difference there. But I agree that overall, when you look at it, every subgroup benefitted from the addition of durvalumab, which goes back to the fact that I think maybe PD-L1 is not really the good marker that everybody thinks it is for these kinds of studies, which is a separate discussion. But I agree.

Benjamin P. Levy, MD: The one group, interestingly, where there was confidence interval cross unity was the EGFR-mutant patients, and that was a small group. And whether they would benefit or not is unclear. Would people feel comfortable with an unresectable EGFR-mutant patient getting concurrent chemoradiation, giving them the durvalumab based on these data?

Roy S. Herbst, MD, PhD: Well, I would give them an EGFR inhibitor. Getting back to this, I think that we don’t know what the PD-L1 status is after chemoradiation, and it’s very likely that after some chemotherapy and radiation, you inflame the tumor, you brought T cells into the tumor, and that microenvironment could have changed. In fact, many theorized that that could be one of the reasons why this works so well. Of course, we need data and I think future studies probably will include biopsies. But I think that’s probably a big part of it. You inflame the microenvironment, you have T cells there, and now you’re relieving the checkpoint.

Naiyer A. Rizvi, MD: I think that this is good potential proof of concept of synergy with radiation plus or minus chemotherapy. The subgroup of patients who were able to be randomized within 14 days of the completion of chemotherapy/RT actually had a more favorable hazard ratio than those who were randomized beyond 14 days. You’re allowed to go on anywhere from 1 to 42 days post therapy, and the sooner you got it, the better you did. And that could be that the patients who had to wait, maybe they had more comorbidities, other things going on, or it could represent true synergy.

Benjamin P. Levy, MD: Yes, you stole my thunder there. Tucked away in the appendix is the subset analysis between the patients who got treatment up to 14 days, a hazard ratio of 0.39, and that’s fairly compelling, which gets me back to the question we were asking before about consolidation chemotherapy. So, now we have a patient who’s stage 3 who’s getting weekly carboplatin/paclitaxel. Do we now say we don’t give consolidation because we’ve got to give the durvalumab right away based on this analysis? We’ve had some comment on this in the tumor board because, like Hoss, I’ve had some uncomfortability not giving consolidation carboplatin when I’m giving the weekly. Based on these data, I would think that the sooner the better for these patients.

Hossein Borghaei, DO, MS: I think you can definitely argue that now that you have the durvalumab data, it’s just that, again, it’s one of those unknown pieces based on a large study or it didn’t really drill down to see who got consolidation, who didn’t, who got carboplatin/Taxol, who didn’t. So, we don’t have that data, but I don’t think I would argue with someone who says, “After weekly carboplatin/Taxol, patient is doing well. I just want to go to durvalumab.” I don’t think I would have any objections to treating patients like that, given the magnitude of benefit that you’re seeing from durvalumab.

Thomas E. Stinchcombe, MD: I think the consolidation carboplatin/Taxol is more out of habit than evidence, which is a little bit of a concern. Now, some of those patients got induction chemotherapy—so they might have gotten this on the PACIFIC trial, so it’s really hard to tease out a role—but I think patients are in a precarious position. I feel much more comfortable just moving to durvalumab and dropping the carboplatin/Taxol.

Suresh S. Ramalingam, MD: And it’s important to keep in mind that the PACIFIC trial did not include consolidation chemotherapy.

Benjamin P. Levy, MD: That’s right, induction interestingly enough. About one-third of patients, 25%, got induction but not consolidation.

Suresh S. Ramalingam, MD: So, that should reassure people who are thinking about giving durvalumab about not being hung up over consolidation or not. They can complete chemotherapy/RT and, if the patient is doing well, continue on to consolidation.

Hossein Borghaei, DO, MS: I think the only point that I would emphasize in this panel is that we are extrapolating a little bit. Again, we don’t have the data necessarily to say that’s exactly what happened, right? Because we don’t know what happened. The chemotherapy/RT part of the PACIFIC is a little bit of an unknown because everybody does something a little different. But we are trying to extrapolate to say that if you don’t give consolidation after low-dose weekly carboplatin/Taxol, durvalumab should be just as effective, given the fact that, as Roy just suggested, it could be because of the inflamed tumor and effect of the radiation. I think it’s a reasonable assumption. We just don’t have the data necessarily.

Roy S. Herbst, MD, PhD: And also, I’m not a big believer that you’re going to cure anyone with lung cancer with chemotherapy. But I am becoming a bit of a believer that you can do that with immunotherapy. The last thing we would want would be to lose that window of opportunity.

Hossein Borghaei, DO, MS: Absolutely.

Roy S. Herbst, MD, PhD: I’d say, given the whole data set, I’d probably want to get the durvalumab in as quickly as possible.

Benjamin P. Levy, MD: Does everybody feel comfortable giving durvalumab at this point, based on the data? Are there patients we wouldn’t give it to? Are we having insurance pushback? Not to bring too much of a financial consideration here, but is everyone getting this done in their patients?

Suresh S. Ramalingam, MD: I’m sure there are patients in whom we wouldn’t want to use checkpoint inhibition, the usual contraindications: preexisting autoimmune disease, patients who received an organ transplant or have serious comorbid conditions, pneumonitis or underlying severe pulmonary disease. But if you have a patient with good performance status who didn’t have any other obvious contraindications, I would say I feel comfortable giving durvalumab.

Naiyer A. Rizvi, MD: One observation is that the uptake has been very strong. At our place, it’s unusual to put a drug on formulary that’s not FDA approved yet. It’s in the NCCN. It’s probably going to be approved by the FDA soon. But they actually did, based on these data, agree to put it on formulary and we’ve been using it pretty regularly. In the community, it seems like the uptake is good as well. I guess one question that I would have is, is there any role for surgery in stage 3 lung cancer?

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: So, let’s move on. That’s a nice segue, Roy, into the PACIFIC trial. This has obviously been an interesting year, and certainly practice-changing data have emerged with looking at consolidation immunotherapy, post concurrent chemoradiation, for these patients. And so, Naiyer, you want to walk us through the PACIFIC trial, the design and rationale and what we found out from this data?

Naiyer A. Rizvi, MD: Sure. So, the PACIFIC trial was consolidation durvalumab, a PD-L1 antibody after concurrent chemotherapy and radiation therapy for unresectable stage 3 disease. It was a phase III randomized trial, 2:1 to durvalumab every 2 weeks for 1 year or placebo. It was an interesting trial because it was designed at a time where we were first gaining experience with these agents. We were nervous about pneumonitis a few years back. And so, I think it was a bold trial, to give a chemotherapy/RT regimen that induces pneumonitis and then follow that with a PD-L1 antibody that also induces pneumonitis. I think it was definitely a groundbreaking sort of experience.

Nevertheless, the data with this trial were reported out last year and published in the New England Journal of Medicine, and the co-primary and primary endpoints were progression-free survival and overall survival. The trial is not mature enough for overall survival yet, but certainly for progression-free survival there was a difference that was statistically significant. It was a number, I think, much bigger than any of us expected. The PFS went from just under 6 months to close to 18 months, just under 18 months, so about a year improvement in progression-free survival. There was also a significant reduction in distant metastases. There’s actually half the number of brain metastases that developed on the durvalumab consolidation. And I think, also as importantly, we really didn’t find any significant excess of pneumonitis or autoimmune AE, suggesting that this was very tolerable.

Benjamin P. Levy, MD: Yes, and in that data set, one of the things I found interesting was the safety profile. The pneumonitis rate in the durvalumab arm was around 5%, which right after radiation, I would have thought it would have been higher, certainly some biological rationale to believe that. But we didn’t see that. Some of the other interesting parts of that trial were that it benefitted all patients independent of their PD-L1. It didn’t seem to matter. Hoss, you have any comments on that?

Hossein Borghaei, DO, MS: No, I think it was very interesting. The only minor comment I would say is that we have data now for less than 25% or greater than 25% PD-L1 expression, but we technically don’t know what happened to PD-L1 0s, for instance. It’s a minor difference there. But I agree that overall, when you look at it, every subgroup benefitted from the addition of durvalumab, which goes back to the fact that I think maybe PD-L1 is not really the good marker that everybody thinks it is for these kinds of studies, which is a separate discussion. But I agree.

Benjamin P. Levy, MD: The one group, interestingly, where there was confidence interval cross unity was the EGFR-mutant patients, and that was a small group. And whether they would benefit or not is unclear. Would people feel comfortable with an unresectable EGFR-mutant patient getting concurrent chemoradiation, giving them the durvalumab based on these data?

Roy S. Herbst, MD, PhD: Well, I would give them an EGFR inhibitor. Getting back to this, I think that we don’t know what the PD-L1 status is after chemoradiation, and it’s very likely that after some chemotherapy and radiation, you inflame the tumor, you brought T cells into the tumor, and that microenvironment could have changed. In fact, many theorized that that could be one of the reasons why this works so well. Of course, we need data and I think future studies probably will include biopsies. But I think that’s probably a big part of it. You inflame the microenvironment, you have T cells there, and now you’re relieving the checkpoint.

Naiyer A. Rizvi, MD: I think that this is good potential proof of concept of synergy with radiation plus or minus chemotherapy. The subgroup of patients who were able to be randomized within 14 days of the completion of chemotherapy/RT actually had a more favorable hazard ratio than those who were randomized beyond 14 days. You’re allowed to go on anywhere from 1 to 42 days post therapy, and the sooner you got it, the better you did. And that could be that the patients who had to wait, maybe they had more comorbidities, other things going on, or it could represent true synergy.

Benjamin P. Levy, MD: Yes, you stole my thunder there. Tucked away in the appendix is the subset analysis between the patients who got treatment up to 14 days, a hazard ratio of 0.39, and that’s fairly compelling, which gets me back to the question we were asking before about consolidation chemotherapy. So, now we have a patient who’s stage 3 who’s getting weekly carboplatin/paclitaxel. Do we now say we don’t give consolidation because we’ve got to give the durvalumab right away based on this analysis? We’ve had some comment on this in the tumor board because, like Hoss, I’ve had some uncomfortability not giving consolidation carboplatin when I’m giving the weekly. Based on these data, I would think that the sooner the better for these patients.

Hossein Borghaei, DO, MS: I think you can definitely argue that now that you have the durvalumab data, it’s just that, again, it’s one of those unknown pieces based on a large study or it didn’t really drill down to see who got consolidation, who didn’t, who got carboplatin/Taxol, who didn’t. So, we don’t have that data, but I don’t think I would argue with someone who says, “After weekly carboplatin/Taxol, patient is doing well. I just want to go to durvalumab.” I don’t think I would have any objections to treating patients like that, given the magnitude of benefit that you’re seeing from durvalumab.

Thomas E. Stinchcombe, MD: I think the consolidation carboplatin/Taxol is more out of habit than evidence, which is a little bit of a concern. Now, some of those patients got induction chemotherapy—so they might have gotten this on the PACIFIC trial, so it’s really hard to tease out a role—but I think patients are in a precarious position. I feel much more comfortable just moving to durvalumab and dropping the carboplatin/Taxol.

Suresh S. Ramalingam, MD: And it’s important to keep in mind that the PACIFIC trial did not include consolidation chemotherapy.

Benjamin P. Levy, MD: That’s right, induction interestingly enough. About one-third of patients, 25%, got induction but not consolidation.

Suresh S. Ramalingam, MD: So, that should reassure people who are thinking about giving durvalumab about not being hung up over consolidation or not. They can complete chemotherapy/RT and, if the patient is doing well, continue on to consolidation.

Hossein Borghaei, DO, MS: I think the only point that I would emphasize in this panel is that we are extrapolating a little bit. Again, we don’t have the data necessarily to say that’s exactly what happened, right? Because we don’t know what happened. The chemotherapy/RT part of the PACIFIC is a little bit of an unknown because everybody does something a little different. But we are trying to extrapolate to say that if you don’t give consolidation after low-dose weekly carboplatin/Taxol, durvalumab should be just as effective, given the fact that, as Roy just suggested, it could be because of the inflamed tumor and effect of the radiation. I think it’s a reasonable assumption. We just don’t have the data necessarily.

Roy S. Herbst, MD, PhD: And also, I’m not a big believer that you’re going to cure anyone with lung cancer with chemotherapy. But I am becoming a bit of a believer that you can do that with immunotherapy. The last thing we would want would be to lose that window of opportunity.

Hossein Borghaei, DO, MS: Absolutely.

Roy S. Herbst, MD, PhD: I’d say, given the whole data set, I’d probably want to get the durvalumab in as quickly as possible.

Benjamin P. Levy, MD: Does everybody feel comfortable giving durvalumab at this point, based on the data? Are there patients we wouldn’t give it to? Are we having insurance pushback? Not to bring too much of a financial consideration here, but is everyone getting this done in their patients?

Suresh S. Ramalingam, MD: I’m sure there are patients in whom we wouldn’t want to use checkpoint inhibition, the usual contraindications: preexisting autoimmune disease, patients who received an organ transplant or have serious comorbid conditions, pneumonitis or underlying severe pulmonary disease. But if you have a patient with good performance status who didn’t have any other obvious contraindications, I would say I feel comfortable giving durvalumab.

Naiyer A. Rizvi, MD: One observation is that the uptake has been very strong. At our place, it’s unusual to put a drug on formulary that’s not FDA approved yet. It’s in the NCCN. It’s probably going to be approved by the FDA soon. But they actually did, based on these data, agree to put it on formulary and we’ve been using it pretty regularly. In the community, it seems like the uptake is good as well. I guess one question that I would have is, is there any role for surgery in stage 3 lung cancer?

Transcript Edited for Clarity 
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