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Implications for Using Durvalumab in Stage 3 NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Karen Kelly, MD, UC Davis Comprehensive Cancer Center; Corey J. Langer, MD, FACP, University of Pennsylvania; Benjamin P. Levy, MD, Sibley Memorial Hospital
Published: Friday, Aug 03, 2018



Transcript: 

Benjamin P. Levy, MD: In the theme of subgroup analysis, I have a couple of comments. One is, again, that the never-smoker group in this patient population benefited. The only group that really didn’t benefit was the one comprised of EGFR-mutant patients. This came up in the discussion. What do we do with those patients? I know it’s a small number. I think it was a total of 20 to 30 patients.

Corey J. Langer, MD, FACP: The confidence intervals overlap, but it was still in the right direction.

Benjamin P. Levy, MD: So, what do we do with an EGFR-mutant patient who has stage III disease? I would still consider giving these patients concurrent chemoradiation followed by durvalumab.

Corey J. Langer, MD, FACP: I would have equipoise for doing a trial in the mutant population, comparing durvalumab to a tyrosine kinase inhibitor. I don’t think we have data on your original trial, Karen, on the percentage of patients who had EGFR mutations and predated the mutation error…?

Karen Kelly, MD: We do not, and that’s unfortunate. It was really getting the samples and doing that. We just don’t have the samples to do that on. That’s unfortunate.

Mark A. Socinski, MD: But yes, there was a small representation of EGFR-mutant patients.

Karen Kelly, MD: Very small.

Mark A. Socinski, MD: It’s hard to know what to do with those patients.

Corey J. Langer, MD, FACP: It’s a dilemma that we have to grapple with.

Benjamin P. Levy, MD: It was the only group that didn’t benefit.

Karen Kelly, MD: Right. My personal preference would be to give them the chemoradiation therapy and not…

Corey J. Langer, MD, FACP: And not give them durvalumab?

Karen Kelly, MD: I would not in that tiny, tiny patient population.

Corey J. Langer, MD, FACP: I think I’m going to reserve judgment until we see the overall survival curves. I’m sure it has to be broken down to that group.

Karen Kelly, MD: It’s a very small group. We have other data to say that patients don’t do well with immuno-oncology therapy. In the stage 4 setting, we have consistently shown that they do not do well.

Mark A. Socinski, MD: At least with an immuno-oncology monotherapy.

Corey J. Langer, MD, FACP: And that’s compared with an active control.

Karen Kelly, MD: Yes, but this is monotherapy that we’re doing.

Benjamin P. Levy, MD: Postradiation.

Karen Kelly, MD: Yes, but still EGFR-positive.

Mark A. Socinski, MD: Were you surprised by the rates of pneumonitis being so low?

Karen Kelly, MD: I am not surprised by that. Again, we could split hairs a little bit, but pneumonitis is a little bit less in PD-L1 inhibitors than it is in PD-1 inhibitors.

Corey J. Langer, MD, FACP: I was surprised. I thought it would be higher. I think that the Hoosier group…looked at straight consolidation with pembrolizumab, and the rates were higher. They were acceptable, but they weren’t 2% or 3%. They were more on the order of 5% to 8%.

Benjamin P. Levy, MD: Wasn’t this initially supposed to be a Cooperative Group study? Weren’t there major concerns about the pneumonitis, the immunotherapy, after radiation, and it sort of put it dead in the water?

Karen Kelly, MD: I don’t know.

Mark A. Socinski, MD: I’m not sure about that. To get back to the 2-week subset analysis, the original design of the trial required patients to be randomized within 2 weeks.

Karen Kelly, MD: That’s true.

Mark A. Socinski, MD: There were accrual issues, and that’s why it went to 6 weeks. To Corey’s point, it does kind of lead to some decision making regarding the timing of radiation, of CT scanning, and that sort of thing. What do you do?

Corey J. Langer, MD, FACP: And also, would you offer this to a patient who has any degree of pneumonitis?

Mark A. Socinski, MD: Right.

Corey J. Langer, MD, FACP: Granted, you’re going to see radiation changes on imaging. That’s not pneumonitis. That’s not clinical or symptomatic…

Mark A. Socinski, MD: Right.

Corey J. Langer, MD, FACP: But for somebody who’s actually starting to get symptomatic, you’re initiating steroids, which we know may counteract. That’s the patient in whom I’ll probably let things quiet down. I may make the decision later. I may just give them a consolidated…

Karen Kelly, MD: Again, we don’t know much about this group of patients and what the radiation fields look like. There are a lot of unanswered questions.

Corey J. Langer, MD, FACP: I would love to see a breakdown for those who’ve had PET simulation.

Karen Kelly, MD: Looking at that and PET simulation, I think they probably have all of that data available.

Corey J. Langer, MD, FACP: I hope so.

Karen Kelly, MD: These are really important questions, particularly as we consider what comes next in this field. What comes next?

Corey J. Langer, MD, FACP: Next comes immuno-oncology combinations, I imagine.

Karen Kelly, MD: The 1 combination that is now not going forward was the IDO and durvalumab combination. That’s not going forward. What other maintenance combinations could you put in there? Anti-CTLA-4 would be put…

Mark A. Socinski, MD: Looking at it currently.

Karen Kelly, MD: And then, moving it concurrently. MD Anderson Cancer Center has completed a trial that they’ll present data on at the World Conference on Lung Cancer. They’ve looked at paclitaxel/carboplatin plus an immuno-oncology.

Corey J. Langer, MD, FACP: And radiation.

Karen Kelly, MD: And radiation.

Corey J. Langer, MD, FACP: Concurrently.

Karen Kelly, MD: It is feasible and promising, and, hopefully, we can move forward in a Cooperative Group situation. I think that would be what many investigators are going to be looking at. Plus, we now have a large body of evidence to say that chemotherapy plus immuno-oncology work well together and are tolerated in the stage 4 setting. And we know that radiation is also a very good immunomodulator. I think some of the questions may become: Do we need the paclitaxel/carboplatin at some point? What chemotherapy do you really need at that point down the road? Or, do you need paclitaxel and carboplatin?

Corey J. Langer, MD, FACP: I think I’d would want to ask the plus/minus radiotherapy question first.

Karen Kelly, MD: Sure.

Corey J. Langer, MD, FACP: That’s the easiest to do, and I think that’s an important one. I don’t think we’re doing well enough in this disease to dial back on the treatment. This is not HPV-positive oropharyngeal cancer, where we were overtreating patients. We may argue that we’re overtreating this and are causing toxicity. But until our outcomes start approaching 70% to 80% and 5 or 6 years of survival, I’m not ready to necessarily cut back.

Karen Kelly, MD: I think you have to remember that even though we may give a lot of paclitaxel and carboplatin, there are still a lot of people who are giving cisplatin/etoposide, which is toxic. And people are giving pembrolizumab/cisplatin, and pembrolizumab/carboplatin, and…

Corey J. Langer, MD, FACP: Well, cisplatin/etoposide often has less pneumonitis after…

Karen Kelly, MD: Yes, but it is toxic at the end. It is not easy. A lot of people still give that. Certainly, weekly paclitaxel/carboplatin. Having said that, again, every patient’s individualized. There are patients who can’t tolerate paclitaxel/carboplatin with radiation therapy. I just had a patient like this the other day. She was hospitalized twice. All of these are rare situations, but I think that was really a provocative question. Much more work does need to be done.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: In the theme of subgroup analysis, I have a couple of comments. One is, again, that the never-smoker group in this patient population benefited. The only group that really didn’t benefit was the one comprised of EGFR-mutant patients. This came up in the discussion. What do we do with those patients? I know it’s a small number. I think it was a total of 20 to 30 patients.

Corey J. Langer, MD, FACP: The confidence intervals overlap, but it was still in the right direction.

Benjamin P. Levy, MD: So, what do we do with an EGFR-mutant patient who has stage III disease? I would still consider giving these patients concurrent chemoradiation followed by durvalumab.

Corey J. Langer, MD, FACP: I would have equipoise for doing a trial in the mutant population, comparing durvalumab to a tyrosine kinase inhibitor. I don’t think we have data on your original trial, Karen, on the percentage of patients who had EGFR mutations and predated the mutation error…?

Karen Kelly, MD: We do not, and that’s unfortunate. It was really getting the samples and doing that. We just don’t have the samples to do that on. That’s unfortunate.

Mark A. Socinski, MD: But yes, there was a small representation of EGFR-mutant patients.

Karen Kelly, MD: Very small.

Mark A. Socinski, MD: It’s hard to know what to do with those patients.

Corey J. Langer, MD, FACP: It’s a dilemma that we have to grapple with.

Benjamin P. Levy, MD: It was the only group that didn’t benefit.

Karen Kelly, MD: Right. My personal preference would be to give them the chemoradiation therapy and not…

Corey J. Langer, MD, FACP: And not give them durvalumab?

Karen Kelly, MD: I would not in that tiny, tiny patient population.

Corey J. Langer, MD, FACP: I think I’m going to reserve judgment until we see the overall survival curves. I’m sure it has to be broken down to that group.

Karen Kelly, MD: It’s a very small group. We have other data to say that patients don’t do well with immuno-oncology therapy. In the stage 4 setting, we have consistently shown that they do not do well.

Mark A. Socinski, MD: At least with an immuno-oncology monotherapy.

Corey J. Langer, MD, FACP: And that’s compared with an active control.

Karen Kelly, MD: Yes, but this is monotherapy that we’re doing.

Benjamin P. Levy, MD: Postradiation.

Karen Kelly, MD: Yes, but still EGFR-positive.

Mark A. Socinski, MD: Were you surprised by the rates of pneumonitis being so low?

Karen Kelly, MD: I am not surprised by that. Again, we could split hairs a little bit, but pneumonitis is a little bit less in PD-L1 inhibitors than it is in PD-1 inhibitors.

Corey J. Langer, MD, FACP: I was surprised. I thought it would be higher. I think that the Hoosier group…looked at straight consolidation with pembrolizumab, and the rates were higher. They were acceptable, but they weren’t 2% or 3%. They were more on the order of 5% to 8%.

Benjamin P. Levy, MD: Wasn’t this initially supposed to be a Cooperative Group study? Weren’t there major concerns about the pneumonitis, the immunotherapy, after radiation, and it sort of put it dead in the water?

Karen Kelly, MD: I don’t know.

Mark A. Socinski, MD: I’m not sure about that. To get back to the 2-week subset analysis, the original design of the trial required patients to be randomized within 2 weeks.

Karen Kelly, MD: That’s true.

Mark A. Socinski, MD: There were accrual issues, and that’s why it went to 6 weeks. To Corey’s point, it does kind of lead to some decision making regarding the timing of radiation, of CT scanning, and that sort of thing. What do you do?

Corey J. Langer, MD, FACP: And also, would you offer this to a patient who has any degree of pneumonitis?

Mark A. Socinski, MD: Right.

Corey J. Langer, MD, FACP: Granted, you’re going to see radiation changes on imaging. That’s not pneumonitis. That’s not clinical or symptomatic…

Mark A. Socinski, MD: Right.

Corey J. Langer, MD, FACP: But for somebody who’s actually starting to get symptomatic, you’re initiating steroids, which we know may counteract. That’s the patient in whom I’ll probably let things quiet down. I may make the decision later. I may just give them a consolidated…

Karen Kelly, MD: Again, we don’t know much about this group of patients and what the radiation fields look like. There are a lot of unanswered questions.

Corey J. Langer, MD, FACP: I would love to see a breakdown for those who’ve had PET simulation.

Karen Kelly, MD: Looking at that and PET simulation, I think they probably have all of that data available.

Corey J. Langer, MD, FACP: I hope so.

Karen Kelly, MD: These are really important questions, particularly as we consider what comes next in this field. What comes next?

Corey J. Langer, MD, FACP: Next comes immuno-oncology combinations, I imagine.

Karen Kelly, MD: The 1 combination that is now not going forward was the IDO and durvalumab combination. That’s not going forward. What other maintenance combinations could you put in there? Anti-CTLA-4 would be put…

Mark A. Socinski, MD: Looking at it currently.

Karen Kelly, MD: And then, moving it concurrently. MD Anderson Cancer Center has completed a trial that they’ll present data on at the World Conference on Lung Cancer. They’ve looked at paclitaxel/carboplatin plus an immuno-oncology.

Corey J. Langer, MD, FACP: And radiation.

Karen Kelly, MD: And radiation.

Corey J. Langer, MD, FACP: Concurrently.

Karen Kelly, MD: It is feasible and promising, and, hopefully, we can move forward in a Cooperative Group situation. I think that would be what many investigators are going to be looking at. Plus, we now have a large body of evidence to say that chemotherapy plus immuno-oncology work well together and are tolerated in the stage 4 setting. And we know that radiation is also a very good immunomodulator. I think some of the questions may become: Do we need the paclitaxel/carboplatin at some point? What chemotherapy do you really need at that point down the road? Or, do you need paclitaxel and carboplatin?

Corey J. Langer, MD, FACP: I think I’d would want to ask the plus/minus radiotherapy question first.

Karen Kelly, MD: Sure.

Corey J. Langer, MD, FACP: That’s the easiest to do, and I think that’s an important one. I don’t think we’re doing well enough in this disease to dial back on the treatment. This is not HPV-positive oropharyngeal cancer, where we were overtreating patients. We may argue that we’re overtreating this and are causing toxicity. But until our outcomes start approaching 70% to 80% and 5 or 6 years of survival, I’m not ready to necessarily cut back.

Karen Kelly, MD: I think you have to remember that even though we may give a lot of paclitaxel and carboplatin, there are still a lot of people who are giving cisplatin/etoposide, which is toxic. And people are giving pembrolizumab/cisplatin, and pembrolizumab/carboplatin, and…

Corey J. Langer, MD, FACP: Well, cisplatin/etoposide often has less pneumonitis after…

Karen Kelly, MD: Yes, but it is toxic at the end. It is not easy. A lot of people still give that. Certainly, weekly paclitaxel/carboplatin. Having said that, again, every patient’s individualized. There are patients who can’t tolerate paclitaxel/carboplatin with radiation therapy. I just had a patient like this the other day. She was hospitalized twice. All of these are rare situations, but I think that was really a provocative question. Much more work does need to be done.

Transcript Edited for Clarity 
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