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I-O Therapy Versus Surgery or Chemotherapy in NSCLC

Panelists: Leora Horn, MD, MSc, FRCPC, Vanderbilt University Medical Center; Edward B. Garon, MD, David Geffen School of Medicine at UCLA; Thomas E. Stinchcombe, MD, Duke Cancer Institute
Published: Tuesday, Oct 16, 2018



Transcript: 

Leora Horn, MD, MSc, FRCPC: What about the patient who is not fit for chemotherapy and just gets radiation? Are you giving them durvalumab after 6 weeks of radiation?

Thomas E. Stinchcombe, MD: I am not. I think that’s a different patient population from what was enrolled in the trial. If you’re not a candidate for chemoradiation, I think you, for the most part, are treating with palliative intent. I’ve not used durvalumab.

Leora Horn, MD, MSc, FRCPC: How about you? I haven’t actually had a patient like this come up yet.

Edward B. Garon, MD: I’ve been reluctant. Sometimes, what I do see happening is sort of dialing down the chemotherapy.

Thomas E. Stinchcombe, MD: So the hurdle is lowered again.

Edward B. Garon, MD: We’re not even doing that. Sometimes things like that will be done for a reimbursement issue. This, I think, is more to treat me rather than the patient. We have been stuck with what the validated approach is, at least somewhat. There’s not great data there. We do have studies looking at durvalumab after SBRT [stereotactic body radiation therapy], for instance, and I think those are interesting studies. So I’ve been reluctant, but I wouldn’t say never, necessarily.

Leora Horn, MD, MSc, FRCPC: That’s an interesting case that you brought up. If you started a patient on concurrent chemoradiation and dropped the chemotherapy halfway through and finished radiation, you would give that patient durvalumab, at that point?

Thomas E. Stinchcombe, MD: I would, definitely.

Edward B. Garon, MD: I think I would.

Leora Horn, MD, MSc, FRCPC: OK.

Edward B. Garon, MD: I know that when we’ve done it, yes. Again, this is what the patients want. Some patients will go on to have pneumonitis and other problems, so it’s not that it’s always a great thing for the individual patient. It’s very hard, after you talk to a patient about this regimen, to say, “Well, since we dropped after a couple of cycles, we’re also going to drop the immunotherapy that we were so excited about before.”

Leora Horn, MD, MSc, FRCPC: And often you’re dropping the chemotherapy for different reasons. They’re cytopenic. Their counts are not there. But, at least there was someone you felt could tolerate it to begin with.

What about those patients who we thought were borderline resectable, whose surgeons would say, “Give some neoadjuvant concurrent chemoradiation and then we can assess for surgery?” Has the PACIFIC data changed how you’re managing those patients? Are your pulmonologists now biopsying more lymph nodes? In the past, our pulmonologists would go in and just biopsy the 1 and 2 node and say it’s stage III disease. I’m now seeing that pulmonologists are actually biopsying multiple N2 nodes. Has PACIFIC changed who’s become a surgical candidate at your institution?

Edward B. Garon, MD: Maybe, I would say. There are some clear cases in both directions. Somebody who has contralateral and mediastinal involvement is somebody we’re not going to send to surgery. Someone who has single station, you know, microscopic or very low burden disease—that’s still somebody who I would approach with surgery.

On the other hand, we all have these discussions in our tumor boards, all the time. We talk about the bulky multiple-station mediastinal lymphadenopathy, or the patients with several lymph nodes, including the subcarinal lymph node. We consider these prognostic features that have generally done quite poorly. And this, in the backdrop, of course, is the largest study ever looking at the comparison between the two, not showing a benefit. I know there are subset analyses and things like that which people have looked at with that. Whereas I was more inclined to let the surgeon duke it out with everyone else before, with this sort of idea of the benefit of the doubt that the surgeon always wants, this has made me a little more aggressive. In an era of chemoimmunotherapy, along with radiation, it is a reasonable treatment option, particularly in these people who I don’t anticipate good surgical outcomes in. I’m interested in hearing if that’s been done by either of the two of you?

Thomas E. Stinchcombe, MD: We were pretty conservative. We generally took the people at a single station disease to chemotherapy induction followed by a surgical resection. We don’t do a lot of chemoradiation induction. I’m fortunate to work at a place with good surgeons. We generally get mediastinoscopies and we know that single stations are really single stations. So I don’t think it’s changed our practice patterns, but we were pretty firm beforehand.

Leora Horn, MD, MSc, FRCPC: Yes, our surgeons are the same. We were actually doing more in neoadjuvant chemotherapy as opposed to concurrent chemotherapy in the potentially surgical patients. What about a patient who gets neoadjuvant chemotherapy, radiation, and surgery? Are you giving them durvalumab, or are you saying that you’re done?

Thomas E. Stinchcombe, MD: I’m saying that we are done. I think that’s a different patient population.

Leora Horn, MD, MSc, FRCPC: Speaking of surgical patients, we saw some data as well at the AACR [American Association for Cancer Research] and ASCO [American Society of Clinical Oncology] annual meetings looking at neoadjuvant checkpoint inhibitors followed by resection. The data was published by Dr Patrick Forde in the New England Journal of Medicine. It showed a nice pathological response rate—in the 40% to 50% range. Where do you think this data is going? Are we ready to think about neoadjuvant immune checkpoint inhibitors, or chemotherapy/immune checkpoint inhibitors for our resectable patients?

Thomas E. Stinchcombe, MD: I think this is the next step. First of all, it’s a small study. I think it’s more of a proof of concept than a practice right now. This is very appealing to me because you can get the biopsy, do the immunotherapy, and then get the resection and have a pathological assessment of the response. It looks very promising. It probably needs some refinement. Who is best for single-agent immunotherapy with the neoadjuvant approach? Or, who needs the chemoimmunotherapy? Who needs to go right to surgery? For some of the early stage patients, I’m not sure if there’s a lot of benefit to an induction approach. It’s more applicable for the higher stage or borderline resectable patients, where we need to get that response to get them to surgery.

Leora Horn, MD, MSc, FRCPC: Are you doing anything different, Eddie?

Edward B. Garon, MD: We have an excellent surgeon, Dr Jay Lee, who’s the co-chair for thoracic surgery in LCMC3, part of the atezolizumab study. There’s beautiful scientific data in the Forde study. The concern that I have for the long term, and studies are going to address this, is, do the responses that we’re seeing pathologically mean something down the road? Obviously, these are not mouse experiments. We’re not trying to get rid of a tumor for the sake of a smaller tumor and to show a nice figure. From a proof of concept, this was a tremendous work. I think that it is going to be exciting to see, in the upcoming, larger studies, whether or not the outcomes that we see correlate with what we really care about: Can our patients live longer?

Leora Horn, MD, MSc, FRCPC: Absolutely. One of the things that I think also makes me think about these studies is, they’re looking at TMB [tumor mutation burden]. For a surgical patient, should we be making them wait for a month to get the TMB data back, to get a checkpoint inhibitor? And then, also, what do you do if there’s not a pathological complete response? Do you say, “Now we’re going to give you 4 cycles of a platinum doublet,” just because it wasn’t as good? I think there’s a lot there, regarding what we’re going to see.

Transcript Edited for Clarity 
 
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Transcript: 

Leora Horn, MD, MSc, FRCPC: What about the patient who is not fit for chemotherapy and just gets radiation? Are you giving them durvalumab after 6 weeks of radiation?

Thomas E. Stinchcombe, MD: I am not. I think that’s a different patient population from what was enrolled in the trial. If you’re not a candidate for chemoradiation, I think you, for the most part, are treating with palliative intent. I’ve not used durvalumab.

Leora Horn, MD, MSc, FRCPC: How about you? I haven’t actually had a patient like this come up yet.

Edward B. Garon, MD: I’ve been reluctant. Sometimes, what I do see happening is sort of dialing down the chemotherapy.

Thomas E. Stinchcombe, MD: So the hurdle is lowered again.

Edward B. Garon, MD: We’re not even doing that. Sometimes things like that will be done for a reimbursement issue. This, I think, is more to treat me rather than the patient. We have been stuck with what the validated approach is, at least somewhat. There’s not great data there. We do have studies looking at durvalumab after SBRT [stereotactic body radiation therapy], for instance, and I think those are interesting studies. So I’ve been reluctant, but I wouldn’t say never, necessarily.

Leora Horn, MD, MSc, FRCPC: That’s an interesting case that you brought up. If you started a patient on concurrent chemoradiation and dropped the chemotherapy halfway through and finished radiation, you would give that patient durvalumab, at that point?

Thomas E. Stinchcombe, MD: I would, definitely.

Edward B. Garon, MD: I think I would.

Leora Horn, MD, MSc, FRCPC: OK.

Edward B. Garon, MD: I know that when we’ve done it, yes. Again, this is what the patients want. Some patients will go on to have pneumonitis and other problems, so it’s not that it’s always a great thing for the individual patient. It’s very hard, after you talk to a patient about this regimen, to say, “Well, since we dropped after a couple of cycles, we’re also going to drop the immunotherapy that we were so excited about before.”

Leora Horn, MD, MSc, FRCPC: And often you’re dropping the chemotherapy for different reasons. They’re cytopenic. Their counts are not there. But, at least there was someone you felt could tolerate it to begin with.

What about those patients who we thought were borderline resectable, whose surgeons would say, “Give some neoadjuvant concurrent chemoradiation and then we can assess for surgery?” Has the PACIFIC data changed how you’re managing those patients? Are your pulmonologists now biopsying more lymph nodes? In the past, our pulmonologists would go in and just biopsy the 1 and 2 node and say it’s stage III disease. I’m now seeing that pulmonologists are actually biopsying multiple N2 nodes. Has PACIFIC changed who’s become a surgical candidate at your institution?

Edward B. Garon, MD: Maybe, I would say. There are some clear cases in both directions. Somebody who has contralateral and mediastinal involvement is somebody we’re not going to send to surgery. Someone who has single station, you know, microscopic or very low burden disease—that’s still somebody who I would approach with surgery.

On the other hand, we all have these discussions in our tumor boards, all the time. We talk about the bulky multiple-station mediastinal lymphadenopathy, or the patients with several lymph nodes, including the subcarinal lymph node. We consider these prognostic features that have generally done quite poorly. And this, in the backdrop, of course, is the largest study ever looking at the comparison between the two, not showing a benefit. I know there are subset analyses and things like that which people have looked at with that. Whereas I was more inclined to let the surgeon duke it out with everyone else before, with this sort of idea of the benefit of the doubt that the surgeon always wants, this has made me a little more aggressive. In an era of chemoimmunotherapy, along with radiation, it is a reasonable treatment option, particularly in these people who I don’t anticipate good surgical outcomes in. I’m interested in hearing if that’s been done by either of the two of you?

Thomas E. Stinchcombe, MD: We were pretty conservative. We generally took the people at a single station disease to chemotherapy induction followed by a surgical resection. We don’t do a lot of chemoradiation induction. I’m fortunate to work at a place with good surgeons. We generally get mediastinoscopies and we know that single stations are really single stations. So I don’t think it’s changed our practice patterns, but we were pretty firm beforehand.

Leora Horn, MD, MSc, FRCPC: Yes, our surgeons are the same. We were actually doing more in neoadjuvant chemotherapy as opposed to concurrent chemotherapy in the potentially surgical patients. What about a patient who gets neoadjuvant chemotherapy, radiation, and surgery? Are you giving them durvalumab, or are you saying that you’re done?

Thomas E. Stinchcombe, MD: I’m saying that we are done. I think that’s a different patient population.

Leora Horn, MD, MSc, FRCPC: Speaking of surgical patients, we saw some data as well at the AACR [American Association for Cancer Research] and ASCO [American Society of Clinical Oncology] annual meetings looking at neoadjuvant checkpoint inhibitors followed by resection. The data was published by Dr Patrick Forde in the New England Journal of Medicine. It showed a nice pathological response rate—in the 40% to 50% range. Where do you think this data is going? Are we ready to think about neoadjuvant immune checkpoint inhibitors, or chemotherapy/immune checkpoint inhibitors for our resectable patients?

Thomas E. Stinchcombe, MD: I think this is the next step. First of all, it’s a small study. I think it’s more of a proof of concept than a practice right now. This is very appealing to me because you can get the biopsy, do the immunotherapy, and then get the resection and have a pathological assessment of the response. It looks very promising. It probably needs some refinement. Who is best for single-agent immunotherapy with the neoadjuvant approach? Or, who needs the chemoimmunotherapy? Who needs to go right to surgery? For some of the early stage patients, I’m not sure if there’s a lot of benefit to an induction approach. It’s more applicable for the higher stage or borderline resectable patients, where we need to get that response to get them to surgery.

Leora Horn, MD, MSc, FRCPC: Are you doing anything different, Eddie?

Edward B. Garon, MD: We have an excellent surgeon, Dr Jay Lee, who’s the co-chair for thoracic surgery in LCMC3, part of the atezolizumab study. There’s beautiful scientific data in the Forde study. The concern that I have for the long term, and studies are going to address this, is, do the responses that we’re seeing pathologically mean something down the road? Obviously, these are not mouse experiments. We’re not trying to get rid of a tumor for the sake of a smaller tumor and to show a nice figure. From a proof of concept, this was a tremendous work. I think that it is going to be exciting to see, in the upcoming, larger studies, whether or not the outcomes that we see correlate with what we really care about: Can our patients live longer?

Leora Horn, MD, MSc, FRCPC: Absolutely. One of the things that I think also makes me think about these studies is, they’re looking at TMB [tumor mutation burden]. For a surgical patient, should we be making them wait for a month to get the TMB data back, to get a checkpoint inhibitor? And then, also, what do you do if there’s not a pathological complete response? Do you say, “Now we’re going to give you 4 cycles of a platinum doublet,” just because it wasn’t as good? I think there’s a lot there, regarding what we’re going to see.

Transcript Edited for Clarity 
 
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