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Molecular Testing in Squamous Cell Tumors

Panelists:Benjamin P. Levy, MD, Mount Sinai Health Systems;Chandra P. Belani, MD, Penn State Cancer Institute;Marina Garassino, MD, National Cancer Institute Milan, Italy;Sarah B. Goldberg, MD, MPH, Yale Cancer Center;Ramaswamy Govindan, MD, Washington University School of Medicine;Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center
Published: Wednesday, Aug 03, 2016


Transcript:

Benjamin P. Levy, MD:
Let’s shift gears one more time and talk a little bit about relevant, potentially actual, mutations in squamous lung cancer. Squamous cell lung cancers, for better/for worse, haven’t shared the same advances or haven’t had the same treatment paradigm as the adenocarcinoma population. The mutually exclusive genetic alterations with an adenocarcinoma is such a clean, nice story where you can wed these drugs based on the target that you define. I don’t think we’ve had that really with the squamous cell population. Things may be changing. Govindan, maybe you can give some historical perspective from your work in the TCG Atlas and then fast forward in where you think we’re heading here.

Ramaswamy Govindan, MD: Sure. The Cancer Genome Atlas looked at 500 squamous cell lung cancer patients and we found that there is a potential—the critical word is potential—monoclonal alteration that we can go after in about two-thirds of our patients. But then they are not your straightforward EGFR mutation, ROS fusion, or ALK kinase alteration. These actually involved predominantly tumor suppressors. In fact, the two most common alterations we find is a CDKN2A loss, which is a tumor cell suppressor, and p53 loss. And these are not easily targetable at the moment. But potentially some of our cell cycle inhibitors, CDK4/6 inhibitors, may have a role in some subpopulation of these patients.

The other thing we do see in about 7% to 10% is FGFR1 (fibroblast growth factor receptor 1) amplification, and there have been some fusion events—the FGFR3-TACC3 fusion that has been reported in a very small number of patients, for those patients are very sensitive FGFR inhibitors. And we also see alterations in BA3 kinase beta in the pathway, but that area has been a bit of a challenge in terms of drug development, and we’ve not seen much activity there. And then there are some alterations in DDR2 (discoidin domain receptor 2) mutations and other things.

So, what we’ve learned is that potentially, these things are something we should target, but we should put in some effort to think creatively. But that may be superseded by what’s happening in the immunotherapy world. We don’t have to always have a targeted therapy; at the end of the day it’s only a means to an end. I think, hopefully, we will be able to bypass that.

Benjamin P. Levy, MD: And in terms of the Lung-MAP trial and trying to define targets that were particularly genotype-driven therapies, where are we with that? And will that help answer some questions? Or has immunotherapy just squashed a lot of the efforts?

Ramaswamy Govindan, MD: I think that we should do both. I don’t think that one should exclude the other. And I really commend the leaders of the Lung-MAP program. They have been very nimble. They have been able to move forward and adjust to reality, and change the study design. And so that is going forward, it’s open in many centers. The NCI has put a lot of money in an effort to moving this forward. I think those trials are ongoing, but we don’t have a finite answer for any of those particular pathways.

Benjamin P. Levy, MD: Right. And do you think in the end, if you had your squamous crystal ball here, do you think it will be a single-drug treatment with targeted therapy, or does the genetic complexity really factor in here? Will it probably be targeted with chemotherapy or another strategy moving forward?

Ramaswamy Govindan, MD: I think for sure chemotherapy. That helps patients. Immunotherapy, definitely yes in that 10%, 20%, and we’ll be moving forward. I’m hopeful that we’ll be able to approach the tumor suppressor loss in unique ways, that we are not right now thinking of. And so I won’t take that off the table right now.

Benjamin P. Levy, MD: Okay. Testing for EGFR and ALK in squamous, is that something that we should be routinely recommending? And, Mark, can you give your perspective?

Mark G. Kris, MD: Again, if you do a comprehensive genetic profile to look at the various abnormalities that Govindan just talked about, you’ll get that automatically. If you go to the NCCN Guidelines today, they do recommend testing of squamous cancers in never smokers, and also in those patients where you have made the diagnosis squamous cancer on a tiny biopsy—because that is the most variability in small biopsy specimens. I would just test everyone.

Benjamin P. Levy, MD: Irrespective of clinical phenotype for the squamous cells as well?

Mark G. Kris, MD: Well, there’s no clinical phenotype really, but that’s what the guidelines say today. I would just test folks, and then you have this information. Then, when ultimately a trial comes up or when one of these agents becomes available, you’re ready to rock and roll. And you do find these other abnormalities.

Sarah B. Goldberg, MD, MPH: What’s nice about the Lung-MAP trial is that’s been incorporated in some of the changes where they’re testing everybody, even during first-line therapy. And they find these abnormalities and hopefully get targeted therapy if they have one. That’s what we’re trying to do at Yale. When we see patients with squamous cell cancer, we put them on this trial, test them comprehensively, and try to find a targeted therapy that works.

Benjamin P. Levy, MD: Yes. I think that for patients who are light smokers or never smokers who are squamous cell, we are routinely testing and then considering testing for other squamous cells. And we’ve picked up some EGFR and ALK in populations that I would have never thought we would—mixed histologies, heavy smokers. We’ve picked these up, and it has helped drive decision making. So, I think the effort should be on to really genetically interrogate those patients as well.

Chandra P. Belani, MD: Are there any data that these abnormalities change after first-line treatment?

Ramaswamy Govindan, MD: In terms of targets?

Chandra P. Belani, MD: In terms of targets.

Ramaswamy Govindan, MD: There are things presented in what I call the founding clause. These are the critical genes that cause the transformation of the cell, and they will be there. In fact, we have done over 30 specimens before and after EGFR TK inhibitors. Not one time have I seen the disappearance of the founding sensitive clone, and so the cause of the lesions will be the subclones may have all come and gone, like T790M. But the critical lesions, like the CDK and others, I suspect will be there in squamous, and EGFR now could be there all the time.

Chandra P. Belani, MD: Because with treatment, we are seeing a reduction in copy numbers and overall. So, there may actually be a change, as you just said. Maybe it’s not the change in the driver but also in subclause.

Ramaswamy Govindan, MD: Quantitative change maybe.

Transcript Edited for Clarity
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Transcript:

Benjamin P. Levy, MD:
Let’s shift gears one more time and talk a little bit about relevant, potentially actual, mutations in squamous lung cancer. Squamous cell lung cancers, for better/for worse, haven’t shared the same advances or haven’t had the same treatment paradigm as the adenocarcinoma population. The mutually exclusive genetic alterations with an adenocarcinoma is such a clean, nice story where you can wed these drugs based on the target that you define. I don’t think we’ve had that really with the squamous cell population. Things may be changing. Govindan, maybe you can give some historical perspective from your work in the TCG Atlas and then fast forward in where you think we’re heading here.

Ramaswamy Govindan, MD: Sure. The Cancer Genome Atlas looked at 500 squamous cell lung cancer patients and we found that there is a potential—the critical word is potential—monoclonal alteration that we can go after in about two-thirds of our patients. But then they are not your straightforward EGFR mutation, ROS fusion, or ALK kinase alteration. These actually involved predominantly tumor suppressors. In fact, the two most common alterations we find is a CDKN2A loss, which is a tumor cell suppressor, and p53 loss. And these are not easily targetable at the moment. But potentially some of our cell cycle inhibitors, CDK4/6 inhibitors, may have a role in some subpopulation of these patients.

The other thing we do see in about 7% to 10% is FGFR1 (fibroblast growth factor receptor 1) amplification, and there have been some fusion events—the FGFR3-TACC3 fusion that has been reported in a very small number of patients, for those patients are very sensitive FGFR inhibitors. And we also see alterations in BA3 kinase beta in the pathway, but that area has been a bit of a challenge in terms of drug development, and we’ve not seen much activity there. And then there are some alterations in DDR2 (discoidin domain receptor 2) mutations and other things.

So, what we’ve learned is that potentially, these things are something we should target, but we should put in some effort to think creatively. But that may be superseded by what’s happening in the immunotherapy world. We don’t have to always have a targeted therapy; at the end of the day it’s only a means to an end. I think, hopefully, we will be able to bypass that.

Benjamin P. Levy, MD: And in terms of the Lung-MAP trial and trying to define targets that were particularly genotype-driven therapies, where are we with that? And will that help answer some questions? Or has immunotherapy just squashed a lot of the efforts?

Ramaswamy Govindan, MD: I think that we should do both. I don’t think that one should exclude the other. And I really commend the leaders of the Lung-MAP program. They have been very nimble. They have been able to move forward and adjust to reality, and change the study design. And so that is going forward, it’s open in many centers. The NCI has put a lot of money in an effort to moving this forward. I think those trials are ongoing, but we don’t have a finite answer for any of those particular pathways.

Benjamin P. Levy, MD: Right. And do you think in the end, if you had your squamous crystal ball here, do you think it will be a single-drug treatment with targeted therapy, or does the genetic complexity really factor in here? Will it probably be targeted with chemotherapy or another strategy moving forward?

Ramaswamy Govindan, MD: I think for sure chemotherapy. That helps patients. Immunotherapy, definitely yes in that 10%, 20%, and we’ll be moving forward. I’m hopeful that we’ll be able to approach the tumor suppressor loss in unique ways, that we are not right now thinking of. And so I won’t take that off the table right now.

Benjamin P. Levy, MD: Okay. Testing for EGFR and ALK in squamous, is that something that we should be routinely recommending? And, Mark, can you give your perspective?

Mark G. Kris, MD: Again, if you do a comprehensive genetic profile to look at the various abnormalities that Govindan just talked about, you’ll get that automatically. If you go to the NCCN Guidelines today, they do recommend testing of squamous cancers in never smokers, and also in those patients where you have made the diagnosis squamous cancer on a tiny biopsy—because that is the most variability in small biopsy specimens. I would just test everyone.

Benjamin P. Levy, MD: Irrespective of clinical phenotype for the squamous cells as well?

Mark G. Kris, MD: Well, there’s no clinical phenotype really, but that’s what the guidelines say today. I would just test folks, and then you have this information. Then, when ultimately a trial comes up or when one of these agents becomes available, you’re ready to rock and roll. And you do find these other abnormalities.

Sarah B. Goldberg, MD, MPH: What’s nice about the Lung-MAP trial is that’s been incorporated in some of the changes where they’re testing everybody, even during first-line therapy. And they find these abnormalities and hopefully get targeted therapy if they have one. That’s what we’re trying to do at Yale. When we see patients with squamous cell cancer, we put them on this trial, test them comprehensively, and try to find a targeted therapy that works.

Benjamin P. Levy, MD: Yes. I think that for patients who are light smokers or never smokers who are squamous cell, we are routinely testing and then considering testing for other squamous cells. And we’ve picked up some EGFR and ALK in populations that I would have never thought we would—mixed histologies, heavy smokers. We’ve picked these up, and it has helped drive decision making. So, I think the effort should be on to really genetically interrogate those patients as well.

Chandra P. Belani, MD: Are there any data that these abnormalities change after first-line treatment?

Ramaswamy Govindan, MD: In terms of targets?

Chandra P. Belani, MD: In terms of targets.

Ramaswamy Govindan, MD: There are things presented in what I call the founding clause. These are the critical genes that cause the transformation of the cell, and they will be there. In fact, we have done over 30 specimens before and after EGFR TK inhibitors. Not one time have I seen the disappearance of the founding sensitive clone, and so the cause of the lesions will be the subclones may have all come and gone, like T790M. But the critical lesions, like the CDK and others, I suspect will be there in squamous, and EGFR now could be there all the time.

Chandra P. Belani, MD: Because with treatment, we are seeing a reduction in copy numbers and overall. So, there may actually be a change, as you just said. Maybe it’s not the change in the driver but also in subclause.

Ramaswamy Govindan, MD: Quantitative change maybe.

Transcript Edited for Clarity
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