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Non-Small Cell Lung Cancer: Other Actionable Mutations

Insights From: Hossein Borghaei, DO, Fox Chase Cancer Center; Corey J. Langer, MD, Perelman School of Medicine; Vassiliki Papadimitrakopoulou, MD, MD Anderson Cancer Center
Published: Wednesday, Aug 15, 2018



Transcript: 

Corey J. Langer, MD: Actionable mutations are found in roughly 20% to 25% of our nonsquamous population, probably only in 2% to 4% of our squamous population. They go above and beyond EGFR mutations. EGFR is seen in 10% to 15%, though it’s much higher in never-smokers, women, and particularly those of East Asian ethnicity. If you look at that population, it’s closer to 50%, 60%, or even 70% of adenocarcinoma. ALK alteration is typically seen as well in never-smokers in 3% to 6%. It doesn’t seem to have relationship to gender but is generally in much younger patients. ROS1 alteration is similar. Those are the molecular aberrations that are typically seen in the nonsmoker subset.

But we see a number of actionable mutations in the broader population, including former or even current heavy smokers, and that includes BRAF, c-MET, and several others. These are also actionable. For BRAF, we have an approved combination, dabrafenib and trametinib, that generates response rates in the 60%-to-70% range with median progression-free survival of 8 to 10 months. It’s quite amazing. In that population, I would give TKIs, preferentially frontline. For c-MET, RET, or HER2, the data are still a bit murky. I would want to know the status. That can be tested individually. It’s much easier to do it in the context of next-generation sequencing. Those folks are probably still best served by chemotherapy or chemotherapy with immunotherapy frontline, with targeted therapy reserved for the second-line setting.

Vassiliki Papadimitrakopoulou, MD: For patients who have mutations other than the known and targetable EGFR, ALK, ROS1, and BRAF, we certainly lack information on how immunotherapy in combination with chemotherapy or combination immunotherapy will work in the frontline setting. As we are treating these patients in clinical trials, we can collect that information so that we can derive useful conclusions about how to treat those patients.

Hossein Borghaei, DO: For patients with molecularly driven tumors—the top ones like EGFR, ALK, or ROS1—I think we have a lot of good options for oral tyrosine kinase inhibitors that are under intense investigation. But there are other, smaller subsets of patients who have defined molecular markers that now have available options, such as patients with BRAF, MET, RET, and other types of mutations. I would say that as long as there are specific targeted therapies for these patients, my preference would be to at least get a patient on a clinical trial with these targeted drugs or test that in the appropriate setting. If I have a patient with a RET mutation or an alteration, my preference would be to offer that patient something directly against RET.

There’s a lot of confusion or problems with offering I-O or treating patients with different molecular subtypes with immuno-oncology drugs, simply because we don’t have the full information. We know from second-line studies and some of the third-line studies that single agent I-O therapy in specific subsets like EGFR and ALK-mutant patients might not be a good idea as an all-comer type of an approach. There are data reflecting that patients with MEK alterations might not benefit from an immuno-oncology drug, but the data sets in these subsets are smaller because we’re dealing with smaller patient subsets to start with. I think this is a patient population where if we have exhausted targeted therapies, we actually need to investigate the clinical activity of I-O combinations or I-O as a single agent in a nice, formalized part of a clinical trial. That’s the way I tend to look at those patients. If patients are appropriate for specific trials, that’s what I would like to do.

Transcript Edited for Clarity 
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Transcript: 

Corey J. Langer, MD: Actionable mutations are found in roughly 20% to 25% of our nonsquamous population, probably only in 2% to 4% of our squamous population. They go above and beyond EGFR mutations. EGFR is seen in 10% to 15%, though it’s much higher in never-smokers, women, and particularly those of East Asian ethnicity. If you look at that population, it’s closer to 50%, 60%, or even 70% of adenocarcinoma. ALK alteration is typically seen as well in never-smokers in 3% to 6%. It doesn’t seem to have relationship to gender but is generally in much younger patients. ROS1 alteration is similar. Those are the molecular aberrations that are typically seen in the nonsmoker subset.

But we see a number of actionable mutations in the broader population, including former or even current heavy smokers, and that includes BRAF, c-MET, and several others. These are also actionable. For BRAF, we have an approved combination, dabrafenib and trametinib, that generates response rates in the 60%-to-70% range with median progression-free survival of 8 to 10 months. It’s quite amazing. In that population, I would give TKIs, preferentially frontline. For c-MET, RET, or HER2, the data are still a bit murky. I would want to know the status. That can be tested individually. It’s much easier to do it in the context of next-generation sequencing. Those folks are probably still best served by chemotherapy or chemotherapy with immunotherapy frontline, with targeted therapy reserved for the second-line setting.

Vassiliki Papadimitrakopoulou, MD: For patients who have mutations other than the known and targetable EGFR, ALK, ROS1, and BRAF, we certainly lack information on how immunotherapy in combination with chemotherapy or combination immunotherapy will work in the frontline setting. As we are treating these patients in clinical trials, we can collect that information so that we can derive useful conclusions about how to treat those patients.

Hossein Borghaei, DO: For patients with molecularly driven tumors—the top ones like EGFR, ALK, or ROS1—I think we have a lot of good options for oral tyrosine kinase inhibitors that are under intense investigation. But there are other, smaller subsets of patients who have defined molecular markers that now have available options, such as patients with BRAF, MET, RET, and other types of mutations. I would say that as long as there are specific targeted therapies for these patients, my preference would be to at least get a patient on a clinical trial with these targeted drugs or test that in the appropriate setting. If I have a patient with a RET mutation or an alteration, my preference would be to offer that patient something directly against RET.

There’s a lot of confusion or problems with offering I-O or treating patients with different molecular subtypes with immuno-oncology drugs, simply because we don’t have the full information. We know from second-line studies and some of the third-line studies that single agent I-O therapy in specific subsets like EGFR and ALK-mutant patients might not be a good idea as an all-comer type of an approach. There are data reflecting that patients with MEK alterations might not benefit from an immuno-oncology drug, but the data sets in these subsets are smaller because we’re dealing with smaller patient subsets to start with. I think this is a patient population where if we have exhausted targeted therapies, we actually need to investigate the clinical activity of I-O combinations or I-O as a single agent in a nice, formalized part of a clinical trial. That’s the way I tend to look at those patients. If patients are appropriate for specific trials, that’s what I would like to do.

Transcript Edited for Clarity 
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