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Less Common Mutations in Lung Adenocarcinoma

Panelists:Benjamin Levy, MD, Mount Sinai Health Systems, ; John W. Longshore, PhD, Carolinas Pathology Group; Gregory J. Riely, MD, PhD, Weill Cornell Medical College; Mark A. Socinski, MD, University of Pittsburgh; Thomas E. Stinchcombe, MD, University of North Carolina at Chapel Hill; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Friday, May 27, 2016

Transcript:

Mark A. Socinski, MD:
Let’s talk very briefly about some of your second-tier drugs and ask Tom to just briefly discuss BRAF. BRAF occurs in a couple percent.

Thomas E. Stinchcombe, MD: It’s about 1% to 3% of lung cancer patients, and, of those, only about half of the V600E, which is the notable mutation.

Mark A. Socinski, MD: And that’s quoted. It’s a little bit of a pet peeve because young Dr. Vilaruz wrote up the Lung Cancer Mutation Consortium (LCMC) data in the LCMC all stage IV patients. It was 80% that had V600E.

Gregory J. Riely, MD, PhD: But did all the sites test for the non-V600E? I think that enriches for the V600Es a little bit.

Mark A. Socinski, MD: That I don’t know.

Thomas E. Stinchcombe, MD: So, I’ll concede a high watermark of 80%—so 50%, 80% of that 1% to 3% with BRAF has a V600E.

Jared Weiss, MD: Small numbers.

Thomas E. Stinchcombe, MD: Small numbers, importantly, but I think this is more common in smoking patients, which I think we focus a lot on the nonsmokers and the mutations common in nonsmokers. So, this is something I think is really important to test for. We know with dabrafenib alone, there’s about a 30% rate observed in these patients. And with a combination of dabrafenib and trametinib, the response rate goes up to 60%, and it sort-of mirrors the activity in melanoma. I think this is an area that we need to focus on, small population but very important population.

Mark A. Socinski, MD: I think I treated the last patient on the combination study before it closed. It was a young lady, very symptomatic, and within 3 days she was obviously enjoying a very nice response. Another second-tier, RET alterations. Greg, you’ve done some work at Sloan Kettering Cancer Center with this.

Gregory J. Riely, MD, PhD: RET rearrangements. So, like ALK and ROS, this is a gene rearrangement, it’s not a mutation. It’s a little harder to detect. It has to be with a FISH assay, or next-generation sequencing. But RET rearrangements are probably about 1% or 2% of patients with lung adenocarcinoma. We need to find a good RET inhibitor to really exploit this identification, but today we have a dirty drug, cabozantinib, which has significant RET inhibitory properties. And, in a prospective trial from our institution, we have seen response rates on the order of what you see for dabrafenib and BRAF-mutant lung cancer: about 30%. It’s not a home run because it’s a response rate in the 30% range, but I think if we find a better RET inhibitor, it’s going to move its way into the first line. Either way, it’s still way better than docetaxel and even—this may be heresy—better than nivolumab in the second-line setting for patients with RET-positive disease.

Mark A. Socinski, MD: Dr. Weiss, the other one, that’s a bit more complicated because there are several different forms of MET alterations, but comment on the MET story.

Jared Weiss, MD: Right. So, what you get with MET depends a lot on how you define it. I think we’re all familiar with the data that when it was defined by IHC for simple overexpression, that was sort-of a graveyard for MET trials. But there are new ways that MET, what it means to have MET, is being looked at. We’ve seen a small number of patients, I think all of 6 presented with high-level MET amplification where it looks like if you’re looking at the high levels of MET to CEP7—looking at ratios of 5:6 or more—that’s probably a unique driver.

Mark A. Socinski, MD: 80% response rate, 5 out of 6.

Jared Weiss, MD: Hey, it was oral at ASCO. It must be. But that’s what’s going to happen. As you get to these rarer and rarer changes, you’re going to have fewer and fewer patients. So, it is kind-of funny, but it also is what we’re going to see in these rare changes. And, in case that wasn’t rare enough. Moving on to MET deletion 14 or these exon-skipping mutations, I think people are still arguing a little bit about exactly what to call them. But more to the point, again, very small patient numbers in terms of the published or formally presented literature. You’re talking about a handful of case studies. But you’re talking again about high rates of efficacy, and including in a population where, typically, we were not used to seeing particularly good efficacy—which is to say the sarcomatoid non–small cell patients. So, to simplify it, it’s a stay- tuned marker looking very promising. Although I would note that looking at some of these rare changes with small numbers of patient data, looking at HER2, at RET, and at the various MET perturbations that you’ve brought up, they are specifically mentioned in NCCN now as things that you should test for and that you should consider actioning with a category 2b recommendation. And that choice to recommend will influence real- world practice and reimbursement decisions.

Mark A. Socinski, MD: Yes, because once you start diagnosing these oncogenic drivers, you as a physician are going to become addicted to the diagnosing of the oncogenic drivers. Because these drugs can work and they make a huge difference in the life of a patient.

Gregory J. Riely, MD, PhD: I’ll just add to the MET exon 14 story that this represents about 4% of people with lung adenocarcinoma. This is much more common, much closer to the ALK story than the other rare events.

Thomas E. Stinchcombe, MD: I’ll say when I read the pulmonary sarcomatoid on the pathology report, I double-check to make sure there’s been some MET exon. Yes, that’s a cue to double-check things.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
Let’s talk very briefly about some of your second-tier drugs and ask Tom to just briefly discuss BRAF. BRAF occurs in a couple percent.

Thomas E. Stinchcombe, MD: It’s about 1% to 3% of lung cancer patients, and, of those, only about half of the V600E, which is the notable mutation.

Mark A. Socinski, MD: And that’s quoted. It’s a little bit of a pet peeve because young Dr. Vilaruz wrote up the Lung Cancer Mutation Consortium (LCMC) data in the LCMC all stage IV patients. It was 80% that had V600E.

Gregory J. Riely, MD, PhD: But did all the sites test for the non-V600E? I think that enriches for the V600Es a little bit.

Mark A. Socinski, MD: That I don’t know.

Thomas E. Stinchcombe, MD: So, I’ll concede a high watermark of 80%—so 50%, 80% of that 1% to 3% with BRAF has a V600E.

Jared Weiss, MD: Small numbers.

Thomas E. Stinchcombe, MD: Small numbers, importantly, but I think this is more common in smoking patients, which I think we focus a lot on the nonsmokers and the mutations common in nonsmokers. So, this is something I think is really important to test for. We know with dabrafenib alone, there’s about a 30% rate observed in these patients. And with a combination of dabrafenib and trametinib, the response rate goes up to 60%, and it sort-of mirrors the activity in melanoma. I think this is an area that we need to focus on, small population but very important population.

Mark A. Socinski, MD: I think I treated the last patient on the combination study before it closed. It was a young lady, very symptomatic, and within 3 days she was obviously enjoying a very nice response. Another second-tier, RET alterations. Greg, you’ve done some work at Sloan Kettering Cancer Center with this.

Gregory J. Riely, MD, PhD: RET rearrangements. So, like ALK and ROS, this is a gene rearrangement, it’s not a mutation. It’s a little harder to detect. It has to be with a FISH assay, or next-generation sequencing. But RET rearrangements are probably about 1% or 2% of patients with lung adenocarcinoma. We need to find a good RET inhibitor to really exploit this identification, but today we have a dirty drug, cabozantinib, which has significant RET inhibitory properties. And, in a prospective trial from our institution, we have seen response rates on the order of what you see for dabrafenib and BRAF-mutant lung cancer: about 30%. It’s not a home run because it’s a response rate in the 30% range, but I think if we find a better RET inhibitor, it’s going to move its way into the first line. Either way, it’s still way better than docetaxel and even—this may be heresy—better than nivolumab in the second-line setting for patients with RET-positive disease.

Mark A. Socinski, MD: Dr. Weiss, the other one, that’s a bit more complicated because there are several different forms of MET alterations, but comment on the MET story.

Jared Weiss, MD: Right. So, what you get with MET depends a lot on how you define it. I think we’re all familiar with the data that when it was defined by IHC for simple overexpression, that was sort-of a graveyard for MET trials. But there are new ways that MET, what it means to have MET, is being looked at. We’ve seen a small number of patients, I think all of 6 presented with high-level MET amplification where it looks like if you’re looking at the high levels of MET to CEP7—looking at ratios of 5:6 or more—that’s probably a unique driver.

Mark A. Socinski, MD: 80% response rate, 5 out of 6.

Jared Weiss, MD: Hey, it was oral at ASCO. It must be. But that’s what’s going to happen. As you get to these rarer and rarer changes, you’re going to have fewer and fewer patients. So, it is kind-of funny, but it also is what we’re going to see in these rare changes. And, in case that wasn’t rare enough. Moving on to MET deletion 14 or these exon-skipping mutations, I think people are still arguing a little bit about exactly what to call them. But more to the point, again, very small patient numbers in terms of the published or formally presented literature. You’re talking about a handful of case studies. But you’re talking again about high rates of efficacy, and including in a population where, typically, we were not used to seeing particularly good efficacy—which is to say the sarcomatoid non–small cell patients. So, to simplify it, it’s a stay- tuned marker looking very promising. Although I would note that looking at some of these rare changes with small numbers of patient data, looking at HER2, at RET, and at the various MET perturbations that you’ve brought up, they are specifically mentioned in NCCN now as things that you should test for and that you should consider actioning with a category 2b recommendation. And that choice to recommend will influence real- world practice and reimbursement decisions.

Mark A. Socinski, MD: Yes, because once you start diagnosing these oncogenic drivers, you as a physician are going to become addicted to the diagnosing of the oncogenic drivers. Because these drugs can work and they make a huge difference in the life of a patient.

Gregory J. Riely, MD, PhD: I’ll just add to the MET exon 14 story that this represents about 4% of people with lung adenocarcinoma. This is much more common, much closer to the ALK story than the other rare events.

Thomas E. Stinchcombe, MD: I’ll say when I read the pulmonary sarcomatoid on the pathology report, I double-check to make sure there’s been some MET exon. Yes, that’s a cue to double-check things.

Transcript Edited for Clarity
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