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Optimizing Molecular Testing Methods in NSCLC

Insights From: Gregory J. Riely, MD PhD, Memorial Sloan Kettering Cancer Center; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Greg Riedlinger, MD, PhD, Rutgers University
Published: Wednesday, Oct 03, 2018



Transcript: 

Jared Weiss, MD: There are 2 fundamental pieces of information that can be gathered from next-generation sequencing, the mutations that lead to carcinogenesis and tumor mutational burden [TMB]. Starting with mutational testing, next-generation sequencing with advanced bioinformatics is challenging a la carte testing in the testing market. The advantages of a la carte testing are that it’s cheaper, that it’s quicker, and that you only get information you know you’re going to use. You don’t get a big confusing report that you have to figure out.

In my opinion, every patient with nonsquamous cancer should, however, be tested for next-generation sequencing. I’m sold on its benefits regarding the question of specific mutations for 2 specific reasons. Number 1, for the classical mutations that we know we can target with an FDA [US Food and Drug Administration]-approved drug, it’s actually more sensitive. In my consultative practice, I have had now at least a half-dozen patients who had negative biomarker testing with a la carte testing for EGFR or EML4-ALK where I’ve done next-generation sequencing, mostly looking for other mutations that weren’t tested, and in fact found EGFR or ALK mutations. In every case, the patient has benefitted from a targeted drug. There’s published literature backing up that experience.

So, that is reason No. 1 for why I consider it as the greater sensitivity. Reason No. 2, the greater breadth of testing. In the current era, we are slowly decreasing the size of the pie that is represented by the unknown and unactionable. We have new mutations coming on nearly a monthly basis. They’re becoming actionable. If you look at a theme, most of these trials are really, really positive. The newest kid on the block is probably RET, where just a month or so ago at ASCO [American Society of Clinical Oncology meeting] we saw some very positive RET data. In that environment, where you have greater sensitivity for the FDA-approved targets, where you have off-label targets that you might consider with data behind them, and where you have clinical trials of great promise, I think the greater sensitivity and greater breadth of next-generation sequencing has sold me, at least in my practice.

The other piece of data that you get from next-generation sequencing that you will not get from a la carte testing is tumor mutational burden. Now, this is a much more controversial biomarker. In my opinion, we have multiple data sets now showing TMB to be a useful biomarker for immunotherapy, but what’s less clear than whether it has predictive value is how to integrate it into clinical practice. In the context of this question, I would just say that it’s useful if you’re considering using it, and if you’re not ready to use it, then it’s of lesser utility.

Repeat biopsy with repeat molecular characterization at progression is appropriate only if you can take action on those results in some way to help the patients. An example of applicability is if you have a patient on a first-generation or second-generation EGFR inhibitor who progresses. In that case, knowledge of their T790M status empowers you to know whether they should get osimertinib, chemotherapy, or something else. Similarly, if you find one of the rare molecular changes or small cell transformation, it tells you exactly what to do. In the case of a patient who starts on a third-generation inhibitor, I think how you can use those results is a little more questionable.

I do reprofile at the time of progression. I consider switching back to gefitinib or erlotinib. I consider clinical trials based on it. In the case of ALK mutation, I think as we get newer generation drugs coming down the pike with slightly different profiles regarding which resistant changes they take out, there’s a case for repeat biopsy. But if you look at a world where most patients with EGFR mutations are starting on osimertinib and most patients with ALK mutations are starting on alectinib, I think in community practice I don’t find it absolutely mandatory to rebiopsy at the time of progression. In my practice, where we have a lot of trials available, I am considering it.

Transcript Edited for Clarity 
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Transcript: 

Jared Weiss, MD: There are 2 fundamental pieces of information that can be gathered from next-generation sequencing, the mutations that lead to carcinogenesis and tumor mutational burden [TMB]. Starting with mutational testing, next-generation sequencing with advanced bioinformatics is challenging a la carte testing in the testing market. The advantages of a la carte testing are that it’s cheaper, that it’s quicker, and that you only get information you know you’re going to use. You don’t get a big confusing report that you have to figure out.

In my opinion, every patient with nonsquamous cancer should, however, be tested for next-generation sequencing. I’m sold on its benefits regarding the question of specific mutations for 2 specific reasons. Number 1, for the classical mutations that we know we can target with an FDA [US Food and Drug Administration]-approved drug, it’s actually more sensitive. In my consultative practice, I have had now at least a half-dozen patients who had negative biomarker testing with a la carte testing for EGFR or EML4-ALK where I’ve done next-generation sequencing, mostly looking for other mutations that weren’t tested, and in fact found EGFR or ALK mutations. In every case, the patient has benefitted from a targeted drug. There’s published literature backing up that experience.

So, that is reason No. 1 for why I consider it as the greater sensitivity. Reason No. 2, the greater breadth of testing. In the current era, we are slowly decreasing the size of the pie that is represented by the unknown and unactionable. We have new mutations coming on nearly a monthly basis. They’re becoming actionable. If you look at a theme, most of these trials are really, really positive. The newest kid on the block is probably RET, where just a month or so ago at ASCO [American Society of Clinical Oncology meeting] we saw some very positive RET data. In that environment, where you have greater sensitivity for the FDA-approved targets, where you have off-label targets that you might consider with data behind them, and where you have clinical trials of great promise, I think the greater sensitivity and greater breadth of next-generation sequencing has sold me, at least in my practice.

The other piece of data that you get from next-generation sequencing that you will not get from a la carte testing is tumor mutational burden. Now, this is a much more controversial biomarker. In my opinion, we have multiple data sets now showing TMB to be a useful biomarker for immunotherapy, but what’s less clear than whether it has predictive value is how to integrate it into clinical practice. In the context of this question, I would just say that it’s useful if you’re considering using it, and if you’re not ready to use it, then it’s of lesser utility.

Repeat biopsy with repeat molecular characterization at progression is appropriate only if you can take action on those results in some way to help the patients. An example of applicability is if you have a patient on a first-generation or second-generation EGFR inhibitor who progresses. In that case, knowledge of their T790M status empowers you to know whether they should get osimertinib, chemotherapy, or something else. Similarly, if you find one of the rare molecular changes or small cell transformation, it tells you exactly what to do. In the case of a patient who starts on a third-generation inhibitor, I think how you can use those results is a little more questionable.

I do reprofile at the time of progression. I consider switching back to gefitinib or erlotinib. I consider clinical trials based on it. In the case of ALK mutation, I think as we get newer generation drugs coming down the pike with slightly different profiles regarding which resistant changes they take out, there’s a case for repeat biopsy. But if you look at a world where most patients with EGFR mutations are starting on osimertinib and most patients with ALK mutations are starting on alectinib, I think in community practice I don’t find it absolutely mandatory to rebiopsy at the time of progression. In my practice, where we have a lot of trials available, I am considering it.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 18th Annual International Lung Cancer Congress®Oct 31, 20181.5
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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