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Molecular Testing: Future Directions 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: Thursday, Oct 11, 2018



Transcript:

Jared Weiss, MD:
Molecular testing keeps getting better and better. We are working on ways to improve the turnaround time of testing, and these approaches are both technical and in developing systems for how to get data to the patient quicker. We have advances where we can do molecular testing on blood for many patients. We talked a bit about tumor mutational burden. This is a new way of using that same information to help predict immunotherapy efficacy. In terms of the integration of PD-L1 [programmed-cell death ligand 1] with molecular testing, it’s notable that some of the providers of this kind of testing will bundle those for you, where they’ll give you molecular testing and an IHC [immunohistochemistry] test for PD-L1 together.

I think this is a smart practice that’s very doctor friendly, very patient friendly. I guess the final thing I would say is that there are new testing modalities using molecular testing and bioinformatics that may answer different questions. What I would particularly highlight are expression signatures. These are mRNA expression patterns that can predict drug efficacy: for example, Genentech’s T-effector signature or some of the interferon-gamma signatures that we’ve seen publications on.

Greg Riedlinger, MD, PhD: In non–small cell lung cancer testing, I think in the future we’re going to see more and more small panels that are able to detect relevant single-nucleotide variance and small insertion deletions in EGFR and KRAS and other genes, but also panels that are able to detect relevant rearrangements such as ALK, ROS, and emerging targets like RET, NTRK1, and NTRK3. We’re also seeing more and more incorporation of tumor mutation burden and PD-L1 status. Now it’s really routine for any advanced non–small cell lung cancer case with an adenocarcinoma component to have NGS [next-generation sequencing] testing performed for the relevant alterations, tumor mutation burden testing, as well as PD-L1. 

I really think what we’re starting to see is that it’s becoming more and more routine for non–small cell lung cancer that clinicians are ordering liquid biopsies. We can detect a lot of these alterations—not necessarily PD-L1, but other alterations that are potential drivers in non–small cell lung cancer—through these assays, as well potential resistant mechanisms to drugs that are being used.

Gregory J. Riely, MD, PhD: As we move forward in understanding the molecular biology of non–small cell lung cancer, we’re certainly going to use mutational testing more. What I thought a few years ago is that we would continue to identify small subsets of patients, those 1% or 2% populations, and continue to build out a pie chart that showed which drivers were important. I think that’s going to continue, but I think that’s probably a little bit less important and probably a little bit more long-term regarding what we’re also going to see, which is a focus on the concurrent molecular events in patients with or without driver oncogenes. I think we can learn a lot from those concurrent molecular events. The big overview of those is probably tumor mutation burden. If there are many concurrent molecular events, that gives a high tumor mutation burden and leads us to identify patients who should get immunotherapy.

But we’ve seen recent data that suggest patients who have EGFR mutations, but who also have P53 alterations, seemed to benefit a little bit less from EGFR-mutant therapy. We’re going to learn more about that. We’re going to identify patients who could benefit from more intensified approaches to their therapy. I think all of this together really builds off the foundation of important molecular testing that can be done for all of our patients.


Transcript Edited for Clarity.
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Transcript:

Jared Weiss, MD:
Molecular testing keeps getting better and better. We are working on ways to improve the turnaround time of testing, and these approaches are both technical and in developing systems for how to get data to the patient quicker. We have advances where we can do molecular testing on blood for many patients. We talked a bit about tumor mutational burden. This is a new way of using that same information to help predict immunotherapy efficacy. In terms of the integration of PD-L1 [programmed-cell death ligand 1] with molecular testing, it’s notable that some of the providers of this kind of testing will bundle those for you, where they’ll give you molecular testing and an IHC [immunohistochemistry] test for PD-L1 together.

I think this is a smart practice that’s very doctor friendly, very patient friendly. I guess the final thing I would say is that there are new testing modalities using molecular testing and bioinformatics that may answer different questions. What I would particularly highlight are expression signatures. These are mRNA expression patterns that can predict drug efficacy: for example, Genentech’s T-effector signature or some of the interferon-gamma signatures that we’ve seen publications on.

Greg Riedlinger, MD, PhD: In non–small cell lung cancer testing, I think in the future we’re going to see more and more small panels that are able to detect relevant single-nucleotide variance and small insertion deletions in EGFR and KRAS and other genes, but also panels that are able to detect relevant rearrangements such as ALK, ROS, and emerging targets like RET, NTRK1, and NTRK3. We’re also seeing more and more incorporation of tumor mutation burden and PD-L1 status. Now it’s really routine for any advanced non–small cell lung cancer case with an adenocarcinoma component to have NGS [next-generation sequencing] testing performed for the relevant alterations, tumor mutation burden testing, as well as PD-L1. 

I really think what we’re starting to see is that it’s becoming more and more routine for non–small cell lung cancer that clinicians are ordering liquid biopsies. We can detect a lot of these alterations—not necessarily PD-L1, but other alterations that are potential drivers in non–small cell lung cancer—through these assays, as well potential resistant mechanisms to drugs that are being used.

Gregory J. Riely, MD, PhD: As we move forward in understanding the molecular biology of non–small cell lung cancer, we’re certainly going to use mutational testing more. What I thought a few years ago is that we would continue to identify small subsets of patients, those 1% or 2% populations, and continue to build out a pie chart that showed which drivers were important. I think that’s going to continue, but I think that’s probably a little bit less important and probably a little bit more long-term regarding what we’re also going to see, which is a focus on the concurrent molecular events in patients with or without driver oncogenes. I think we can learn a lot from those concurrent molecular events. The big overview of those is probably tumor mutation burden. If there are many concurrent molecular events, that gives a high tumor mutation burden and leads us to identify patients who should get immunotherapy.

But we’ve seen recent data that suggest patients who have EGFR mutations, but who also have P53 alterations, seemed to benefit a little bit less from EGFR-mutant therapy. We’re going to learn more about that. We’re going to identify patients who could benefit from more intensified approaches to their therapy. I think all of this together really builds off the foundation of important molecular testing that can be done for all of our patients.


Transcript Edited for Clarity.
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