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Understanding the Molecular Targets of 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: 

Gregory J. Riely, MD, PhD: We have many standard molecular markers that we test for in every patient with non–small cell lung cancer. These include EGFR, ALK, ROS1, and BRAF. We test for these because we have FDA [US Food and Drug Administration]-approved drugs that are approved in this indication. But in addition to this defined extended-spectrum mutation testing, we are also looking at a bunch of other genes that have important clinical relevance, and I think we learn more and more that these things can be identified and have clinical relevance going forward.

My favorite is probably the one we’ve known about longest, and that’s KRAS. Now, KRAS mutations occur in about 20% of people with non–small cell lung cancer. Currently, we can’t target KRAS mutations. But what we do know is that if we identify a KRAS mutation, we’re not going to identify another oncogenic driver in the main group. There are certain examples where people have overlapping EGFR and KRAS mutations, but those are extraordinarily uncommon. By far the most common thing is that there is no overlap of driver oncogenes. If you identify a patient with a KRAS mutation, in many senses you can stop looking for mutations. You don’t need to look at RET, you don’t need to look at ROS1, you don’t need to look at ALK, and you don’t need to look at MET exon 14. KRAS has defined that patient’s tumor.

Jared Weiss, MD: KRAS is a very, very, very important target. In terms of patient frequency, it represents more patients than EGFR, ALK, and ROS1 mutations combined. If we’re looking to help people, potentially targeting KRAS mutations is of far more importance than any of the other targets we’re talking about. Despite being the most common oncogenic driver in adenocarcinoma of the lung and despite being researched since the dawn of the internet, we have yet to come up with an effective treatment against KRAS mutation.

There is hope, however, for an effective treatment against KRAS mutation, and I think there are 2 avenues of active research that I’m excited about. One is small molecule inhibitors that seem to actually inhibit KRAS. The weakness there is that they are specific to the specific KRAS isoform that they inhibit. The other area that I’ve invested a lot of time and some energy into are silencing RNAs against KRAS, where some of these seem to be able to broadly inhibit the different KRAS isoforms. These are early stage efforts, but I think there’s legitimate hope there for this common mutation.

Gregory J. Riely, MD, PhD: Over the past few years, we’ve learned a lot about MET. Now, MET is a very complicated biomarker because there’s MET overexpression, there’s MET gene amplification, and there’s MET exon 14 splicing. These all happen in relatively overlapping amounts. There was a large clinical development program looking at MET expression and using MET antibodies. That largely failed. And so, MET expression by immunohistochemistry is probably not the best biomarker and not one we should be testing.

By contrast, MET exon 14 is something we’ve learned a lot about over the past couple years. MET exon 14 mutations lead to splicing and removing of MET exon 14, and that stabilizes protein causing that protein to be more active in a patient’s cancer cell. We can target MET using drugs like crizotinib as well as available MET inhibitors, and we’ve learned that this leads to response for a significant number of patients. MET exon 14 alterations happen in about 4% of patients in non–small cell lung cancer. Remember, that’s about as frequent as ALK mutations. If we think we should test ALK, we should probably be testing MET exon 14 as well.

MET gene amplification probably overlaps with MET exon 14 splice mutations. We have a lot less information about the prognostic and predictive impact of MET gene amplification, but I think it’s certainly something we want to see as we do broad-based testing.

Jared Weiss, MD: NTRK and RET are 2 of the newer kids on the block for actionable molecular changes in non–small cell lung cancer, and they share a few themes in common. These are both fairly rare in adenocarcinoma of the lung, representing a small percentage of lung cancer each. They’re actually both more common in other cancers. We find them more often in lung cancer because we do molecular testing more often in lung cancer. They also share in common that people were targeting them for several years with other tyrosine kinase inhibitors that happened to have off-label effects on NTRK and RET respectively, but those results were a little less impressive when the drug wasn’t targeted towards them.

With both of these targets, we now have clean target-specific narrow kinase inhibitors that actually take out target cleanly, seem tolerable, and in the early data, seem as efficacious as all other targeted therapies. Responses are seen in 3-quarters or so of patients, with the toxicity profile that we expect from targeted therapy as well as durability. I would highlight both of these as exciting new targets that should be making their way towards standard of care.

Transcript Edited for Clarity 
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Transcript: 

Gregory J. Riely, MD, PhD: We have many standard molecular markers that we test for in every patient with non–small cell lung cancer. These include EGFR, ALK, ROS1, and BRAF. We test for these because we have FDA [US Food and Drug Administration]-approved drugs that are approved in this indication. But in addition to this defined extended-spectrum mutation testing, we are also looking at a bunch of other genes that have important clinical relevance, and I think we learn more and more that these things can be identified and have clinical relevance going forward.

My favorite is probably the one we’ve known about longest, and that’s KRAS. Now, KRAS mutations occur in about 20% of people with non–small cell lung cancer. Currently, we can’t target KRAS mutations. But what we do know is that if we identify a KRAS mutation, we’re not going to identify another oncogenic driver in the main group. There are certain examples where people have overlapping EGFR and KRAS mutations, but those are extraordinarily uncommon. By far the most common thing is that there is no overlap of driver oncogenes. If you identify a patient with a KRAS mutation, in many senses you can stop looking for mutations. You don’t need to look at RET, you don’t need to look at ROS1, you don’t need to look at ALK, and you don’t need to look at MET exon 14. KRAS has defined that patient’s tumor.

Jared Weiss, MD: KRAS is a very, very, very important target. In terms of patient frequency, it represents more patients than EGFR, ALK, and ROS1 mutations combined. If we’re looking to help people, potentially targeting KRAS mutations is of far more importance than any of the other targets we’re talking about. Despite being the most common oncogenic driver in adenocarcinoma of the lung and despite being researched since the dawn of the internet, we have yet to come up with an effective treatment against KRAS mutation.

There is hope, however, for an effective treatment against KRAS mutation, and I think there are 2 avenues of active research that I’m excited about. One is small molecule inhibitors that seem to actually inhibit KRAS. The weakness there is that they are specific to the specific KRAS isoform that they inhibit. The other area that I’ve invested a lot of time and some energy into are silencing RNAs against KRAS, where some of these seem to be able to broadly inhibit the different KRAS isoforms. These are early stage efforts, but I think there’s legitimate hope there for this common mutation.

Gregory J. Riely, MD, PhD: Over the past few years, we’ve learned a lot about MET. Now, MET is a very complicated biomarker because there’s MET overexpression, there’s MET gene amplification, and there’s MET exon 14 splicing. These all happen in relatively overlapping amounts. There was a large clinical development program looking at MET expression and using MET antibodies. That largely failed. And so, MET expression by immunohistochemistry is probably not the best biomarker and not one we should be testing.

By contrast, MET exon 14 is something we’ve learned a lot about over the past couple years. MET exon 14 mutations lead to splicing and removing of MET exon 14, and that stabilizes protein causing that protein to be more active in a patient’s cancer cell. We can target MET using drugs like crizotinib as well as available MET inhibitors, and we’ve learned that this leads to response for a significant number of patients. MET exon 14 alterations happen in about 4% of patients in non–small cell lung cancer. Remember, that’s about as frequent as ALK mutations. If we think we should test ALK, we should probably be testing MET exon 14 as well.

MET gene amplification probably overlaps with MET exon 14 splice mutations. We have a lot less information about the prognostic and predictive impact of MET gene amplification, but I think it’s certainly something we want to see as we do broad-based testing.

Jared Weiss, MD: NTRK and RET are 2 of the newer kids on the block for actionable molecular changes in non–small cell lung cancer, and they share a few themes in common. These are both fairly rare in adenocarcinoma of the lung, representing a small percentage of lung cancer each. They’re actually both more common in other cancers. We find them more often in lung cancer because we do molecular testing more often in lung cancer. They also share in common that people were targeting them for several years with other tyrosine kinase inhibitors that happened to have off-label effects on NTRK and RET respectively, but those results were a little less impressive when the drug wasn’t targeted towards them.

With both of these targets, we now have clean target-specific narrow kinase inhibitors that actually take out target cleanly, seem tolerable, and in the early data, seem as efficacious as all other targeted therapies. Responses are seen in 3-quarters or so of patients, with the toxicity profile that we expect from targeted therapy as well as durability. I would highlight both of these as exciting new targets that should be making their way towards standard of care.

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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