Evolution of Molecular Testing in NSCLC

Transcript: Edward B. Garon, MD: The reason these are somewhat difficult with our current methodology is the same reason we were somewhat surprised by these mutations in the first place. We have set up our testing paradigms to look for mutations in the exons. And that is, again, generally not the case here. And so we are often, with our current methodologies, not finding these mutations. There are many panels. If one sends out for next-generation sequencing, one generally does get the appropriate result on this. But many of the methodologies that are used currently do not get this.

There are many different mutations that can lead to the lack of MET exon 14 in the eventual protein product. That complexity is real, and it makes it more difficult to look for than, for instance, an EGFR L858R mutation. Certainly, it is very possible to do—and good tests will be available—but it does pose a greater challenge than what one would see looking for an exon 19 deletion or L858R mutation in the EGFR gene.

Alexander Spira, MD, PhD, FACP: There are currently guidelines by the NCCN [National Comprehensive Cancer Network] that recommend looking for molecular testing, and this includes exon 14 MET skipping rearrangements as well. It’s important to do this and even check at the outset, because again, one would not want to miss an opportunity to treat a patient for this, should it come up. And it’s on guidelines right now. Unfortunately, it’s probably underused, either because of a lack of improved agents or a lack of understanding of what’s available now and coming.

Edward B. Garon, MD: I think there is definitely a very active evolution of the appropriate way to test for these mutations. On 1 hand, it would be nice to just send and get the results for all these mutations at once. I think the limitation on that is that many of the laboratories that do this tend to have a very slow turnaround time. That may be appropriate for mutations that are clearly second-line therapy informing—meaning that they aren’t going to change what you do as initial treatment but may change what you do if frontline therapy is not successful.

It is very difficult to wait 3 weeks to a month to get an EGFR result back, because that is a result that we want to be able to act on immediately. Even the College of American Pathologists says that result should be returned in 2 weeks.

Currently, in our practice, we still are getting a rapid turnaround of EGFR and ALK—with the idea that those are tests for which we need to make immediate decisions—and then a more delayed turnaround for a broader panel. In terms of what the appropriate and best way to test for MET exon 14 skipping mutations is, I think that is something that should probably be best left to a time when we have approved inhibitors of this target. At that point, there will presumably be diagnostics that have gone through the rigorous evaluation that is required by the FDA to direct patients to a specific therapy. And so for that reason, I’m very hesitant today to say what I anticipate the best way of testing for this mutation is. I think that’s something for which we will have a good, quality answer that has been rigorously vetted by the US FDA.

Alexander Spira, MD, PhD, FACP: Most of us oncologists who see a lot of lung cancer do believe that all patients should probably have next-generation sequencing done—probably an entire panel done. You can check for the mutations individually, but there are so many new ones and probably some coming in the future as well, so it’s really important to probably just do complete next-generation sequencing to look for all of them.

We know the EGFR and ALK story very well. But with the emergence of many other ones, especially exon 14 in MET, as well as some other emerging ones, it’s very important to test for these at the outset, so you don’t miss an opportunity to treat a patient with a targeted therapy.

Transcript Edited for Clarity