Impact of Driver Mutations in NSCLC

Edward B. Garon, MD:Non—small cell lung cancer in many respects has been a disease that has been at the forefront of molecular medicine, subdividing the groups of patients that have specific driver mutations and then devising therapies that are specific for those driver mutations.

The first 1 that we had, of course, were mutations in epidermal growth factor receptor,EGFR, and that was known to be a major driver in lung cancer. There are several other drivers that over time have been identified that potentially can be essentially what leads to the development of lung cancer. The approvals of other targeted therapies are therapies directed againstALK,ROS1,BRAF, and most recentlyNTRK. They are sort of a furthering of that story of subdividing the group of patients.

METis an oncogene that has been evaluated for quite a while in many histologies, including non—small cell lung cancer. Traditionally, when investigators looked atMETas a driver, what they largely looked at was gene amplifications. Of course, physicians who take care of all sorts of malignancies are familiar with the role of amplification. At UCLA [Health], the amplification of theHER2[human epidermal growth factor receptor] gene is very near and dear to all our hearts, of course, as a driver in lung cancer.

There is a small population of patients who do have an amplification of theMETgene. And there were reports several years ago that drugs that effectively targetMETcould potentially be effective approaches there.

But more recently there has been recognition that a significant chunk of patients with lung cancer have a mutation. It’s actually a host of different mutations that lead to the same consequence, which is the skipping ofMETexon 14 in the eventual product ofMET. This leads to decreased ability forMETto be destroyed, and that has more recently been recognized as an important driver mutation in maybe 3% to 4% of patients with non—small cell lung cancer.

The role of gene amplification is near and dear to our hearts at UCLA and my division. Chair Dennis Slamon, of course, was a driver in characterizing theHER2new gene. And that, of course, is a gene where you see amplification as really a driver of malignancy, in that instance, breast cancer.

Exon 14 skipping inMETis somewhat different from most of our mutations, and as a result it has not been routinely tested in the way thatEGFRorBRAFhave been tested. In general, what one sees in these mutations are several different mutations. And what these mutations do is they lead to the corresponding part of the protein that would correspond toMETexon 14 not being part of the eventual protein. Of course, in general we’re not used to the idea that loss of a significant part of the protein would lead to a driver mutation. But in this, the part of the protein that is lost is important in destruction ofMET. On a functional level, the protein doesn’t get destroyed, and that is at least proposed as why this can be a driver in the setting of thisMETexon 14 skipping.

Transcript edited for clarity.