Advances in Biomarker-Driven Therapy for Advanced NSCLC - Episode 2

Targetable Gene Alterations in NSCLC

Briana Contreras

,
Paul K. Paik, MD

An expert in non-small cell lung cancer describes targetable gene alterations and how these impact treatment selection.

Briana Contreras: What are the different types of gene alterations that can be targeted with therapeutics of non–small cell lung cancer? For example, not all these alterations are mutations or rearrangements, fusions, copy number, and so on.

Paul K. Paik, MD: Right. There are many gene alterations that can be targeted in the treatment of non–small cell lung cancers that we have identified. All of these, at the end of the day, lead to changes in the protein, and it’s that change in the protein that’s the target. Those changes can be different. Some of these things are what we call point mutations. It’s a single alteration in the DNA that leads to a change in the protein—in part of the protein—in such a way that the protein now becomes very active, and that’s something we can target. Sometimes, the protein is altered in different ways; for example, there are gene rearrangements or fusions, where part of the protein ends up being stuck together with another part of a protein—that’s a gene rearrangement—that leads to a fusion event that we can target in ALK rearrangements, for an example of this in ALK fusions.

Copy number alterations are things that we’re also trying to target; this is basically when many copies of the gene are present in the cancer cell. Usually, you have 2 copies: 1 is from your dad, and 1 is from your mom. Cancer cells are clever, and sometimes they will have mechanisms that generate many of these copies, and so much of the protein ends up getting expressed. Lastly, there’s a more novel event that we have discovered called exon skipping. This is where there are mutations that happen not in the coding sequence but in the sequences that we’ve considered “junk sequences” of the exon. These are important because they lead to what’s called alternative splicing, or a resulting RNA and protein that is different from normal, different in a way that we can target.

Briana Contreras: How do each of these types of gene alterations impact cancer growth or progression?

Paul K. Paik, MD: All these alterations ultimately lead to increased growth rate, and many of these lead to an increased propensity for developing metastatic disease or metastatic spread. They do this in different ways, but ultimately all these will funnel into the same set of fundamental core machinery in the cancer cell. An example of this would be the fact that many of these alterations end up affecting these receptors—these things on the surface of the cell that are normally highly regulated by the environment around the cell—that lose that ability to be regulated because those proteins are always on at the surface of the cell. Some of these alterations affect intermediates within the cell that are regulated, but all these things end up funneling into the same core machinery that ends up causing uncontrolled growth and progression.

Briana Contreras: What actionable gene alterations have been identified in non–small cell lung cancer, and how common is each 1?

Paul K. Paik, MD: That question is going to challenge my memory, because there are so many at this point. I mentioned that there are 7 alterations that we target that have approved drugs. It’s important to mention that there are others that we’re testing in clinical trials that have very promising signals. Examples of these would be alterations in genes like EGFR, ALK, RET, ROS1, TRAC, BRAF, HER2 [human epidermal growth factor receptor 2], KRAS G12C—a specific kind of KRAS alteration—and MET. There’s the MET exon 14 skipping, which is this more novel event that we have identified. There are a whole host of these gene alterations that we need to test for. In terms of the ones that are most common—it probably makes the most sense to talk about the ones that are most common—they would be alterations in KRAS. EGFR mutations impact about 15% of our patients and are important to test for; ALK rearrangements occur for about 7% of patients. The frequency goes down from there, but in total—which is what matters a great deal—we are talking about alterations occurring in the cases of about 3 of 4 patients.

Transcript edited for clarity.