Advances in Biomarker-Driven Therapy for Advanced NSCLC - Episode 4

The Role of MET in NSCLC

Briana Contreras

,
Paul K. Paik, MD

A key opinion leader thoracic oncology reviews the clinical significance of MET exon 14 skipping in NSCLC as well as recent advances in MET-directed therapy.

Briana Contreras: What’s the role of MET in cancer pathophysiology? For example, why is it an important treatment target?

Paul K. Paik, MD: We’ve known about MET in cancer for decades, so we have a very good understanding of how it works when it’s activated in unregulated cancer growth, such as cell division. It has a role in a mechanism called EMT [epithelial-mesenchymal transition], which is a transition or transformation that normal cells will take under MET to become more invasive—that’s the best way to refer to that. MET also has a role in the development cancer spreading to other sites. We’ve known that it’s quite important to target but have not been able to target it well until recently.

Briana Contreras: What’s the significance of exon 14 skipping specifically?

Paul K. Paik, MD:MET exon 14 skipping is important for a few reasons. The first is that it’s 1 of the newest biomarkers that we’ve identified. It works in a very different way from what we’re used to. I had referred to the different mechanisms by which these biomarkers function on genes and proteins, and in this case exon 14 skipping ends up causing alterations. Or it’s caused by alterations that happen in these flanking junk DNA segments between the coding segments for exon 14, that leads to deletion or skipping of that exon 14. The reason why that’s important is because it’s a regulatory domain. It’s important for that to be in place for the cellular machinery to identify MET and to get rid of it or to be able to control MET. When that’s gone, you get lots of MET present, and we think that’s why a cancer cell ends up becoming addicted to MET for targeting purposes, which is why we can end up targeting it with different drugs.

Briana Contreras: What do we know about the patient characteristics and prognosis associated with MET exon 14 skipping alterations, and how is smoking status relevant?

Paul K. Paik, MD: Patients who have MET exon 14 skipping are different from what we’re used to with other biomarker-defined patient populations. Many patients who end up having a positive hit on the biomarker profile—this would be for EGFR or ALK, for example—are younger, patients whose median age is 50, so we get some of these diagnoses happening in patients in their 30s. It’s not really an older population for these patients, and it’s also a population that tends to be never-smokers, so there’s some mechanism going on that’s not related to cigarette smoking. That’s not the case with patients who have MET exon 14 skipping. The median age of this population is 72, so they’re some 2 decades older than the median age for other alterations. On the other side, a lot of our patients diagnosed with MET exon 14 skipping are in their 80s, and that’s particularly important for reasons I mentioned. They are frailer and they have more medical conditions, so we must be much more careful in how we think about the ways that we construct treatment plans. We need to make sure we don’t end up harming patients with the therapies that we have. The other interesting thing about MET exon 14 skipping is that these happen in equal proportion in patients who have smoked cigarettes and patients who have never smoked cigarettes. There’s something to the biology of this that we do not understand, but that’s another clinical characteristic that has emerged that’s different from other biomarker-divided populations.

Briana Contreras: What are the treatment options for patients with non–small cell lung cancer with MET exon 14 skipping alterations?

Paul K. Paik, MD: Apart from the standard treatment options that are available for all patients with non–small cell lung cancers—chemotherapy drugs and immunotherapies, either by themselves or in combination with chemotherapy—as of last year and earlier this year, there are 2 FDA-approved MET inhibitors for patients with exon 14 skipping. The first to be approved was a drug called capmatinib, approved last year. The second drug, which was approved earlier this year, was called tepotinib.

Transcript edited for clarity.