MET Exon 14 Skipping Mutations in Non–Small Cell Lung Cancer - Episode 7

MET Inhibitors in NSCLC: Treatment Selection

April 19, 2021
Lyudmila A. Bazhenova, MD, University of California San Diego

,
Joshua M. Bauml, MD, Perelman School of Medicine, University of Pennsylvania

,
Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center

A comparison between the MET inhibitors available to treat MET exon 14 skipping mutations in non–small cell lung cancer and factors that should be considered when selecting a type 1 or type 2 MET-directed therapy.

Lyudmila A. Bazhenova, MD: Capmatinib and tepotinib are both MET tyrosine kinase inhibitors. They work by interrupting the signal through the activated MET receptor. There are 2 types of MET inhibitors—type 1 and type 2—and the distinction between each type is based on where the MET tyrosine kinase inhibitor binds to. Examples of type 1 tyrosine kinase inhibitors are crizotinib, capmatinib, tepotinib, savolitinib. Examples of type 2 MET inhibitors are cabozantinib and glesatinib. We think there could be potential for using a type 2 MET inhibitor after a type 1 MET inhibitor for some patients who develop resistance to type 1 MET inhibitors in the binding site of a MET tyrosine kinase inhibitor.

Benjamin Levy, MD: There are different types of MET-directed therapies. The most common ones, or the ones that are approved, are the type 1 inhibitors capmatinib and tepotinib. These drugs work fairly similarly in terms of their mechanisms of action. That’s why we’re seeing some similarities in the data in terms of response rates. There may be a few differences in terms of their adverse effects, but overall, these drugs are designed and work very similarly at the level of the tumor.

There are other MET-directed therapies. Type 2 MET-directed therapies include cabozantinib. These drugs may be better suited to overcome MET resistance with secondary mutations. But overall, the take-home point here is these drugs are relatively similar in their efficacy, mechanisms of action, and adverse effects. There are not big differences. There may be a few differences in toxicity between savolitinib and capmatinib and tepotinib, but overall, these drugs are relatively the same.

Joshua M. Bauml, MD: Both capmatinib and tepotinib have excellent efficacy, as well as pretty similar adverse-effect profiles. The big things that differentiate them are how they are dosed. Capmatinib is given 2 times a day, while tepotinib is given once a day. That’s pretty much it. I will say that I have more experience utilizing capmatinib, so I tend to use that as my first choice. However, if a patient’s insurance would only provide for tepotinib, I would have no concerns about giving them that. I will note that in the trial of capmatinib as first-line therapy, capmatinib had a much higher response rate compared with tepotinib in the first line. I’m not sure if that’s a statistical fluke or something real. We’ll have to follow these patients and figure this out.

TRANSCRIPT EDITED FOR CLARITY