David Hughes, PharmD, and Jessica Freydman, PharmD, Discuss the Mechanism of Action of Tepotinib for MET exon 14+ NSCLC


A clinical pharmacy manager and a pharmacy resident detail the unique mechanism of action of tepotinib for metastatic non–small cell lung cancer with mutations in MET exon 14.

David Hughes, PharmD, BCOP, and Jessica Freydman, PharmD, spoke with ONCOLOGY® about the mechanism of action of tepotinib (Tepmetko) for the treatment of patients with metastatic non–small cell lung cancer harboring METexon 14 skipping alterations. Patients who have this alteration have high expression of exon 14, for which tepotinib can help regulate.


Freydman: [Tepotinib] is a MET kinase inhibitor. The MET kinase has downstream signaling through the RAS and the RAF pathways and the PI3K pathway, and an overexpression of this [MET kinase] leads to cell proliferation and survival. Losing exon 14 in this MET kinase deletes the spot on the juxtamembrane, which leads to decreased ubiquitination, which then leads to increased expression of MET. If you have too much MET [expression], then you have too much cell proliferation and survival. Tepotinib is approved for the [MET] exon 14 skipping mutation, which then causes the overexpression.

Hughes: Another interesting point is that when we think about MET as a whole, most people think of a biomarker-based or precision-based strategy [where] a patient is diagnosed with metastatic [disease] and then a MET mutation or amplification comes up. To frame it, there are 2 different variants: the MET exon 14 skipping mutation seen in about 2% to 3% of adenocarcinoma lung cancer, and the amplifications that occur within that cohort.

The other interesting piece with MET is that it’s been identified as a secondary mutation or acquired resistance to pressure. Several studies have evaluated that when you pressure patients who are on EGFR inhibitors—drugs like osimertinib [Tagrisso] and others—you can see MET amplification as one of the resistance mechanisms to that. It highlights another unique niche area to really focus in on and see how we can incorporate it into the landscape of lung cancer.