MET Exon 14 Skipping Mutations in NSCLC Respond to Targeted Therapies

Lyudmila A. Bazhenova, MD, a medical oncologist and professor of medicine at UC San Diego, discusses targeted therapies for patients with MET-mutated non–small cell lung cancer (NSCLC).

MET mutations are found in 3% to 5% of patients with lung cancer. There are 2 separate, significant MET mutations: MET exon 14 skipping and MET amplification.

Bazhenova says that 2 drugs, capmatinib (Tabrecta) and tepotinib (Tepmetko), are approved by the FDA for patients with MET exon 14 skipping mutations. Tepotinib was approved for patients with advanced or metastatic NSCLC based on the phase 2 VISION study (NCT02864992), which showed an overall response rate (ORR) of 46% and a median duration of response (DOR) of 11.1 months.

In the GEOMETRY Mono-1 study (NCT02414139), investigators found that capmatinib had an ORR of 41% and a DOR of 9.7 months in patients who had 1 or 2 previous lines of therapy, and 68% ORR in patients and a DOR of 12.6 months in patients who were treatment naive.

Acccording to Bazhenova, amplicon-based next-generation sequencing (NGS) DNA assays may not detect MET exon 14 skipping mutations reliably. Recent studies have shown that RNA-based assays may find these mutations at a significantly higher rate, making these targeted therapies available to more patients.

TRANSCRIPTION:

0:08 | In MET exon 14 skipping mutations, it is important to notice that [these mutations] happen in approximately 3% to 5% of patients with lung cancer. We have 2 separate [mutations]: MET exon 14 skipping mutations and MET amplifications. Currently, our approved drugs are only approved in MET exon 14 skipping mutations. And those are capmatinib based on [the GEOMETRY Mono-1] study and tepotinib based on the VISION study, which showed ORR of about 45% on tepotinib, and 68% in treatment-naive and 41% in pretreated patients in the capmatinib study.

The medications seem to have durable responses, which were reported anywhere from about 10 to 12 months. I think the caveat [is], what’s important to understand is MET exon 14 skipping mutations is that they can be missed on a DNA assay, especially if your DNA assay is using amplicon-based NGS. And there [were] data that I presented from Memorial Sloan Kettering [Cancer Center], showing that if you do an RNA-based assay, you actually pick up more MET exon 14 skipping mutations.