Targeting MET Exon 14 Skipping Mutations in NSCLC

Challenges for Following NCCN Guidelines for MET Inhibitors in NSCLC

Martin Dietrich, MD, PhD, discusses the National Comprehensive Cancer Network guidelines for using MET inhibitors in patients with non–small cell lung cancer and their impact on sequencing therapies.

Martin Dietrich, MD, PhD, assistant professor of Internal Medicine at the University of Central Florida, discusses the National Comprehensive Cancer Network (NCCN) guidelines for using MET inhibitors in patients with non–small cell lung cancer (NSCLC).

MET inhibitors target the MET exon skipping 14 mutation, an oncogenic driver for NSCLC found in 3% to 4% of patients. Capmatinib (Tabrecta) was approved in May 2020 based on the results of the phase 2 Geometry mono-1 trial (NCT02414139) while tepotinib (Tepmetko) was approved in February 2021 based on the results of the phase 2 VISION trial (NCT02864992). MET inhibitors showed a high overall response rate and duration of response in trials.

According to Dietrich, the NCCN guidelines recommend giving a MET inhibitor in the first line in patients with the MET exon skipping 14 mutation and use non-targeted treatments in later lines when the patient’s disease progresses. However, patients may have begun treatment with non-targeted chemoimmunotherapy before the targeted MET inhibitors were approved. Additionally, identifying a MET alteration requires molecular testing with next-generation sequencing (NGS) or fluorescence in situ hybridization (FISH) assay, so the rare mutation may not be identified immediately.

This presents a challenge to following the NCCN guidelines since giving MET inhibitors in the first line is not always possible. Oncologists may be unable to give MET inhibitors in the first line and must decide whether to switch to a MET inhibitor following detection of the biomarker or wait for disease progression, Dietrich says.

TRANSCRIPTION:

0:08 | The NCCN guidelines have a difficult stand with the MET exon 14 mutations because the label and the biology are not necessarily in alignment. The NCCN guidelines recommend the first line usage of targeted inhibition of c-MET. But we oftentimes run into the problem that we are starting a label-appropriate different therapy, oftentimes chemoimmunotherapy with limited effect, and then the transition becomes more difficult upon discovery of c-MET [alteration], are we using an arbitrary transition point? Is there a treatment until progression or unacceptable toxicity and then switching over to a MET inhibitor? The ideal case scenario, and I think this is what the NCCN guidelines are trying to emphasize, is that we are supposed to be using targeted inhibitors in the first-line space and move other therapies backwards and try to deprioritize them if possible.