Interest Builds in Targeting MET Mutations in Non-Small Cell Lung Cancer

Lisa Astor
Published: Wednesday, Feb 28, 2018
Emmanuel S. Antonarakis, MD
Balazs Halmos, MD, MS
Although checkpoint blockade immunotherapies have advanced rapidly in the treatment paradigm for patients with non–small cell lung cancer (NSCLC), interest in developing targeted therapies for this malignancy has remained high. Building on the success of molecularly targeted drugs aimed at relatively small subsets of patients, researchers are increasingly aiming at the MET oncogene

During the past several years, interest in MET activity has grown as investigators have considered it both as a biomarker and target for treatment, particularly since the focus on MET exon 14 skipping mutations has led to the development of several second-generation MET inhibitors, according to Balazs Halmos, MD, MS.

MET is a transmembrane receptor tyrosine kinase whose aberrant activity can influence important cell-signaling networks (FIGURE7 ).1 This pathway can be activated in one of several ways, explained Halmos, director of thoracic oncology and director of clinical cancer genomics, Montefiore Medical Center, during a presentation at the 12th Annual New York Lung Cancers Symposium, hosted by Physicians’ Education Resource®, LLC, in December 2017.


Figure 1. MET Signaling Network in Cancer

The pathway can be activated through MET protein overexpression; increased expression of its ligand, hepatocyte growth factor; MET mutations; gene amplification; and alternative splicing or exon 14 skipping. Each of these methods has been investigated as a potential approach to utilize this pathway for the treatment of patients with cancer. “This plethora of possibilities led to a lot of confusion in the field over the years over which biomarker to use for selecting patients for MET-targeted therapy,” Halmos said.

Search for Correct Biomarker

Using MET protein overexpression as a biomarker led to the failure of several randomized studies. For example, the phase III METLung trial of onartuzumab (MetMAb) in combination with erlotinib (Tarceva) failed to meet its primary endpoint of improved overall survival (OS) with added onartuzumab in patients with previously treated locally advanced or metastatic NSCLC.

Onartuzumab is a monoclonal antibody that binds to the extracellular domain of MET, yet the combination regimen with onartuzumab demonstrated a median OS of 6.8 months compared with 9.1 months for erlotinib and placebo (HR, 1.27; 95% CI, 0.98-1.65;  P  = .067).2   The investigators noted that there may be better ways to select patients for MET-targeted therapy than with MET immunohistochemistry.

A greater signal for MET as an actionable target was seen with the use of MET amplification. In the PROFILE 001 study, crizotinib (Xalkori) was investigated in patients with MET–amplified, advanced NSCLC. Although crizotinib is indicated for patients with ALK- or ROS1-rearranged lung cancers, the tyrosine kinase inhibitor (TKI) was originally developed as a type Ia MET inhibitor, Halmos noted. A small trial showed several responses to crizotinib, especially among patients with a higher MET-to-chromosome 7 centromere (MET/CEP7) ratio of ≥5.3

“In patients with a very high copy number of MET, suddenly there’s a lack of other critical driver oncogenes being presented; [this] suggested that in those cancers, MET amplification can be the sole clinical driver,” Halmos said. However, he noted that it was difficult for investigators to find the right MET/ CEP7 threshold for identifying patients for such MET-targeted treatment. Although the threshold changes from study to study, the minimum has been set at 5 for high MET amplification.

Combinations Explored

The effect of MET inhibition has also been investigated in combinations as a method of bypassing resistance to treatments. The overall frequency of MET-driven acquired resistance is likely to be about 2% to 5%, Halmos said.

“It seems that the overexpressed MET kinase clusters on the cell surface along with EGFR, and basically creates a complex on the cell surface that leads to an unconventional EGFR signaling not requiring the ATP binding activity of EGFR. As a result, EGFR inhibition on its own is not successful and dual inhibition is necessary.”

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