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

 

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.

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.
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