New Data Suggest Potential Role for c-MET Inhibition in EGFR TKI-Resistant NSCLC

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c-MET, although rarer than T790M, may be a promising therapeutic target for patients who progress on EGFR TKI therapy.
c-MET, although rarer than T790M, may be a promising therapeutic target for patients who progress on EGFR TKI therapy.

Approximately 1 in 10 patients with non–small cell lung cancer (NSCLC) have EGFR mutations, making them eligible for EGFR tyrosine kinase inhibitor (TKI) therapy in the first line. Almost 100% of these patients will, however, develop resistance to the drugs, which occurs on average 1 year after treatment initiation.

About half of EGFR TKI–resistant patients have the T790M mutation, though in other cases the acquired resistance is associated with other mechanisms, including amplification of the MET proto-oncogene or aberrations that activate the c-MET pathway.

“cMET in an emerging new target in NSCLC that plays a major role in 2 subsets of NSCLC patients,” explained Yanis Boumber, MD, PhD, of the department of thoracic medical oncology and the Molecular Therapeutics Program at Fox Chase Cancer Center in Philadelphia, Pennsylvania. “The first role of c-MET is as a driver mutation in a subset of lung cancers. The second role is in resistance in patients with EGFR-mutant NSCLC that progresses on EGFR TKIs.”

“Although it is difficult to estimate, c-MET driver mutations probably occur in about 2% to 3% of patients, and testing for this mutation is slightly more complex than testing for EGFR,” said Dr Boumber, noting that these primary mutations are relatively rare.

The larger group of patients who might benefit from c-MET inhibition includes those with NSCLC that are resistant to EGFR TKI therapy associated with aberrant c-MET activity.

“Currently, if you have resistant disease and do not have a T790M mutation, there is no standard of care,” Dr Boumber said. “A lot of patients receive chemotherapy, where there is a tumor shrinkage rate of about 25%, and clearly, based on limited existing data, EGFR-mutant patients derive less benefit from newer immunotherapy drugs compared with lung cancer patients without EGFR mutations.

“We urgently need new combinations because the options for these patients are relatively limited.”

Several trials are examining the potential of c-MET inhibition in NSCLC resistant to EGFR TKIs: one phase 3 trial (ClinicalTrials.gov Identifier: NCT01456325), for example, evaluated onartuzumab, an anti-c-MET monoclonal antibody, in combination with EGFR-targeting erlotinib compared with erlotinib alone. No improvement in overall survival was, however, noted at an interim analysis, leading to trial discontinuation.

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