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Rare Drivers Emerge as Successful Targets in NSCLC

Caroline Seymour
Published: Friday, Jan 04, 2019

Dr Alexander Drilon
Alexander Drilon, MD
Although rare, alterations in MET, RET, and NTRK are showing significant responses to investigational targeted therapies, several of which have already been granted FDA approval or are on track to receive it, explained Alexander E. Drilon, MD.

on Advanced Non–Small Cell Lung Cancer, Drilon, a medical oncologist at Memorial Sloan Kettering (MSK) Cancer Center, discussed the emerging targetable biomarkers in NSCLC and the investigational therapies designed to target them.

OncLive: Beyond EGFR, ALK, and ROS1, what other biomarkers are emerging in the NSCLC space?

Drilon: Several other biomarkers are paired to match targeted therapies. The first group are the MET exon 14 alterations; these are found in about 4% of patients with NSCLC and have a frequency that is very similar to ALK in some series. These mutations result in activation of the MET pathway, and fortunately, they’re amenable to targeted therapy with MET inhibitors. Several MET inhibitors were in development when we detected these exon 14 alterations in clinical samples, so trials evolved very rapidly. Now, we have data on crizotinib, capmatinib, and tepotinib; capmatinib and tepotinib are selective inhibitors, whereas crizotinib is a multikinase inhibitor. Across the board, the response rates are about 30%; these rates are not quite what we’re used to seeing for EGFR, ALK, ROS1, and BRAF combination therapies.

However, there was a recent report on the use of capmatinib in TKI-naïve patients, which showed a response rate that exceeded 70%. We’re not quite sure how durable those responses are, but it’s something to look forward to. Crizotinib now has a breakthrough designation from the FDA. We hope to see some type of approval for this genomic subset in the future.

What is the rationale for exploring a MET inhibitor in combination with an EGFR inhibitor?

There are 2 major states for MET activation in cancer. The cancer can either be dependent on MET alone—as is the case with de novo MET amplification or MET exon 14 alterations—or cancers can acquire dependence on MET even when they have another primary driver, such as EGFR. When we used a first- or second-generation EGFR TKI for an EGFR-mutant lung cancer, we saw the emergence of MET amplification. Even osimertinib (Tagrisso) showed a substantial number of patients who had MET amplification.


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