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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.

In May 2018, the FDA granted crizotinib (Xalkori) a breakthrough therapy designation for patients with metastatic non–small cell lung cancer (NSCLC) who harbor MET exon 14 alterations.

Moreover, the investigational agent capmatinib showed a 72% overall response rate (ORR) as frontline therapy in patients with MET exon 14 skipping mutations in the phase II GEOMETRY mono-1 trial.1 In previously treated patients, the ORR was 39.1%.

“The MET space is moving forward very quickly,” said Drilon. Additionally, LOXO-292 and BLU-667 are 2 potent and specific RET inhibitors that have shown impressive efficacy for patients with RET fusions. In September 2018, LOXO-292 received a breakthrough therapy designation from the FDA for the treatment of patients with RET-fusion–positive NSCLC, RET fusion–positive thyroid cancer who require systemic therapy, or RET-mutant medullary thyroid cancer.2 Regarding BLU-667, the agent showed an ORR of 37% in the phase I ARROW trial.3

NTRK is another emerging target of interest, for which there are currently 2 targeted therapies under investigation: larotrectinib and entrectinib. The FDA granted an approval to larotrectinib in November 2018 for adult and pediatric patients with locally advanced or metastatic solid tumors with an NTRK gene fusion. Moreover, a pooled analysis presented at the 2018 ESMO Congress revealed that of 54 evaluable patients with advanced solid tumors harboring a NTRK fusion, 57.4% responded to entrectinib.4

In an interview during the 2018 OncLive® State of the Science SummitTM 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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