Advances in Targeting MET Exon 14 Skipping Mutations in NSCLC

Joshua M. Bauml, MD: The history of MET alterations in lung cancer is a long one. We have looked at multiple drugs targeting MET, recognizing that MET is a critical part of the signaling cascade in lung cancer. There have been monoclonal antibodies targeting this, but we have really struggled to figure out what the real predictive biomarker is here, whether it’s circulating biomarkers, whether it is immunohistochemistry for MET. But in the process of learning about this, MET exon 14 skipping alterations were identified. These are splice site variants that lead to loss of exon 14. We have learned that such patients responded quite well to MET-based therapies. Historically, we had crizotinib, which was a PAN inhibitor but did have MET activity. Some efficacy was demonstrated with the use of that drug. But capmatinib and tepotinib, the 2 recently approved MET inhibitors, have much higher affinity for MET and have led to very nice response rates.

Benjamin Levy, MD: We’ve come a long way in regard to the therapeutic options for patients with MET exon 14 skipping mutations in lung cancer. This is a relevant genetic alteration in lung cancer. It makes up anywhere from 2% to 4% of all lung cancer cases. We’ve made significant advances here.

The first drug that we started exploring in this molecular niche was crizotinib. Crizotinib data looked fairly promising. In highly pretreated groups of patients with MET exon 14 skipping mutations, we’ve seen that crizotinib elicits response rates anywhere from 30% to 35%. The PFS [progression-free survival] is around 7 to 8 months.

Now we have 2 new approvals for targeted therapies that selectively inhibit tumors that harbor MET exon 14 skipping mutations. The first is capmatinib. This is an oral therapy. We’ve now got data generated that show that this drug elicits meaningful responses for patients with lung cancer with MET exon 14 skipping mutations. We’ve seen response rates in previously untreated patients of close to 70%, and we’ve seen response rates in previously treated patients to be around 40%.

The second approval is for tepotinib, another MET-directed therapy recently approved. Again, in patients with lung cancer harboring MET exon 14 skipping mutations, for treatment-naive patients we’ve seen roughly 45% response rates. In previously treated patients, we’ve seen a 45% response rate. So I think overall, we’ve made significant advances. We’ve come a long way. Crizotinib, of course, was the first, but we have 2 new drug approvals—capmatinib and tepotinib—that are exciting to use and are big wins for our patients as we try to advance the field.

Transcript Edited for Clarity