Recent FDA-Approvals: MET Exon 14 Mutations in NSCLC

Benjamin Levy, MD: Great overview. For the sake of time, we’re going to move on to MET exon 14 skipping mutations and new approvals in 2020, 2021 for these rare but actionable mutations. Melissa, in 2 minutes or less—sorry to put you under the gun—[give us] a high-level overview of capmatinib and tepotinib and maybe a little about the ctDNA [circulating tumor DNA] story we saw at ASCO [American Society of Clinical Oncology Annual Meeting].

Melissa Johnson, MD: Sure. That’s easy to do, Ben, because neither of these drugs is new to our audience. Capmatinib and tepotinib have been FDA approved for MET exon 14 skipping mutations for 6 months to a year, and both showed updated analysis. The capmatinib data reported at ASCO was in the front line. Response rate is 65%, the PFS [progression-free survival] is 10 months, and overall survival is 20 months—not too shabby. Adverse-effect profile with both drugs is similar—edema, nausea, vomiting, diarrhea. Nothing new there, but it’s solidifying the use of capmatinib in the front line as well as in refractory patients.

Tepotinib had an interesting analysis. They looked at patients who had ctDNA tested at baseline when they started tepotinib at 6 weeks, at 12 weeks, and then end of treatment. All the outcome data were what had been previously reported in this group, but what they found is that as ctDNA became unmeasurable, patients’ responses were better. The faster the ctDNA disappeared from the bloodstream, the more likely that patient was to have a response. This isn’t a new paradigm. We’ve seen this with EGFR TKIs. We saw it with ALK TKIs at this meeting as well. We’ve seen it with RET TKIs as well. It was interesting to me that we saw it in MET because we don’t always see MET mutations in the blood so well, but when you see them, they’re real, and they predict a response.

Benjamin Levy, MD: I look forward to chapters 4 and 5 of this longitudinal ctDNA story and whether we can get real traction and approval and making treatment decisions. We’ve learned, as you said, drops are good. They correlate with longer PFS. What to do with those that don’t drop is the real question for a lot of us. Alex, are there any real differences, in your mind, between tepotinib and capmatinib? Would you use 1 over the other?

Alex Spira, MD, PhD, FACP: No. I view them as interchangeable at this point. I know everybody is going to go back and do the cross-trial comparisons that we’re not supposed to do and look for subtle differences, but in my mind they’re equivalent. I’m sure others feel otherwise. I must be the magnet, because I saw 2 patients today on these drugs. One was 89 years old, and 1 was 90. I have to say: Edema is a tough thing to manage. I don’t know if people have other experiences than I do. They’re both well-tolerated drugs except for that, but I view them as being interchangeable.

Benjamin Levy, MD: What a win for patients, though. Two new drug approvals potentially to use obviously in the first line. It underscores the importance of testing. You can’t give these drugs obviously unless we can identify these mutations either in tissue or in blood.

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