MET Exon 14 Mutations in Non–Small Cell Lung Cancer



Benjamin Levy, MD: We have 2 more new genotypes to talk about. The first is MET exon 14 skipping mutation, and the last is NTRK fusion. Becca, do you want to talk to us about the relevance of MET exon 14 skipping mutations and some of the new drugs that are either being tested or approved? It’s incredible to try to keep up with all these drugs for the different genotypes. I don’t envy the challenges that exist for community oncologists in trying to keep up with this. But this is another approval that we’ve had in the past 2 or 3 months, with another probably coming soon.

Rebecca Heist, MD: MET is interesting. People have been trying to target MET for a long time, and there are many different ways to measure MET. This is an area where when we get to the testing discussion, it’s important to talk about. There’s MET overexpression, MET amplification, and MET exon 14 skipping. With exon 14 skipping, there are a host of different changes at the genomic level. These are primarily mutations or insertions/deletions around the splice-site regions. What they do is cause the exon 14 to be spliced out, and the receptor that gets expressed is 1 that is more stable on the cell membrane. It’s not degraded as much. In the patients who have these MET exon 14 mutations in their cancer, it does seem to behave as a driver.

There are multiple MET inhibitors that have been looked at. Crizotinib, as you all know, was initially developed as a MET inhibitor and in MET skipping. It’s been published, and the response rate was 32%. The waterfall plot looked more impressive than that response rate because the majority of patients had some degree of benefit.

The other 2 more selective MET inhibitors that currently have some data out there include tepotinib, which was just recently published. The response rate was 46%. There are multiple response rates reported for a liquid biopsy vs tumor biopsy, or independently reviewed vs investigator reviewed. They all fall around the same 46% number. Then capmatinib is FDA approved. There, the data are broken down by first line and then subsequent lines. In the first-line setting, in patients who had never had prior treatment, the response rate was 68%. Then in the second and third lines, it was 41%. At ASCO [the American Society of Clinical Oncology Annual Meeting], the second-line capmatinib cohort was reported, and there the response rate was 48%.

Overall, there are several potential options in this setting with nice response rates. With the capmatinib data, I would be using it in the first-line setting and would expect to have nice responses there.

Benjamin Levy, MD: Lyuda or Josh, do you have any experience with either of those 2 drugs? Is there any experience with toxicities? I have not used either capmatinib or tepotinib yet. Josh, what is your take on the data or experience with the drugs?

Joshua Bauml, MD: I have just recently prescribed a couple of patients capmatinib. I haven’t seen any toxicity yet, but it’s too early. It feels like yesterday that it was approved, so that’s too fast for a toxicity take. But 1 of the things that is most interesting about the MET population is this drop-off in the response rate from the first line to the later lines. It really emphasizes the importance of using the best drug first. Patients with MET exon 14 skipping alterations tend to be older. They may have more comorbidities, so it’s really important to use targeted therapy first. I had been using crizotinib. This is a different setting from what I described before with entrectinib and crizotinib. In ROS1, crizotinib works well. It doesn’t have CNS [central nervous system] penetration. In this setting, crizotinib works OK—maybe a bit worse—and doesn’t have CNS penetration. I’m much more likely to replace capmatinib in this setting than I was in ROS1. But it’s a complicated space, for sure. When tepotinib becomes available, it will be a coin flip. Both drugs are very active, CNS penetrant, and well tolerated.

Benjamin Levy, MD: Lyuda, what are your thoughts?

Lyudmila Bazhenova, MD: I don’t have personal experience with those drugs because I have trials that I put my patients on for the MET exon 14. The data presented are certainly compelling enough that if I didn’t have a trial, the next patient with MET exon 14 mutations I saw would be prescribed capmatinib.

Rebecca Heist, MD: In general, as a class effect, peripheral edema is seen with the MET inhibitors. It seems like the more selective and potent the MET inhibitor, the more edema we see. There is definitely more edema than with crizotinib. That tends to be something that accumulates over time. I found that compression stockings help a lot. Lymph edema massage actually helps a lot. In general, these are pretty well-tolerated drugs, and the edema seems to be 1 of the major issues we see.

Just to highlight what Josh was saying, we see MET skipping across all histologies in non–small cell lung cancer. That includes adenocarcinoma, squamous cell carcinoma, and pulmonary sarcomatoid carcinoma. We see it in smokers, as well as never smokers, and there is this predominance in older adults. The importance of testing is really highlighted by this particular alteration.

Transcript Edited for Clarity

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