Part 4: Whether to Switch Treatments After Discovery of MET Mutations in NSCLC

Martin Dietrich, MD, PhD (Moderator)

DISCUSSION QUESTIONS

• What factors would influence your decision to use or not use a MET inhibitor in the first line for an eligible patient? What factors would influence which agent you recommend/select?
• What if a patient had a MET amplification instead of a MET exon 14 skipping mutation?

MARTIN DIETRICH, MD, PHD: What are your thoughts on using the medication in the first-line setting over chemoimmunotherapy? We don’t know exactly how chemoimmunotherapy works [in this setting], since nobody has studied this specifically; but the biology would predict it to be less efficacious, similar like we do with EGFR inhibitors.

Are there any factors that would influence your decision-making, such as adherence or brain metastases? If you see a patient that has started on chemoimmunotherapy, how would you switch? Is there a little bit of a practice-share? How do you choose between capmatinib [Tabrecta] and tepotinib [Tepmetko]?

LUIS RAEZ, MD: I think either drug is OK. I have treated more people with capmatinib because it came first. But I am also interested in using tepotinib, and I think we really use 1 of the 2 instead of crizotinib [Xalkori] because we have plenty of evidence that crizotinib doesn’t protect the brain very well. That’s why I think we should go for capmatinib or tepotinib. I would advocate that you restart the chemoimmunotherapy because you didn’t get the NGS [next-generation sequencing] on time. I think we should stop it and give the patients a chance with the target therapy, as we do with other targets, and then don’t wait until they fail the chemoimmunotherapy to consider the target therapy.

OLEG GLIGICH, MD: I agree, you can go back and forth between the 2. But convenience is huge, because with tepotinib it’s only 2 pills, whereas with capmatinib it’s 4. If patients aren’t going to be tolerating multiple pills, that’s one way.

The other thing to take a look at is MET amplification. With MET exon 14 skipping, you would probably feel more comfortable just using tepotinib. But I think for MET amplifications, you could either use capmatinib for both amplifications and exon 14 skipping mutations; I wanted to know what everybody else’s thoughts on that approach are.

HARSH AMIN, MD: I just want to add one thing about capmatinib and tepotinib. Capmatinib is [available as] a sample, so it’s easily available. I think the company’s doing a good job. If I have a patient, if a sample is ready to go, that influences a little bit in decision-making. Otherwise, like I said earlier, there’s no head-to-head comparison that first-line capmatinib does look better than tepotinib, if you look at the numerical value of overall response rates, so that’s another reason I use capmatinib. When there is a sample, so the label is available to go, that’s another factor that plays a role. I think both drugs have the same brain response rate, so I don’t think that will make a difference.

DIETRICH: It’s a good problem to have, to have 2 very efficacious drugs in this setting. I think convenience is probably the biggest differentiator.

AMIN: I believe MET amplification response rate is much lower, and so I think the chemoimmunotherapy is probably better, at least in the first line. Maybe in the second line, the drug can be used. But that’s as MET amplification is a different situation than MET exon 14 skipping.

DIETRICH: For the MET amplifications, the level of amplifications is something that is really important.

AMIN: Correct, more than 10 [patients], I believe, had a higher response, about 30%.¹ Maybe in that situation, it can be used.

DISCUSSION QUESTIONS

• What if a MET exon 14 skipping mutation was found after front-line chemotherapy or chemoimmunotherapy had been started?
• Would you switch therapy or wait to progression?
• In cases of progression on first-line chemotherapy or chemoimmunotherapy, what regimen would you be most likely to choose for a patient with a MET exon 14 skipping mutation?

DIETRICH: In the post-osimertinib [Tagrisso] EGFR setting, we see the MET amplifications as a major resistance factor. I typically try to not [switch treatments] by getting a liquid biopsy first, but when I make a first step, I typically treat until the patient progresses, and I don’t really switch arbitrarily. I try to avoid it if I can.

KOCH: I would tend to agree with that. These patients are incurable, so the goal is quality of life, and maybe extension of life. If a patient is tolerating whatever therapy they’re on, and they are either responding or stable, I tend to stick with that mode of therapy before I entertain switching to anything else.

DIMITRIOS AGALIOTIS, MD: In the positive cases for the MET exon 14 skipping, what kind of histology would the patients have? Say, in non–small cell lung cancer, was their histology adenocarcinoma, squamous, or non-squamous?

DIETRICH: It goes 2 ways for the MET exon 14 skipping. It’s most often found in adenocarcinomas. It’s somewhere between 1% and 5% [of them]. If it is a sarcomatoid histology, I think the percentage is over 50%. If you have a sarcomatoid differentiation in the lung, the MET exon 14 skipping is probably the highest probability. I don’t think there are much data in squamous or other histologies.

I do want to say that, now that KRAS [inhibition] is approved, and so many other investigational markers are coming, I would sequence all non–small cell lung cancer histologies—squamous, large-cell, and adenocarcinomas. We still have most data in the adenocarcinomas, but it is no longer a big issue in getting it approved. Sometimes the histology assignment is wrong, and sometimes we get surprised by what we find based on the genetics. While the probability is higher, I think the chance for finding them in all other parts here is important.

_REFERENCE

_{1. Paik PK, Felip E, Veillon R, et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407}