Recent Advances in Treatment of MET Exon 14 Skipping Mutations in NSCLC

Ben Levy, MD: Martin, let’s move on to MET exon 14 skipping mutations. Obviously, you get more approvals and options. It’s exciting. It’s sometimes difficult to identify MET exon 14 skipping mutations. Nevertheless, we’ve got 2 new drugs approved. Do you want to walk us through some of the data?

Martin Dietrich, MD: We have a number of options here. Some are approved, and some aren’t approved but are available, which makes it a little more exciting. Obviously, there are diagnostic challenges with splicing products, or theoretically if you don’t capture the DNA intron splicing site, less sensitivity. Tissue is preferred for an RNA-based assessment. We have 2 oral therapies approved in this space: tepotinib and capmatinib. They both have very interesting data. The VISION trial that led to the approval of tepotinib showed a response rate of almost 50% in follow-up and an additional 20% of disease stabilization, with a duration of response of a little over a year. That’s a reasonable option. They’ve also submitted the data that are now available for intracranial activity that look almost identical between intra- and extracranial space. This is a very good option.

We have capmatinib based on the GEOMETRY mono-1 trial that looks similar. There are some differences in terms of handling. Tepotinib has once-daily dosing, which makes it easier for patients to manage. But overall, you have 2 very good options in this space that are available for patients. The question is, where do they fit in? It isn’t an EGFR slam dunk with 80% response rates. There’s also a question of the value of immunotherapy in cMET, especially with smoking. That’s a topic of hot debate.

There would be many who wouldn’t automatically extrapolate the data into the first-line space. There may be some tolerance considerations. A head-to-head trial data set against chemoimmunotherapy in the first-line setting is needed to determine the optimal sequence. It’s obviously a rare mutation, but in our area, it isn’t quite as rare. We have a lot of smokers, and we find [it] more commonly. Interestingly, the data here [were] as seen in a broad background of patients, and the geriatric population did as well or better.

The problem with the cMET exon 14 skipping mutations is we don’t have any specificity for targeting. There isn’t a mutation or an ATP [adenosine triphosphate] pocket configurational change that could be specifically targeted. We’re suffering the full width of on-target effects, and vascular integrity and edema are at the heart and center. There are many ways of approaching this. I’m not sure that there has been 1 standard recipe, from extremity elevation to physical measures, compression stockings, or diuretics. They have all had limited opportunities.

It’s interesting. When I look at GeoMETry-III, which was at least in concept presented as an option, we’re looking at a trial design that aims more at placing the drug confidently in the second-line setting. Those data are still evolving, and it has to be adjusted to the individual clinical situation where it fits in.

We do have an additional option. We talked earlier about amivantamab[-vmjw] as a bispecific antibody in the EGFR exon 20 space. With extracellular domain targeting, you have a great deal of versatility. You’re using both effects of targeted therapy as well as some immunogenic effects that may be helpful. We’ve seen some very small data sets from the CHRYSALIS trial in the MET exon 14 cohort that showed response rates in the 60%-plus range as well. Those were very small numbers, and the handling here is obviously more complex than for an oral TKI [tyrosine kinase inhibitor], but I do think most of these patients will eventually see 1 oral agent followed by amivantamab or vice versa in sequence.

I’m not sure that there’s going to be a clarification scientifically on this question. I don’t think there’s going to be a lot of exchange unless it’s for toxicity between the 2 oral agents. It comes down to convenience, availability, and access that will make the decision on what’s going to be utilized in either the first- or later-line setting. The approvals are pretty permissive to initiate those patients. But the question is whether they’re superior to chemoimmunotherapy in the first-line setting. They’re probably better tolerated, but we’re not sure if they’re necessarily going to be superior in efficacy. For me, the standard right now is chemoimmunotherapy in the first-line setting and waiting for more data to change that sequence, even though they’re tempting and the data look quite good.

Ben Levy, MD: Correct me if I’m wrong, but for a patient who’s [positive for] MET exon 14 skipping, you would start with chemotherapy–IO [immuno-oncology] first, and then how do you choose between capmatinib and tepotinib?

Martin Dietrich, MD: They’re both good agents—there’s no question—and have shown similar levels of efficacy and safety. The data are comparable within the margin of error of cross-trial comparison. The once-daily dosing is probably the main argument. Especially practicing in Florida, having a robust geriatric data set is reassuring, but I’m not sure if I’d expect the data to be much different with capmatinib. It comes down to provider choice, but typically once daily is a meaningful argument for me.

Transcript edited for clarity.