MET Inhibitors in NSCLC: Mechanisms of Resistance

Joshua M. Bauml, MD: It’s absolutely critical, as I said before, to utilize targeted therapy in the first line. We have seen that the response rate drops substantially as targeted therapy is used in later lines. Also, just in principle, we like to use our best drug first. There’s no doubt in my mind that targeted therapy is the best approach for patients who have a molecular driver alteration.

I tend to utilize chemotherapy with or without immunotherapy in the second line for patients who have progressed on a MET TKI [tyrosine kinase inhibitor]. We look for mechanisms of resistance, but we don’t really have any clear data indicating that there are reproducible and targetable mechanisms of resistance that can respond to other drugs we have.

Lyudmila A. Bazhenova, MD: Despite the fact that MET inhibitors are active in lung cancer, one can see the median progression-free survival [PFS] with those drugs is not as long as we see with, for example, ALK inhibitors or EGFR inhibitors. For example, the median PFS for capmatinib was about 12.4 months in the first line and 5.4 months in the second line. The median PFS for tepotinib was 8.5 months in the first line and 10.9 months in the second line. We also have data on savolitinib, which reported a median PFS of somewhere around 6 months. So it is clear that resistance will eventually develop in those patients. 

Very similar to what we have learned about other tyrosine kinase inhibitors and resistance, one can divide resistance to MET TKIs into 2 major categories: on-target resistance, where something happens with the MET receptor itself—either amplification or a secondary mutation and a binding domain, for example—or off-target resistance, where you can see amplifications or mutations in other drivers.

If one talks about MET on-target resistance, we have seen mutations in 12;28 and 12;30 positions. This is very commonly described after using type 1 inhibitors. Those mutations are thought to interfere with the binding of the type 1 inhibitor to the ATP-binding pocket. Because type 2 inhibitors bind differently, it is possible that those drugs may be able to overcome those mutations because the binding site is different. We have an in vitro study confirming that.

Off-target resistance is very diverse. In terms of what has been described for off-target resistance, we have seen KRAS amplifications, EGFR amplifications, acquired BRAF mutations, acquired KRAS mutations. How to manage those patients who have off-target resistance through MET is unknown. Theoretically, one can consider using an acquired abnormality targeted drug, but we do not have any trials telling us what the right way of managing acquired off-target resistance is in those patients.

Benjamin Levy, MD: We’re just beginning to scratch the surface in terms of mechanisms of resistance for patients with MET exon 14 skipping mutations. I think we can look at them to 3 broad categories. The first is on-target secondary mutations that may be responsive to other MET-directed therapies. There are also off-target mechanisms of resistance that include things like EGFR amplifications, KRAS mutations, KRAS amplifications. Then there’s a large swath of unknown. We’re still trying to understand how we can leverage this knowledge about mechanisms of resistances to make better decisions moving forward. This is a call for biopsies upon progression for patients. This is a call for both tissue and liquid analyses. This is a call for trials. For a patient who has a MET exon 14 skipping mutation who receives something like capmatinib in the first-line setting, we’re not really sure what to do next in terms of routine clinical care. We’re not sure if we should use chemotherapy. Should it be chemotherapy plus immunotherapy? What are the new novel agents that can really attack certain mechanisms of resistance?

There are on-target mechanisms, off-target mechanisms, and then there’s the unknown. In the next 5 years, if not sooner, we will have other drugs available that we can learn how to sequence. So use capmatinib first, then post-capmatinib, understand mechanisms of resistance. Then maybe use another MET-directed therapy. We’ll be there sooner than 5 years. I say that for a potential FDA approval. I look forward to the science moving forward. I look forward to a better understanding of mechanisms of resistance over the next couple of years.

TRANSCRIPT EDITED FOR CLARITY