The Prevalence of MET Fusions in NSCLC

Yonina R. Murciano-Goroff, MD, MSc, DPhil, a medical oncologist at Memorial Sloan Kettering Cancer center, discussed the prevalence of MET fusions in patients with non-small cell lung cancer (NSCLC) and the impact of identifying them when making treatment decisions.

One such MET fusion was recently identified as the MET G1090A resistance mutation identified as a driver of resistance to type 1 MET tyrosine kinase inhibitors (TKIs).1 This was identified by researchers using serial targeted genomic sequencing with results presented at the American Association for Cancer Research Annual Meeting 2022.

Investigators looked at an analysis of resistance to crizotinib (Xalkori) and the activity of MET inhibitors with alternative binding modes with structural modeling and in vitro kinase assays. Results of the analysis showed that by switching the type 2 MET inhibitors after the patient developed resistance to type 1 inhibitors it helped overcome the resistance to these mutations. This study was pre-clinical, but according to Murciano-Goroff, this underscores the need for further research in this rare but important mutation.

Transcription:

0:08 | It is an interesting and complex question, because what we know is that MET fusions are rare oncogenic drivers in NSCLC. But on the other hand, they may be somewhat under reported, and part of that is because the standard assays that we use for next generation sequencing in the clinic are really DNA based assays. We know from our experience with other fusions, that some can be missed on DNA based testing and really get picked up on RNA based testing. So, they may be under reported, but at the same time, it still is the case that even accounting for that these are rare in patients with NSCLC. On the other hand, we do see them across several different cancer types. They're probably especially enriched in gliomas where they've been reported in as many as 12%-14% of cases.

1:10 | So, it is an important but rare oncogenic driver. That said, we now have more and more instances of fusions in NSCLC that are rare but on the other hand, if we're able to characterize them biologically and clinically they can be very targetable, with NTRK being a classic example. And really, that's where we see MET fusions as truly an unmet need, as it were, in terms of really kind of trying to better characterize them, trying to improve outcomes through better biological and clinical understanding of this subset of NSCLC.