For our ASCO presentation we focussed on MET exon 14 mutant non-small cell lung cancer. We and others have been working on this topic for a few years to characterise MET mutations in lung cancer. They are present in about 3% of non-small cell lung cancer and they’re very important to look for in all patients with non-small cell lung cancer because now we have approved targeted therapies with capmatinib in the United States, tepotinib in Japan, and likely other drugs to be approved in the near future.
The focus of the ASCO presentation was to further characterise the genomic and pathologic features of MET exon 14 mutant non-small cell lung cancers. So, in collaboration with Foundation Medicine, they had access to over 1,300 MET exon 14 mutant lung cancers. Through next generation sequencing and immunohistochemistry staining we found that in general this group of lung cancers has a high PD-L1 level but tends to have a lower tumour mutational burden relative to other non-small cell lung cancers. We often found frequent co-alterations in other genes such as MDM2 amplification, CDK4 amplification and amplification of the MET gene itself, which is also mutated.
In this study we also looked to see potential mechanisms of resistance to targeted therapies. So several dozen patients had multiple biopsies sent where we had sequencing done on their tumour both before and after therapies. We saw findings that help us to understand how these lung cancers can develop acquired resistance to targeted therapies. So, for example, we’ve seen on target point mutations within the MET kinase domain at positions D1228, Y1230, L1195, as well as amplification in other genes and pathways such as EGFR and KRAS and others. So, hopefully, through a deeper understanding of the genomic features of this molecular subtype of lung cancer we will hopefully develop the next generation of therapies to both delay and overcome acquired resistance once it develops to our approved treatments.
What are the potential clinical impacts of these results?
We know that MET tyrosine kinase inhibitors can be very effective for treating MET exon 14 mutant non-small cell lung cancer but we also know that many patients can develop acquired resistance to these treatments over time and in some patients that can be six months, nine months or twelve months. So, in part we’d like to understand why we see variation in terms of when resistance develops, why do some patients develop resistance soon whereas others can stay on the therapy for many years without developing resistance.
So that is one part, to understand why patients develop resistance. Then once resistance does develop we would love to be able to target those specific resistance mechanisms by combining or switching to another therapy to overcome resistance. So the hope with this effort is by gaining a deeper understanding of the genomic features of this type of cancer we hope that we can build upon our existing treatments to develop even better therapies in the future.