Determining whether the level of MET amplification is clinically significant in non-small cell lung cancer (NSCLC) is still difficult. However, researchers expect that enrichment for MET-dependent states is associated with a decrease in oncogene overlap and a decrease in the size of the MET amplicon. To determine which of the 16,782 patients with newly diagnosed advanced NSCLC had MET amplification, they analyzed their cell-free DNA NGS results with Guardant360. Each sample was analyzed for copy number variations and genomic mutations simultaneously. They also examined the amplicon size for MET when it was available and applied an exploratory technique to account for tumor fraction.

A total of 207 samples (1.2% of the total) showed evidence of MET amplification. Between 2.1 and 52.9, pCN was found. Among these, 23 (11.1%) carried a METex14 skipping mutation or another MET mutation, and 43 (20.8%) had an overlapping oncogenic driver. As pCN increased, the degree to which these non-MET oncogenes overlapped decreased. Patients with MET pCN greater than or equal to 2.7 had fewer overlapping drivers than those with MET pCN less than 2.7 (6.1% vs. 16.3%, P=.033). There was no overlapping driver in any of the 7 individuals with a pCN greater than 6.7. Even after considering tumor proportion, the median adjusted pCN (ApCN) for individuals with overlapping drivers was lower than that for those without (4.9 vs. 7.3, P=.024). The amplicon size was inversely proportional to the pCN.

Investigators hypothesize that patients most likely to benefit from MET-targeted therapy are those with a high MET pCN and/or ApCN, the absence of overlapping oncogenic drivers, and a small MET amplicon size.

Source: sciencedirect.com/science/article/abs/pii/S1525730422001590