Molecular Characteristics of Non-Small Cell Lung Cancer with MET Fusions


Jacob Zaemes, Tolulope Adeyelu, Andrew Elliott, Abdul Rafeh Naqash, Misako Nagasaka, So Yeon Kim, Ravi Chakra Turaga, Matthew Oberley, Jorge Nieva, Hossein Borghaei, Balazs Halmos, George W. Sledge, Stephen V. Liu, Patrick C. Ma, Chul Kim


Introduction: The MET pathway in non-small cell lung cancer (NSCLC) can be dysregulated through various mechanisms. Both MET exon 14 skipping mutations and MET gene amplification have been effectively targeted with MET kinase inhibitors. There are also reports of NSCLC harboring MET fusions responding to MET inhibitors. Here, we provide a comprehensive characterization of MET fusions in NSCLC.

Methods: NSCLC samples (n=29460) underwent molecular profiling at Caris Life Sciences (Phoenix, AZ). Next-generation sequencing of DNA (592-gene panel or whole-exome sequencing) was performed for all samples, with fusions detected via whole transcriptome sequencing (n=21603) and ArcherDx FusionPlex assay (n=7858). PD-L1 expression was assessed using IHC (22c3 pharmDx; positive (+): ≥ 1%). Tumor mutational burden (TMB)-high was defined as ≥ 10 mutations/Mb. Real-world overall survival (OS) information was obtained from insurance claims data, with Kaplan-Meier estimates calculated from time of tissue collection until last date of contact. Mann-Whitney U, chi-square, and Fisher exact tests were applied using p<0.05 to define statistical significance, with p-values adjusted for multiple comparisons.

ResultsMET fusions were identified in 0.10% of patients with NSCLC (n=30). The most common MET fusion partners were CAPZA2 (36.7%, n=11), CD47 (26.7%, n=8), ST7 (10%, n=3), and GPRC5C (6.7%, n=2). Concurrent MET amplification (16.7%, n=5) or MET exon 14 skipping (3.3%, n=1) was observed in MET fusion-positive cases. Other co-occurring alterations included mutations in EGFR (L858R, n=2; E746_A750del, n=1), BRAF (V600E, L597Q, n=1 each), KRAS (Q61L, n=1), and RET-KIF5B fusion (n=1). EGFR and KRAS mutations were identified exclusively with CAPZA2MET fusions, occurring in 3 (27.3%) and 1 (10.0%), respectively. Median cMET expression level was higher in patients with MET fusions compared to those harboring no MET alterations (115.6 vs 62, p=0.0019, q=0.08).
Of the 29 tumors with available PD-L1 expression data, 22 (75.9%) were PD-L1 positive with 8 exhibiting low PD-L1 expression (1-49%) and 14 showing high PD-L1 expression (≥ 50%). 25% of the samples were found to have high TMB. Patients with NSCLC harboring a MET fusion (n=19) showed lower median overall survival (mOS) compared to those with NSCLC not harboring a MET fusion (n=16986): mOS 7.8 months [95% CI: 3.4-10.8] vs. 16.5 months [95% CI: 16.0-17.1], hazard ratio 2.4 [95% CI: 1.5-3.8], p<0.001).

ConclusionsMET fusions are a rare, but potentially actionable, genomic alteration. Our study provides a comprehensive characterization of MET fusions in NSCLC, revealing their diverse fusion partners and co-occurring genomic alterations. Further research is warranted to elucidate the clinical implications of MET fusions in the treatment of various types of cancer, including lung cancer.