MET exon 14 skipping mutations in non-small-cell lung cancer a 3 years screening experience

Abstract

MET exon 14 skipping is an oncogenic driver observed in 1 to 4% of non-small cell lung cancer (NSCLC). MET exon 14 mutations affect splice sites and are highly heterogeneous which makes them difficult to detect. Because of the approval of capmatinib for patients with MET exon 14 mutated tumors and the related poor response to immunotherapy (ICI) for a subset of patients with MET mutated tumors, MET screening has become mandatory for first line treatment decision. Here we report our testing experience based on 1143 consecutive NSCLC addressed for molecular diagnosis. Two strategies using either DNA sequencing (NGS) and fragment analysis or DNA-RNA sequencing (NGS) were developed and validated to accurately detect MET exon 14 alterations including large deletions. For patients with MET tumors (n = 46), demographic characteristics, treatments and outcomes were obtained from medical records and discussed. 46 MET exon 14 alterations were identified, 4 were not called by DNA sequencing and rescued by fragment analysis or RNA sequencing. Sixty-seven percent tumors had a high PD-L1 expression > 50 and 42% of cases had co-occurring alterations, mainly TP53 mutations (24%) and PIK3CA mutations (9%). Response to MET inhibitors (Crizotinib and Capmatinib) was evaluated for 15 patients. The ORR (Objective Response Rate) and the median of PFS (Progression Free Survival) were 44% and 5.5 months [1.6-18.2 months] respectively. Thirteen patients were treated by immunotherapy, ORR and median PFS (Progression Free Survival) median were 30% and 4 months [0.7-55.5 months] respectively. The response to immunotherapy was not correlated with PD-L1 status but smokers seemed to better respond to ICIs. This study highlights that a multimodal approach may be necessary to detect MET exon 14 mutations as large deletions may not be detected by DNA sequencing. Targeted DNA-ARN sequencing strategies broadly interrogate the diverse druggable genomic variations and permits direct detection of altered splicing or gene fusions. Because patients with MET exon 14 mutated tumors, demonstrate low response to immunotherapy despite high PDL1 and because MET exon 14 is druggable the detection of MET mutations is mandatory to optimize treatment.

Keywords: MET exon 14; Capmatinib; Crizotinib; ICI; NGS; NSCLC; PD-L1.