Durable responses to immunotherapy of non-small cell lung cancers harboring MET exon-14–skipping mutation: A series of 6 cases.

• 46.2 % (6/13) patients with METex14 mutations response to immunotherapy. • Disease control lasted more than 18 months with partial or complete response. • No predictive factor of response to immunotherapy was identified. • Tolerance profile is that of patients without oncogenic mutations. About 2–3% of non-small–cell lung cancers (NSCLCs) harbor MET exon-14–skipping (METex14) mutations. Efficacy of the MET-inhibitor crizotinib has been reported, but progression-free survival (PFS) was very short. Immune-checkpoint inhibitors (ICIs) have become a cornerstone of NSCLC treatment but appear to be less effective in non-smokers and against tumors exhibiting oncogenic addiction. We describe 6 remarkable (PFS exceeding 18 months) and durable responses to ICIs of NSCLCs harboring a METex14 mutation. Each patient's clinical and biological characteristics, and tumor responses after ICIs were examined. Complete tumor-DNA sequencing was available after starting second-line ICIs, which followed first-line chemotherapy. Tumor-cell programmed cell-death protein-1 ligand-1 (PD-L1) expression on tumor cells was evaluated using antibody clone E1L3N (Cell Signaling Technology). Among 25 patients with METex14 -mutated NSCLCs, 13 of whom were ICI-treated, 6 had prolonged responses: 5 women, 1 man; 57–80 years old; 3 never-smokers, 1 ex-smoker and 2 smokers; 5 adenocarcinomas, 1 sarcomatoid carcinoma; 5 received nivolumab, 1 pembrolizumab. No EGFR , BRAF or KRAS mutations (only 1 minority KRAS mutation), or ALK or ROS translocations were detected. No concurrent MET amplification was observed. Tumor-mutation burden was low (<10 mutations/Mb) in 3 tested tumors. Four partial and 2 complete responses were obtained during the first 3 months for 5 patients, while pseudoprogression was initially observed in 1. Tolerance was excellent, with only 1 grade-3 immune-related adverse event. Response was maintained for 18–49 months. ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs. [ABSTRACT FROM AUTHOR]