The molecular and immune characteristics, antitumor activity of crizotinib in non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping alterations

Author:Jiadi Gan, Wenfeng Fang, Weineng Feng, Jiexia Zhang, Huojin Deng, Lei Zhang, Yadan Li, Juanjuan Qian, Hongli Luo, Yanhui Chen, Ying Yang, Henghui Zhang, Li Zhang

Background: MET exon 14 (METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. 

Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. 

Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8+ T cells were observed in tumor region and significantly less infiltrated than in stroma region (P< 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. 

Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( < 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8+ T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.