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

person Jiadi Gan Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China info_outline 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

Authors person Jiadi Gan Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China info_outline 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 Organizations Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China, Department of Head and Neck/Thoracic Oncology, The First People's Hospital of Foshan, Foshan, China, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China, Department of Respiratory Medicine, Zhujiang Hospital, Southern MedicaI University, Guangzhou, 510280, China, Guangzhou, China, Genecast Precision Medicine Technology Institute, Beijing, China, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China, Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China, Genecast Precision Medicine Technology Institute, Beijing, China, Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China Abstract Disclosures Research Funding Other Background: MET exon 14 ( MET ex14) skipping caused by certain mutations in splice sites of MET ex14 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 MET ex14 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 MET ex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in MET ex14 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 MET ex14 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 MET ex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of MET ex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( < 1%) MET ex14 mutations usually co-exist with other driver mutations while high frequency MET ex14 mutations do not. That little infiltration of CD8 + T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying MET ex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring MET ex14 skipping alterations.