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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and has a poor prognosis. Current treatments for advanced NSCLC included traditional chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The efficacy of targeted therapy relies on oncogene addiction. Mesenchymal-epithelial transition factor (MET) gene can encode unconventional receptor tyrosine kinases with pleiotropic functions, when signals are abnormally activated, it can initiate and maintain tumor transformation, promote cell proliferation, survival, tumor invasion and angiogenesis. Thus, it is a promising therapeutic target. Previous studies have shown that elevated levels of HGF and/or overexpression of c-Met are associated with poor prognosis in lung cancer. In preclinical and clinical trials, c-MET inhibitors have shown some antitumor activity in NSCLC. Although the efficacy results of MET inhibitors in Phase III clinical trials are disappointing, given the molecular heterogeneity of NSCLC, only subgroups of patients with MET gene alterations may benefit from c-MET inhibitors. The challenge for the future is to screen out the potential beneficiaries. To solve this problem, there is need for large data analysis for the detection methods and treatment effects, to establish standards that meet the MET activation status, and determine reliable thresholds to achieve effective patient stratification and clinical decision making. This article summarized the structure of the hepatocyte growth factor (HGF)/c-Met axis, the different mechanisms of MET addiction, as well as MET amplification as acquired resistance mechanism to epidermal growth factor receptor-tyrosine kinase inhibitors, the latest advances of MET inhibitors, and immuotherapy in the treatment of NSCLC with MET alterations.

Hongge Liang1, Di Ma2, Yan Xu1, Jing Zhao1, Minjiang Chen1, Xiaoyan Liu1, Wei Zhong1, Junling Li2, Mengzhao Wang1 1Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Oncology, Chinese Academy of Medical Sciences Cancer Institute and Hospital, Beijing, People’s Republic of ChinaCorrespondence: Wei ZhongDepartment of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, No. 1 Shuanfuyuan Wangfujing Dongcheng District, Beijing 100730, People’s Republic of ChinaTel +86 0 106 915 5039Email zw_pumch@126.comMengzhao WangDepartment of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, No. 1 Shuanfuyuan Wangfujing Dongcheng District, Beijing 100730, People’s Republic of ChinaTel +86 0 106 915 5154Email mengzhaowang@sina.comBackground: Targeted therapy is an important treatment for advanced non-small cell lung cancer (NSCLC) patients with specific genetic mutations, crizotinib can prolong survival in advanced NSCLC patients with echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase (EML4-ALK) rearrangement. We performed a retrospective analysis to investigate the association between the lactate dehydrogenase (LDH) levels and progression-free survival (PFS) in patients with EML4-ALK rearrangement NSCLC receiving treatment with crizotinib.Methods: Advanced (stage IIIb–IV) NSCLC patients with EML4-ALK rearrangement receiving treatment with crizotinib were enrolled between January 2007 and January 2016 at Peking Union Medical College and Cancer Hospital Chinese Academy of Medical Sciences.Results: Overall, 212 patients were enrolled. Kaplan–Meier univariate analysis showed that elevated pre-treatment LDH level (7.9 vs 14.1 months, HR =1.251, CI: 1.008–1.553, P=0.004) was significantly associated with shorter PFS, while the post-treatment mean-LDH level (13.3 vs 14.3 months, HR=1.439, 95% CI: 0.994–2.082, P=0.970) was not significantly associated with PFS. Cox proportional hazards model also identified that pre-treatment LDH level (HR=2.085, 95% CI: 1.150–3.781, P=0.016) was associated with the PFS. Logistic regression analysis showed that post-treatment LDH level was associated with creatine kinase (OR=6.712, 95% CI 3.395–13.273, P250 U/L) was significantly associated with shorter PFS in patients with EML4-ALK rearrangement NSCLC. Post-treatment elevated serum LDH level was not significantly associated with PFS, which related to adverse events including muscle damage and anemia.Keywords: non-small cell lung cancer, lactate dehydrogenase, crizotinib, echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase, progression-free survival

In the latest years, some drugs have been approved by European Medicines Agency (EMA) and/or the US Food and Drug Administration (FDA) for the treatment of patients with advanced non-small cell lung cancer (NSCLC), particularly for the treatment of those who have no targeted gene mutations or who have progressed on previously targeted therapy or platinum-containing dual-agent chemotherapy. In general, these drugs fall into two categories: anti-angiogenic agents and immune checkpoint inhibitors (ICIs). Anti-angiogenic agents currently approved by the FDA and/or EMA for advanced NSCLC treatment include bevacizumab, nintedanib, and ramucirumab. Anlotinib has been approved in advanced NSCLC by Chinese Food and Drug Administration (CFDA). These anti-angiogenic agents can induce anti-angiogenesis by targeting vascular endothelial growth factor (VEGF)/VEGF2 or inhibiting multiple small molecules involved in angiogenic and proliferative pathways such as platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs). Although these drugs show significant therapeutic efficacy, most patients inevitably experience disease progression resulting in death. ICIs approved by the FDA and/or EMA for advanced NSCLC treatment include nivolumab, pembrolizumab, and atezolizumab. These ICIs can significantly improve efficacy compared with standard chemotherapy by targeting programmed cell death protein 1 (PD-1) receptor or PD-2 receptor with longer response duration and acceptable toxicity. However, the response rate of ICIs is suboptimal, and only a few patients ultimately benefit from immunotherapy. So current efforts have focused on exploring new potential combinatorial strategies with synergistic antitumor activity. Here, we summarized the theoretical basis, current clinical data, and potential future perspective of immunotherapy combined with anti-angiogenic agents for advanced NSCLC.