Guangdong Lung Cancer Institute, Guangdong General Hospital (GGH) & Guangdong Academy of Medical Sciences, Guangzhou, China.
National University Cancer Institute, National University Health System, Singapore.
Cancer Treat Rev. 2017 Dec;61:70-81. doi: 10.1016/j.ctrv.2017.10.003. Epub 2017 Oct 25.
Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5-20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c-Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC. Selective c-Met TKIs exhibit more favorable properties, targeting both hepatocyte growth factor (HGF)-dependent and -independent c-Met activity, with a reduced risk of toxicity compared to non-selective c-Met TKIs. Phase Ib/II trials of the selective c-Met TKIs capmatinib and tepotinib have shown encouraging signs of efficacy. Factors affecting the success of ongoing and future trials of c-Met inhibitors in patients with EGFR TKI-resistant, c-Met-positive NSCLC are considered.
非小细胞肺癌（NSCLC）不可避免地会对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）治疗产生耐药性。在 5-20%的病例中，这可以归因于异常的 c-Met 活性，为这些患者使用 c-Met 抑制剂提供了明确的理由。EGFR TKI 耐药的肿瘤通常仍然对 EGFR 信号敏感，因此 c-Met 抑制剂与持续的 EGFR TKI 治疗联合使用可能最有效。III 期试验中 c-Met 抑制剂 onartuzumab 和 tivantinib 未能在 NSCLC 患者中显示出显著获益，但排除了 EGFR TKI 耐药疾病的患者，这并不允许将 c-Met 排除为 EGFR TKI 耐药 NSCLC 的合理靶点。选择性 c-Met TKI 具有更有利的特性，靶向肝细胞生长因子（HGF）依赖性和非依赖性 c-Met 活性，与非选择性 c-Met TKI 相比，毒性风险降低。选择性 c-Met TKI 卡马替尼和 tepotinib 的 Ib/II 期试验显示出令人鼓舞的疗效迹象。考虑了影响正在进行和未来 c-Met 抑制剂在 EGFR TKI 耐药、c-Met 阳性 NSCLC 患者中试验成功的因素。
