Grüllich Carsten
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Medical Center, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
Recent Results Cancer Res. 2018;211:67-75. doi: 10.1007/978-3-319-91442-8_5.
Cabozantinib is a receptor tyrosine kinase inhibitor (TKI) with activity against a broad range of targets, including MET, RET, AXL, VEGFR2, FLT3, and c-KIT. Activity of cabozantinib towards a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Cabozantinib is clinically approved for the treatment of medullary thyroid cancer (MTC) and for renal cell cancer (RCC) in the second line. In MTC gain of function mutations, mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC up to 50% of cases RET mutations occur. Both MET and AXL have been described as mechanisms facilitating resistance against VEGFR-targeted tyrosine kinase therapy in clear cell RCC. Accordingly, cabozantinib has shown activity in RCC patients progressing after first-line VEGFR-TKI therapy in the pivotal METEOR trial. This phase III trial reported a benefit of 4.9 months in survival and an increase in response rate compared to standard everolimus over all patient subgroups. Of particular interest are the effects on patients with bone metastasis, which have a worse prognosis. In these patients, the beneficial effects of cabozantinib over everolimus were even more pronounced. Side effects of interest include diarrhea, hypertension, fatigue, and hand-foot syndrome.
卡博替尼是一种受体酪氨酸激酶抑制剂（TKI），对多种靶点具有活性，包括MET、RET、AXL、VEGFR2、FLT3和c-KIT。在多项临床前研究中可检测到卡博替尼对多种肿瘤模型的活性。值得注意的是，与安慰剂或靶向VEGFR且对MET无活性的药物相比，卡博替尼可降低转移潜能和肿瘤侵袭性。卡博替尼在临床上被批准用于治疗甲状腺髓样癌（MTC）和二线肾细胞癌（RCC）。在MTC功能获得性突变中，RET突变是肿瘤发生的核心。遗传性MTC（MEN II）由RET的种系突变引起，在散发性MTC中，高达50%的病例发生RET突变。MET和AXL均被描述为促进透明细胞RCC对VEGFR靶向酪氨酸激酶治疗产生耐药性的机制。因此，在关键的METEOR试验中，卡博替尼在一线VEGFR-TKI治疗后进展的RCC患者中显示出活性。该III期试验报告称，与标准依维莫司相比，所有患者亚组的生存期均延长了4.9个月，缓解率有所提高。对骨转移患者的影响尤其令人关注，这些患者的预后较差。在这些患者中，卡博替尼相对于依维莫司的有益效果更为明显。感兴趣的副作用包括腹泻、高血压、疲劳和手足综合征。
