Tannir Nizar M, Schwab Gisela, Grünwald Viktor
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1155 Pressler St., Unit 1374, Houston, TX, 77030, USA.
Exelixis, Inc., 210 E. Grand Avenue, South San Francisco, CA, 94080, USA.
Curr Oncol Rep. 2017 Feb;19(2):14. doi: 10.1007/s11912-017-0566-9.
Clear cell renal cell carcinoma (RCC) is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. VHL loss drives tumor angiogenesis and accounts for the clinical activity of VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs), the first-line standard of care for advanced RCC. Within the last year, three new second-line treatments have received FDA approval for use after anti-angiogenic therapy: the immune checkpoint inhibitor nivolumab, the TKI cabozantinib, and the combination of the TKI lenvatinib and the mTOR inhibitor everolimus. Cabozantinib inhibits VEGFRs, MET, and AXL, kinases that promote tumorigenesis, angiogenesis, metastasis, and drug resistance. Compared with everolimus, cabozantinib has shown statistically significant improvements in the three key efficacy endpoints of overall survival, progression-free survival, and objective response rate in patients with RCC who were previously treated with a VEGFR TKI. Herein, we summarize the translational research and clinical development that led to approval of cabozantinib as second-line therapy in RCC.
透明细胞肾细胞癌（RCC）的特征是冯·希佩尔-林道（VHL）肿瘤抑制基因失活。VHL缺失驱动肿瘤血管生成，并解释了VEGF受体（VEGFR）酪氨酸激酶抑制剂（TKIs）的临床活性，TKIs是晚期RCC的一线标准治疗方法。在过去一年中，三种新的二线治疗药物已获得FDA批准，可在抗血管生成治疗后使用：免疫检查点抑制剂纳武单抗、TKI卡博替尼以及TKI乐伐替尼与mTOR抑制剂依维莫司的联合用药。卡博替尼可抑制VEGFR、MET和AXL，这些激酶可促进肿瘤发生、血管生成、转移和耐药性。与依维莫司相比，在先前接受VEGFR TKI治疗的RCC患者中，卡博替尼在总生存期、无进展生存期和客观缓解率这三个关键疗效终点上均显示出具有统计学意义的改善。在此，我们总结了使卡博替尼获批用于RCC二线治疗的转化研究和临床开发情况。
