Department of Medical Oncology, Hôpital Européen Georges-Pompidou, AP-HP, René Descartes University Paris 5, 20 Rue Leblanc, 75015 Paris, France.
Cancer Treat Rev. 2012 Dec;38(8):981-7. doi: 10.1016/j.ctrv.2011.12.009. Epub 2012 Jan 30.
Multiple targeted agents are now available for the treatment of patients with metastatic renal cell carcinoma (mRCC). Although targeted agents offer improvements over previous treatments and significantly prolong progression-free survival, most patients eventually experience disease progression. For these patients, sequential treatment with multiple lines of therapy may afford sustained clinical benefit. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) are recommended as first-line therapy for most patients with mRCC. Current clinical practice guidelines uniformly recommend treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus after initial VEGFr-TKI failure. Recent results of the AXIS phase 3 trial demonstrated improved efficacy with second-line axitinib compared with sorafenib in patients who progressed on a variety of first-line therapies, including the VEGFr-TKI sunitinib. Available clinical evidence, individual patient profile, and toxicity concerns should be carefully evaluated when deciding whether to administer an mTOR inhibitor or a second VEGFr-TKI after progression on a first-line VEGFr-TKI. In patients who progress on a VEGFr-TKI and an mTOR inhibitor, retrospective analyses indicate that treatment with a second VEGFr-TKI in the third-line setting provides additional clinical benefit. Recent results from a prospective phase 1/2 trial indicate that third-line therapy with the investigational TKI, dovitinib, may have promising efficacy in patients who progress on a VEGFr-TKI and an mTOR inhibitor; a phase 3 trial of dovitinib versus sorafenib in this patient population is ongoing. This review discusses and evaluates current clinical evidence for sequential therapy with targeted agents in patients with mRCC.
目前有多种靶向药物可用于治疗转移性肾细胞癌（mRCC）患者。虽然靶向药物比以前的治疗方法有所改进，并显著延长了无进展生存期，但大多数患者最终还是会出现疾病进展。对于这些患者，采用多线治疗方案进行序贯治疗可能会带来持续的临床获益。血管内皮生长因子受体酪氨酸激酶抑制剂（VEGFr-TKIs）被推荐作为大多数 mRCC 患者的一线治疗药物。目前的临床实践指南一致推荐在初始 VEGFr-TKI 治疗失败后使用哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂依维莫司进行治疗。AXIS 三期试验的最新结果表明，与索拉非尼相比，二线阿昔替尼在接受多种一线治疗（包括 VEGFr-TKI 舒尼替尼）后进展的患者中具有更好的疗效。在决定是否在一线 VEGFr-TKI 治疗进展后使用 mTOR 抑制剂或第二种 VEGFr-TKI 时，应仔细评估可用的临床证据、患者个体特征和毒性问题。在接受 VEGFr-TKI 和 mTOR 抑制剂治疗后进展的患者中，回顾性分析表明，在三线治疗中使用第二种 VEGFr-TKI 可提供额外的临床获益。一项前瞻性 1/2 期试验的最新结果表明，在接受 VEGFr-TKI 和 mTOR 抑制剂治疗后进展的患者中，使用研究性 TKI 多韦替尼进行三线治疗可能具有良好的疗效；一项多韦替尼与索拉非尼在该患者人群中的 3 期试验正在进行中。本文讨论和评估了 mRCC 患者序贯靶向药物治疗的现有临床证据。
