Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.
Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.
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DOI：
10.1016/s0140-6736(16)00559-6
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发表时间：
2016-05-14
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通讯作者：
DiPaola RS
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作者：
Haas NB;Manola J;Uzzo RG;Flaherty KT;Wood CG;Kane C;Jewett M;Dutcher JP;Atkins MB;Pins M;Wilding G;Cella D;Wagner L;Matin S;Kuzel TM;Sexton WJ;Wong YN;Choueiri TK;Pili R;Puzanov I;Kohli M;Stadler W;Carducci M;Coomes R;DiPaola RS
肾细胞癌是高度血管化的，并且主要通过血管内皮生长因子（VEGF）途径的失调而增殖。我们测试了舒尼替尼和索拉非尼，这两种口服抗血管生成药物对晚期肾细胞癌有效，在切除的局部疾病复发风险高的患者中。在这项双盲、安慰剂对照、随机、III期试验中，我们在美国和加拿大的226个研究中心招募了患者。符合条件的患者病理分期为高级别T1 b或更高，非转移性肾细胞癌完全切除，心脏、肾脏和肝脏功能良好。根据复发风险、组织学、东部肿瘤协作组（ECOG）体能状态和手术方式对患者进行分层，并使用排列区组集中进行计算机化双盲随机化。患者被随机分配（1：1：1）接受54周的舒尼替尼50 mg/天口服整个6周周期的前4周，索拉非尼400 mg/天口服两次整个周期，或安慰剂。安慰剂可以是舒尼替尼安慰剂，每6周周期连续给药4周，或索拉非尼安慰剂，在整个研究期间每天给药两次。主要目的是在意向治疗人群中比较每个实验组和安慰剂组之间的无病生存率。安全性分析包括至少有一次随访评估的所有治疗患者。本试验在ClinicalTrials.gov注册，编号NCT 00326898。在2006年4月24日至2010年9月1日期间，来自国家临床试验网络的1943名患者被随机分配到舒尼替尼（n=647），索拉非尼（n=649）或安慰剂（n=647）。在1323例患者入组后，毒性相关停药率较高（舒尼替尼组438例患者中有193例[44%]停药，索拉非尼组441例患者中有199例[45%]停药），降低每种药物的起始剂量，然后单独滴定至原始全剂量。2014年10月16日，由于主要终点的条件把握度较低，ECOG-ACRIN数据安全性监查委员会建议停止盲态随访并发布结果。初步分析显示无病生存期无显著差异。中位无病生存期为5·8年舒尼替尼（IQR 1·6-8·2）（风险比[HR] 1.02，97.5% CI 0.85 - 1.23，p= 0.8038），6·1年索拉非尼（HR 0.97，97.5%CI 0.80 - 1.17，p= 0.7184）和安慰剂组6.6年（IQR 1.5-NE）。最常见的3级或更严重的不良事件是高血压（舒尼替尼组105例[17%]患者，索拉非尼组102例[16%]患者），手足综合征（舒尼替尼组94例[15%]患者，索拉非尼组208例[33%]患者），皮疹（舒尼替尼组15例[2%]患者，索拉非尼组95例[15%]患者）和疲劳（舒尼替尼组110例[17%]患者，索拉非尼组44例[7%]患者）。有5例死亡与治疗有关或发生在治疗结束后30天内; 1例接受索拉非尼治疗的患者在治疗期间死于感染性结肠炎，4例接受舒尼替尼治疗的患者死亡，各有1例死亡是由于神经系统后遗症、胃穿孔后遗症、肺栓塞和疾病进展。修改后的剂量仍导致高毒性。在一项确定性的3期研究中，VEGF受体酪氨酸激酶抑制剂索拉非尼或舒尼替尼的辅助治疗与安慰剂相比无生存获益。此外，尽管降低了剂量，但仍因过度毒性而发生大量治疗中止。这些结果提供了一个强有力的理由，反对使用这些药物的高风险肾癌的辅助设置，并表明癌症复发的生物学可能是独立的血管生成。美国国家癌症研究所和ECOG-ACRIN癌症研究小组，辉瑞和拜耳。
Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6–8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85–1·23, p=0·8038), 6·1 years (IQR 1·7–not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80–1·17, p=0·7184), and 6·6 years (IQR 1·5–NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue (110 [17%] patients on sunitinib and 44 [7%] patients on sorafenib). There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.