Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan.
Ann Oncol. 2019 Feb 1;30(2):259-265. doi: 10.1093/annonc/mdy526.
The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients.
Patients with KRAS exon 2 wild-type metastatic colorectal cancer after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence [cetuximab ± irinotecan followed by regorafenib (C-R arm)]. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), safety, and quality of life. Exploratory end points included serial biomarker analyses, including oncogenic alterations from circulating tumor DNA or multiple serum or plasma proteins.
One-hundred one patients were randomized and eligible for efficacy analysis. Sequential treatment was successful in 86% patients in both arms. Median OS for R-C and C-R was 17.4 and 11.6 months, respectively (P = 0.0293), with a hazard ratio (HR) of 0.61 for OS [95% confidence interval (CI) 0.39-0.96]. The HR for PFS1 (regorafenib in R-C versus cetuximab in C-R) was 0.97 (95% CI 0.61-1.54), and PFS2 (C in R-C versus R in C-R) was 0.29 (95% CI 0.17-0.50). No unexpected safety signals were observed. The quality of life scores during the entire treatment period was not significantly different between the two arms. Circulating biomarker analyses showed emerging oncogenic alterations in RAS, BRAF, EGFR, HER2, and MET, which were more commonly detected after cetuximab than after regorafenib.
The therapeutic sequence of regorafenib followed by cetuximab suggests a longer OS than the current standard sequence.
本随机二期试验旨在评估瑞戈非尼序贯西妥昔单抗对比西妥昔单抗序贯瑞戈非尼的疗效和安全性，前者是转移性结直肠癌患者的标准治疗序贯。
KRAS 外显子 2 野生型转移性结直肠癌患者氟嘧啶类、奥沙利铂和伊立替康治疗失败后，被随机分为瑞戈非尼序贯西妥昔单抗±伊立替康（R-C 组）或序贯反转[西妥昔单抗±伊立替康序贯瑞戈非尼（C-R 组）]。主要终点为总生存期（OS）。关键次要终点包括初始治疗的无进展生存期（PFS1）、二线治疗的无进展生存期（PFS2）、安全性和生活质量。探索性终点包括连续的生物标志物分析，包括循环肿瘤 DNA 或多种血清或血浆蛋白的致癌改变。
101 例患者随机分组，可进行疗效分析。两组均有 86%的患者成功完成序贯治疗。R-C 和 C-R 组的中位 OS 分别为 17.4 和 11.6 个月（P=0.0293），OS 的风险比（HR）为 0.61[95%置信区间（CI）0.39-0.96]。R-C 中瑞戈非尼与 C-R 中西妥昔单抗的 PFS1（regorafenib in R-C versus cetuximab in C-R）HR 为 0.97（95% CI 0.61-1.54），C-R 中西妥昔单抗与 C-R 中瑞戈非尼的 PFS2（C in R-C versus R in C-R）HR 为 0.29（95% CI 0.17-0.50）。未观察到意外的安全性信号。两组在整个治疗期间的生活质量评分无显著差异。循环生物标志物分析显示，RAS、BRAF、EGFR、HER2 和 MET 的致癌改变在使用西妥昔单抗后比使用瑞戈非尼后更常见。
瑞戈非尼序贯西妥昔单抗的治疗序贯比现行标准序贯有更长的 OS。
