Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital, Columbus, Ohio.
Cancer. 2018 Aug 1;124(15):3118-3126. doi: 10.1002/cncr.31552. Epub 2018 Jun 15.
Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer.
Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1.
One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension.
The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society.
regorafenib 是一种多激酶抑制剂，可抑制血管生成、生长和增殖，作为难治性结直肠癌的单一疗法可延长患者的生存期。这项国际性、双盲、安慰剂对照、多中心试验评估了regorafenib 联合亚叶酸、氟尿嘧啶和伊立替康（FOLFIRI）作为转移性结直肠癌二线治疗的疗效。
在美国和爱尔兰的 45 个地点招募转移性结直肠癌患者，这些患者在一线奥沙利铂和氟嘧啶治疗后进展。根据既往贝伐珠单抗的使用情况，将患者分层，随机以 2:1 的比例接受regorafenib 或安慰剂治疗。治疗方案为每 28 天周期的第 1 天和第 2 天及第 15 天和第 16 天给予 FOLFIRI，第 4 天至第 10 天及第 18 天至第 24 天给予 160mg regorafenib 或安慰剂。不允许交叉。主要终点是无进展生存期（PFS）。根据 75%的事件发生率，假设 135 例事件需要 180 例患者，以达到 90%的效力，检测到风险比（HR）为 0.65，单侧 α 值为 0.1。
181 例患者被随机分组（120 例接受regorafenib-FOLFIRI，61 例接受安慰剂-FOLFIRI），中位年龄为 62 岁。其中，117 例（65%）患者接受过贝伐珠单抗或阿柏西普治疗。与安慰剂-FOLFIRI 相比，regorafenib-FOLFIRI 的 PFS 更长（中位 PFS：6.1 个月 vs 5.3 个月；HR：0.73；95%置信区间[CI]：0.53-1.01；对数秩 P=0.056）。中位总生存期无延长（HR：1.01；95%CI：0.71-1.44）。与安慰剂-FOLFIRI 相比，regorafenib-FOLFIRI 的缓解率更高（34% vs 21%；95%CI：25%-44% vs 11%-33%；P=0.07）。绝对增加超过 5%的regorafenib 相关 3/4 级不良事件包括腹泻、中性粒细胞减少、发热性中性粒细胞减少、低磷血症和高血压。
regorafenib 联合 FOLFIRI 作为转移性结直肠癌的二线治疗，与单独使用 FOLFIRI 相比，仅适度延长 PFS。癌症 2018. © 2018 美国癌症协会。
