呋喹替尼：作用机制、临床与转化科学

文献信息

中文摘要

呋喹替尼是一种高选择性口服抑制剂，可抑制全部三种血管内皮生长因子受体（-1、-2和-3），已在中国、美国和欧盟获批，用于治疗既往接受过治疗的转移性结直肠癌（mCRC）。呋喹替尼对mCRC的疗效已在随机、双盲、3期临床研究中得到一致证实，包括在中国入组患者的FRESCO研究（NCT02314819）和在北美、欧洲、亚洲和澳大利亚14个国家入组患者的FRESCO-2研究（NCT04322539）。在这两项研究中，患者按2:1随机接受口服呋喹替尼5 mg或匹配安慰剂每日一次，用药3周、停药1周，以28天为周期，并联合最佳支持治疗，直至疾病进展或出现不可接受的毒性。FRESCO和FRESCO-2均达到其主要终点，证明与安慰剂相比，呋喹替尼显著改善总生存期（OS）：在FRESCO研究中（呋喹替尼：n=278；安慰剂：n=138），呋喹替尼组中位OS为9.3个月，安慰剂组为6.6个月（风险比[HR]，0.65；95%置信区间[CI]，0.51-0.83；p<0.001）；在FRESCO-2研究中（呋喹替尼：n=461；安慰剂：n=230），呋喹替尼组中位OS为7.4个月，安慰剂组为4.8个月（HR，0.66；95% CI，0.55-0.80；p<0.001）。呋喹替尼最常见的任何级别治疗中出现的不良事件（在任一项研究中发生率≥20%，排除实验室异常）为高血压、掌跖红细胞感觉异常、蛋白尿、发音困难、腹泻、乏力、食欲减退、甲状腺功能减退和疲劳。本小型综述总结了呋喹替尼的作用机制、药代动力学、关键临床试验以及临床疗效和安全性数据。

英文摘要

Fruquintinib is a highly selective, oral inhibitor of all three vascular endothelial growth factor receptors (-1, -2, and -3) that was approved, including in China, the United States, and the European Union, for the treatment of previously treated metastatic colorectal cancer (mCRC). The efficacy of fruquintinib for mCRC has been consistently demonstrated in randomized, double-blind, Phase 3 clinical studies, including FRESCO (NCT02314819), which enrolled patients in China, and FRESCO-2 (NCT04322539), which enrolled patients across 14 countries in North America, Europe, Asia, and Australia. In both studies, patients were randomized 2:1 to receive oral fruquintinib 5 mg or a matching placebo once daily, 3 weeks on, 1 week off, in 28-day cycles, plus best supportive care, until progression or unacceptable toxicity. Both FRESCO and FRESCO-2 met their primary endpoints, demonstrating significant improvements in overall survival (OS) with fruquintinib versus placebo: in FRESCO (fruquintinib: n = 278; placebo: n = 138), median OS was 9.3 with fruquintinib versus 6.6 months with placebo (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.51-0.83; p < 0.001); in FRESCO-2 (fruquintinib: n = 461; placebo: n = 230), median OS was 7.4 with fruquintinib versus 4.8 months with placebo (HR, 0.66; 95% CI, 0.55-0.80; p < 0.001). The most common any-grade treatment-emergent adverse events with fruquintinib (incidence ≥ 20% in either study, excluding laboratory abnormalities) were hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, diarrhea, asthenia, decreased appetite, hypothyroidism, and fatigue. This mini-review summarizes the mechanism of action, pharmacokinetics, key clinical trials, and clinical efficacy and safety data for fruquintinib.