Goel Gaurav
Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Cancer Manag Res. 2018 Mar 6;10:425-437. doi: 10.2147/CMAR.S88825. eCollection 2018.
Colorectal cancer (CRC) is a major public health problem in the United States with an estimated 50,260 deaths in 2017. Over the past two decades, several agents have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic CRC (mCRC). Regorafenib (BAY 73-4506) is a small-molecule multikinase inhibitor that was approved for the treatment of mCRC in 2012. This agent is a novel oral diphenylurea-based multikinase inhibitor that is active against several angiogenic receptor tyrosine kinases (RTKs; VEGFR-1, VEGFR-2, VEGFR-3, TIE-2), oncogenic RTKs (c-KIT, RET), stromal RTKs (PDGFR-B, FGFR-1), and intracellular signaling kinases (c-RAF/RAF-1, BRAF, BRAF). Preclinical studies have documented its broad-spectrum activity against different solid tumor types including CRC. Phase I studies showed that it had an acceptable safety profile in advanced refractory mCRC. A subsequent Phase III trial (CORRECT) demonstrated significant clinical efficacy of regorafenib in patients with refractory or advanced mCRC, which eventually led to its FDA approval for the treatment of mCRC in September 2012. However, the drug was associated with significant toxicity in clinical practice when administered at the approved doses, which necessitated a thorough reassessment of its dosing schedule and toxicity profile. This review summarizes the development of regorafenib from the initial preclinical studies to the Phase III trials and critically examines the current clinical space occupied by regorafenib in the treatment of mCRC, at 5 years after its initial FDA approval.
结直肠癌（CRC）是美国一个重大的公共卫生问题，2017年估计有50260人死亡。在过去二十年中，几种药物已被美国食品药品监督管理局（FDA）批准用于治疗转移性结直肠癌（mCRC）患者。瑞戈非尼（BAY 73 - 4506）是一种小分子多激酶抑制剂，于2012年被批准用于治疗mCRC。该药物是一种新型的基于二苯基脲的口服多激酶抑制剂，对多种血管生成受体酪氨酸激酶（RTKs；VEGFR - 1、VEGFR - 2、VEGFR - 3、TIE - 2）、致癌性RTKs（c - KIT、RET）、基质RTKs（PDGFR - B、FGFR - 1）以及细胞内信号激酶（c - RAF/RAF - 1、BRAF、BRAF）具有活性。临床前研究已证明其对包括CRC在内的不同实体瘤类型具有广谱活性。I期研究表明，它在晚期难治性mCRC中具有可接受的安全性。随后的一项III期试验（CORRECT）证明了瑞戈非尼在难治性或晚期mCRC患者中的显著临床疗效，这最终导致其于2012年9月获得FDA批准用于治疗mCRC。然而，在临床实践中，按批准剂量给药时该药物具有显著毒性，这需要对其给药方案和毒性特征进行全面重新评估。本综述总结了瑞戈非尼从最初的临床前研究到III期试验的研发过程，并严格审视了瑞戈非尼在最初获得FDA批准5年后在mCRC治疗中目前所占据的临床地位。
