Regorafenib: A Review in Metastatic Colorectal Cancer

Abstract

Regorafenib (Stivarga) is an oral small-molecule multiple kinase inhibitor. It is indicated worldwide for patients with metastatic colorectal cancer (mCRC). In the EU and USA it is indicated for patients with mCRC who have been previously treated with, or are not considered candidates for available therapies, including fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and, if RAS wild-type, an anti-EGFR therapy. In Japan, it is indicated for the treatment of unresectable, advanced/recurrent CRC. The addition of regorafenib to best supportive care prolonged median overall survival (OS; by up to 2.5 months) and progression-free survival (PFS; by up to 1.5 months) relative to the addition of placebo in double-blind phase 3 studies (CORRECT and CONCUR) in patients with mCRC who had progressed after failure of standard therapy. Health-related quality of life was not adversely affected with regorafenib relative to placebo. A large open-label phase 3 study (CONSIGN) and several large real-world studies supported the efficacy of regorafenib in this setting. Regorafenib had a generally manageable tolerability profile, which was consistent with the profile of a typical small-molecule multiple kinase inhibitor. Treatment-related adverse events (AEs), mostly of mild or moderate severity, were reported in the majority of patients receiving regorafenib, with dermatological toxicities and liver enzyme elevations among the most common AEs. Although identification of biomarkers/parameters predicting efficacy outcomes with regorafenib will help to individualize therapy, current evidence indicates that regorafenib is a valuable treatment option for patients with refractory mCRC who have a very poor prognosis.

BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy

“…Regorafenib is a multityrosine kinase inhibitor that mainly inhibits antigenic and oncogenic kinases, such as VEGFR, PDGFR, FGFR, and BRAF. Two randomized phase III clinical studies (CORRECT and CONCUR) evaluated the efficacy of regorafenib in mCRC treatment and the results indicate that regorafenib is a promising treatment option for patients with mCRC who had poor prognosis [ 156–158 ].…”

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

“…Regorafenib is an oral multikinase inhibitor approved for the treatment of metastatic colorectal cancers, gastrointestinal stromal tumors, and hepatocellular carcinomas . Compared with conventional cytotoxic chemotherapeutics, regorafenib has demonstrated activity against a variety of diseases that were previously essentially resistant to standard chemotherapy and reduced toxicity to normal tissues.…”

Long Non-coding RNA MIR570MG Causes Regorafenib Resistance in Colon Cancer by Repressing miR-145/SMAD3 Signaling

“…Regorafenib is an oral multi-kinases inhibitor that targets angiogenesis-related genes, including VEGFR1, VEGFR2, VEGFR3, and TIE2, as well as various oncogenes such as KIT, RET, RAF1, BRAF, PDGFR, FGFR, and p38 MAPK (11). Regorafenib has been used for late line treatment for several cancers including advanced colorectal cancer (12), hepatocellular carcinoma (13), and gastrointestinal stromal tumors (14). Particularly, regorafenib monotherapy for treating metastatic colorectal cancer was approved by the U.S. Food and Drug Administration due to the 1.5 months improvement in the CORRECT trial compared to the placebo (15).…”