Chapter 20 – Regorafenib

Regorafenib (Stivarga, Bayer) is a multikinase inhibitor active on angiogenic, stromal, and oncogenic receptor tyrosine kinases, and the first oral drug in its class indicated for metastatic colorectal cancer (mCRC). In 2012, the Food and Drug Administration (FDA) granted approval for the treatment of patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy, anti-VEGF therapy, and/or, KRAS wild type, anti-EGFR therapy. In 2013, the new indication for patients with locally advanced, unresectable, or metastatic gastrointestinal stromal tumors (GIST), who had been previously treated with imatinib and sunitinib, was acknowledged. In 2013, the European Medicines Agency (EMA) granted approval for treatment of adult patients with mCRC previously treated with, or not considered candidates for, available therapies, including fluoropyrimidine-based chemotherapy, anti-VEGF therapy, and anti-EGFR therapy. In 2014, the indication was extended to adult patients with unresectable or metastatic GIST who had progressed on, or were intolerant to, prior treatment with imatinib and sunitinib. The initial safety profile of regorafenib in mCRC was primarily based on data from Study 14387 in 500 patients exposed to the standard dose (160 mg/d) of regorafenib. The safety profile in GIST was primarily based on Study 14874 in 132 exposed patients. Data of patients in monotherapy were examined as three separate pools, for a total of 3500 patients exposed to regorafenib in clinical trials, and 500 exposed in access and compassionate programs. Its safety profile was consistent across studies, and typical for an antiangiogenetic kinase inhibitor. Vascular (hypertension), cutaneous (hand-foot skin reaction, rash), and gastrointestinal disorders (diarrhea, mucositis) were most common, whereas hematological toxicities were infrequent. The overall reaction severity was mild to moderate. No new adverse reactions emerged in patients with GIST. The most serious events in patients receiving regorafenib were hemorrhage, severe liver injury, and gastrointestinal perforation.