Regorafenib

Regorafenib is an oral anticancer medicine belonging to the multikinase inhibitor class. It blocks the activity of several protein kinases involved in tumour growth, blood vessel formation, and the development of tumour-supporting tissue. Its targets include kinases associated with angiogenesis, such as VEGFR1–3 and TIE2, as well as signalling pathways involved in cell proliferation and tumour progression, including RAF, KIT, RET, and PDGFR. By inhibiting these pathways, regorafenib can slow cancer progression in selected patients whose disease has advanced despite previous treatment.

The medicine is administered as film-coated tablets and is generally prescribed as monotherapy for specific advanced malignancies after prior therapies have been unsuccessful or unsuitable. Its established uses include metastatic colorectal cancer, unresectable or metastatic gastrointestinal stromal tumours, and hepatocellular carcinoma previously treated with sorafenib, subject to the applicable regulatory indication. Regorafenib is clinically important because it provides an additional systemic treatment option for these difficult-to-treat cancers. However, its use requires careful assessment because it can cause significant liver injury, skin reactions, hypertension, bleeding, and other serious complications. Treatment selection, dose adjustments, and monitoring should be managed by an oncology team in accordance with current prescribing information and the patient's clinical condition.

Regorafenib was developed as an oral multikinase inhibitor targeting pathways involved in tumour angiogenesis, oncogenic signalling, and tumour microenvironment regulation. Its clinical development included the phase 3 CORRECT trial in previously treated metastatic colorectal cancer, the GRID trial in advanced gastrointestinal stromal tumours following imatinib and sunitinib, and the RESORCE trial in hepatocellular carcinoma previously treated with sorafenib. The United States Food and Drug Administration (FDA) initially approved regorafenib in September 2012 for advanced colorectal cancer, followed by approval for gastrointestinal stromal tumours in 2013 and hepatocellular carcinoma in 2017. The European Medicines Agency (EMA) granted marketing authorisation for Stivarga on 26 August 2013, with approved indications covering eligible adults with metastatic colorectal cancer, unresectable or metastatic gastrointestinal stromal tumours, and hepatocellular carcinoma previously treated with sorafenib. Current indications and prescribing requirements should be checked against the relevant national product information.

Regorafenib is used as monotherapy in adults with selected advanced cancers that have progressed after previous treatment or for which other available treatments are unsuitable. In metastatic colorectal cancer, it is indicated after treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, where applicable, anti-EGFR therapy. In gastrointestinal stromal tumours (GIST), it is used for locally advanced, unresectable, or metastatic disease previously treated with imatinib and sunitinib. In hepatocellular carcinoma (HCC), it is indicated for patients previously treated with sorafenib who meet the applicable clinical criteria. Treatment suitability depends on tumour type, previous therapies, performance status, liver function, and local regulatory guidance. Regorafenib is not interchangeable across these indications, and its use should be determined by an oncology specialist.

Regorafenib is administered orally as tablets. The standard recommended adult starting dose is 160 mg once daily for the first 21 days of each 28-day treatment cycle, followed by seven days without treatment. Tablets should be taken at approximately the same time each day with a low-fat meal. Treatment is generally continued while clinical benefit persists and adverse effects remain manageable. The dose may be reduced, treatment temporarily interrupted, or therapy discontinued according to toxicity and the prescribing information. Liver function should be assessed before treatment and monitored closely during therapy. Blood pressure, skin reactions, blood counts, and other clinically relevant parameters should also be reviewed. Patients should not change the dose or restart treatment after an interruption without guidance from their oncology team.

Common adverse effects of regorafenib include fatigue, weakness, hand-foot skin reaction, diarrhoea, reduced appetite, weight loss, mouth inflammation, nausea, abdominal discomfort, and changes in voice. Hypertension and abnormal liver function tests may also occur. Hand-foot skin reaction can cause redness, swelling, tenderness, pain, or blistering on the palms and soles and may interfere with walking or daily activities. The severity of adverse effects varies between patients and may require supportive treatment, dose reduction, or temporary interruption. Patients should report persistent diarrhoea, painful skin changes, reduced oral intake, or worsening fatigue to their healthcare team. Early recognition and appropriate management can help maintain treatment tolerability.

Regorafenib carries a boxed warning in US prescribing information for severe and sometimes fatal hepatotoxicity. Liver function must be assessed before treatment and monitored regularly, with treatment interrupted, reduced, or discontinued according to the severity and persistence of abnormalities. Other important risks include severe bleeding, gastrointestinal perforation or fistula, serious infections, significant hypertension, cardiac ischaemia or infarction, impaired wound healing, and rare reversible posterior leukoencephalopathy syndrome. Severe skin toxicity may also require treatment modification. Regorafenib should be discontinued when serious toxicity warrants permanent cessation under the applicable prescribing information. It can cause fetal harm, so pregnancy must be avoided during treatment and for the specified period after the final dose. New jaundice, dark urine, severe abdominal pain, chest pain, major bleeding, neurological changes, or signs of serious infection require urgent medical assessment.

Before starting regorafenib, assess liver function, blood pressure, bleeding risk, cardiovascular history, wound-healing concerns, and concomitant medicines. Patients with pre-existing hepatic impairment require particular care, and use in severe hepatic impairment is generally not recommended because of insufficient safety information. Blood pressure should be controlled before treatment begins. Regorafenib may impair wound healing, so treatment timing around major surgery should be planned according to prescribing guidance. Strong CYP3A4 inhibitors can increase exposure to regorafenib, while strong CYP3A4 inducers can reduce exposure; these combinations should generally be avoided where specified in the product information. Regorafenib may also affect medicines handled by certain drug-metabolising enzymes and transporters, including UGT1A9 and BCRP. Patients should disclose all prescription medicines, over-the-counter products, and supplements. Pregnancy and breastfeeding require specific consideration because of potential harm to the developing fetus and uncertainty regarding exposure through breast milk.

Confirm the tumour indication, previous treatment history, performance status, and baseline hepatic function before prescribing regorafenib. Check and control blood pressure before treatment, and establish a monitoring plan for liver enzymes, bilirubin, skin toxicity, bleeding, infection, and cardiovascular symptoms. US prescribing information recommends liver function testing before treatment and at least every two weeks during the first two months, followed by monthly monitoring or more frequent testing when clinically indicated. Counsel patients to take tablets with a low-fat meal and to report early signs of hand-foot skin reaction, persistent diarrhoea, jaundice, or unusual bleeding. Review concomitant medicines for CYP3A4-related interactions and plan treatment interruptions around surgery when necessary. Pharmacists should reinforce adherence to the 21-days-on, seven-days-off schedule and verify dose modifications carefully. All dose adjustments should follow the current product information and the treating oncologist's assessment.