Regorafenib, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.1, 2, 3, 4, 5
Regorafenib is used for the treatment of metastatic colorectal cancer in adult patients who have received fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens; a vascular endothelial growth factor inhibitor (anti-VEGF therapy); and, in those with tumors bearing the wild-type (nonmutated) KRAS gene, an epidermal growth factor receptor inhibitor (anti-EGFR therapy).1, 2
The use of regorafenib in the treatment of metastatic colorectal cancer is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (CORRECT) in patients with previously treated metastatic colorectal cancer.1, 2 The primary measure of efficacy was overall survival.1, 2 The median age of patients was 61 years.1, 2 Patients enrolled in the study received a median of 3 prior therapies for their disease; all patients received previous treatment with bevacizumab and with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens.1 With one exception, all patients with tumors bearing the wild-type KRAS gene previously received panitumumab or cetuximab therapy.1 In this study, 760 patients were randomized in a 2:1 ratio to receive either regorafenib (160 mg orally once daily) or placebo for 3 consecutive weeks of each 4-week cycle; all patients received best supportive care.1, 2 Treatment was continued until disease progression, death, or unacceptable toxicity occurred or treatment was discontinued for other reasons.1, 2 The median duration of treatment was 1.7 months for patients receiving regorafenib.1 Results of a planned interim analysis indicated that patients receiving regorafenib had a longer median overall survival (6.4 versus 5 months; hazard ratio for death: 0.77) and longer median progression-free survival (2 versus 1.7 months) than those receiving placebo.1, 2 Overall response rates were low (1 versus 0.4%, respectively) and were not substantially different between regorafenib-treated patients and placebo-treated patients, suggesting that the drug's main effect in this patient population was disease stabilization; none of the patients achieved a complete response.1, 2 Subgroup analysis according to primary site of disease suggested that regorafenib had a greater effect on overall survival relative to placebo in patients with colon cancer than in those with rectal cancer; an overall survival benefit for the drug versus placebo was not apparent in the small subgroup of patients with primary disease involving both the colon and rectum.2 Subgroup analysis suggested that the drug's effect on progression-free survival was uniform across all 3 subgroups.2
The American Society of Clinical Oncology (ASCO) guideline for the treatment of patients with late-stage colorectal cancer generally recommends doublet or triplet fluoropyrimidine-based chemotherapy with or without bevacizumab regardless of RAS mutation status; however, patients with wild-type RAS and certain comorbidities or risk factors who are not candidates for chemotherapy may be offered monotherapy with anti-EGFR therapy (e.g., cetuximab, panitumumab).17 Immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab, nivolumab in combination with ipilimumab) may also be considered in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) colorectal cancer (regardless of RAS mutation status) who are not candidates for intensive chemotherapy.17
First-line treatment options for patients with late-stage colorectal cancer are the same regardless of whether the intent is curative or palliative.17 Second-line treatment options for the treatment of metastatic colorectal cancer include immune checkpoint inhibitors or chemotherapy with or without anti-EGFR therapy or ziv-aflibercept, and should be chosen based on the regimen used in the first-line setting (e.g., bevacizumab, oxaliplatin, irinotecan) and disease characteristics (e.g., RAS or BRAF mutation status, dMMR, microsatellite instability [MSI] status).17 ASCO states that regorafenib or trifluridine/tipiracil may be considered in the third- or fourth-line setting in patients with any RAS / BRAF status; however, the drugs are recommended in patients with metastatic colorectal cancer harboring wild-type RAS who were previously treated with fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR therapy.17
Regorafenib is used for the treatment of locally advanced, unresectable, or metastatic GI stromal tumor (GIST) in adult patients who previously received imatinib and sunitinib therapy;1, 3, 4 regorafenib has been designated an orphan drug by FDA for the treatment of this cancer.8
The use of regorafenib in the treatment of GIST is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (GRID) in patients with locally advanced, unresectable, or metastatic GIST following failure of both imatinib and sunitinib therapy.1, 3 The primary measure of efficacy was progression-free survival based on radiographic evidence.1, 3 The median age of patients was 60 years; all patients enrolled in the study had a baseline ECOG performance status of 0 or 1.1, 3 In this study, 199 patients were randomized in a 2:1 ratio to receive either regorafenib (160 mg orally once daily) or placebo for 3 consecutive weeks of each 4-week cycle; all patients received best supportive care.1, 3 Treatment cycles were continued until disease progression or unacceptable toxicity occurred or treatment was discontinued for other reasons; upon radiographic progression, patients previously randomized to receive placebo were permitted to cross over to open-label regorafenib treatment.1, 3 The median duration of treatment was 5.7 months for patients receiving regorafenib.1 A planned interim analysis indicated that patients receiving regorafenib had longer median progression-free survival (4.8 months) compared with those receiving placebo (0.9 months).1, 3 The overall response rate was 4.5% for patients receiving regorafenib and 1.5% for those receiving placebo; none of the patients achieved a complete response.3 Median overall survival had not been reached at the time of the interim analysis; however, no significant difference in overall survival was observed between the treatment groups.1, 3
In a randomized, open-label, phase 3 study, regorafenib was compared with avapritinib for the treatment of patients with unresectable or metastatic GIST previously treated with 2 lines of therapy.18 Median progression-free survival was not significantly different between regorafenib (5.6 months) and avapritinib (4.2 months).18 Treatment-related adverse events also were similar between the treatment groups.18
Treatment of GIST includes surgical resection and/or the use of tyrosine kinase inhibitors depending on the extent of disease and tumor sensitivity to the tyrosine kinase inhibitor.61 Approximately 85% of all GIST contain a mutation in KIT and/or platelet-derived growth factor receptor alpha ( PDGFRA ) which result in constitutive activation of the receptor tyrosine kinase; therefore, inhibition of KIT is a primary therapeutic modality for the treatment of GIST.61 Regorafenib is generally recommended in the third-line setting in patients with imatinib-sensitive mutations and imatinib-nonsensitive-mutations.60, 61
Although the majority of GIST cases have either a mutation in KIT or PDGFRA , approximately 10-15% of cases do not have a detectable KIT or PDGFRA mutation.62 Loss-of-function mutations in succinate dehydrogenase ( SDH ) or loss of SDHB expression have been identified in a majority of KIT / PDGFRA -wild-type GIST (also referred to as SDH -deficient GIST); such tumors are usually resistant to imatinib, but may have some sensitivity to sunitinib and regorafenib.61, 62
Regorafenib is used for the treatment of hepatocellular carcinoma in adult patients who previously received sorafenib therapy;1, 14 regorafenib has been designated an orphan drug by FDA for the treatment of this cancer.8
The use of regorafenib in the treatment of hepatocellular carcinoma is based principally on the results of a randomized, double-blind, placebo-controlled, phase 3 study (RESORCE) in patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma following failure of sorafenib therapy.1, 14 Patients were enrolled in the study if they were not eligible for surgical or locoregional therapies; 81% of patients enrolled in the study had macroscopic vascular invasion and/or extrahepatic disease.1, 14 Patients who permanently discontinued prior therapy with sorafenib because of toxicity or who were unable to tolerate a sorafenib dosage of 400 mg once daily were excluded from the study.1, 14 The median age of patients was 63 years; 98% had mild (Child-Pugh class A) hepatic impairment, 88% were male, 87% had BCLC stage C disease, 61% had received prior locoregional therapies, and 41% were Asian.1, 14 All patients enrolled in the study had a baseline ECOG performance status of 0 or 1.1, 14 Chronic hepatitis B virus (HBV) infection, alcohol consumption, chronic hepatitis C virus (HCV) infection, or nonalcoholic steatohepatitis were risk factors for underlying cirrhosis in 38, 25, 21, or 7% of patients, respectively.1, 14 The median duration of prior sorafenib treatment was 7.8 months.1, 14 The primary measure of efficacy was overall survival.1, 14
In this study, 573 patients were randomized in a 2:1 ratio to receive either regorafenib (160 mg orally once daily) or placebo for 3 consecutive weeks of each 4-week cycle; all patients received best supportive care.1, 14 Treatment cycles were continued until disease progression or unacceptable toxicity occurred or treatment was discontinued for other reasons;1, 14 placebo recipients were permitted to cross over to open-label regorafenib treatment after the primary analysis.14 The median duration of treatment was 3.5 months for patients receiving regorafenib.1 Median overall survival was 10.6 months in patients receiving regorafenib compared with 7.8 months in those receiving placebo.1, 14 In addition, patients receiving regorafenib had prolonged progression-free survival (3.1 versus 1.5 months) and higher objective response rates (11 versus 4%) according to modified Response Evaluation Criteria in Solid Tumors (RECIST) assessment for hepatocellular carcinoma (mRECIST) compared with those receiving placebo; complete responses were achieved in 0.5% of regorafenib-treated patients.1, 14 Use of either mRECIST or RECIST version 1.1 to assess progression-free survival and objective response rates resulted in comparable findings.1, 14 Subgroup analysis according to disease etiology (HCV infection, HBV infection, alcohol consumption), tumor burden (presence or absence of macroscopic vascular invasion and/or extrahepatic disease), ECOG performance status (0 or 1), Child-Pugh score (A5 or A6), α-fetoprotein (AFP) concentration, age, gender, and geographic region suggested that regorafenib consistently improved median overall and progression-free survival and time to progression across all subgroups.14
Management of early stage hepatocellular carcinoma includes liver transplantation, surgical resection, and ablation.20 Survival is usually less than 6 months in patients with untreated advanced stage hepatocellular carcinoma.20 Treatment of hepatocellular carcinoma is complicated by the presence of underlying liver disease, the extent and location of tumor, comorbidities, and performance status.20, 51
The ASCO guideline on systemic therapy for advanced hepatocellular carcinoma states that lenvatinib, sorafenib, or durvalumab may be offered as first-line therapy for patients with advanced hepatocellular carcinoma, Child-Pugh class A, and an ECOG performance status of 0 or 1 if therapy with atezolizumab + bevacizumab or durvalumab + tremelimumab is contraindicated.51 ASCO also states that following first-line treatment with sorafenib or lenvatinib, second-line therapy with another tyrosine kinase inhibitor (cabozantinib or regorafenib), ramucirumab, nivolumab + ipilimumab, or durvalumab may be recommended for appropriate candidates.51
The decision to pursue second-line therapy and choice of treatment should be based on patient and clinician preferences and other factors (i.e., comorbidities, liver function, performance status, and potential for benefit and risk of harm).51
Regorafenib is administered orally with water following a low-fat meal containing less than 600 calories and less than 30% fat at the same time each day.1 The tablets should be swallowed whole.1
If a dose of regorafenib is missed, the prescribed dose should be taken as soon as possible on the same day; two doses should not be administered on the next day to replace the missed dose.1
Store regorafenib in its original container in a dry place at controlled room temperature (20-25ºC); excursions are permitted between 15-30ºC.1 Discard any unused tablets 7 weeks after first opening the bottle.1
Dosage of regorafenib, which is commercially available as the monohydrate, is expressed in terms of anhydrous regorafenib.1
For the treatment of metastatic colorectal cancer in patients who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens, anti-vascular endothelial growth factor (anti-VEGF) therapy, and, in those with tumors bearing the wild-type (nonmutated) KRAS gene, anti-epidermal growth factor receptor (anti-EGFR) therapy, the recommended dosage of regorafenib is 160 mg once daily for 21 days followed by a 7-day rest period; courses of therapy are given in 28-day cycles.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of locally advanced, unresectable, or metastatic GI stromal tumor (GIST) in patients who previously received imatinib and sunitinib therapy, the recommended dosage of regorafenib is 160 mg once daily for 21 days followed by a 7-day rest period; courses of therapy are given in 28-day cycles.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
For the treatment of hepatocellular carcinoma in patients who previously received sorafenib therapy, the recommended dosage of regorafenib is 160 mg once daily for 21 days followed by a 7-day rest period; courses of therapy are given in 28-day cycles.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
When dosage modification is necessary, the daily dosage of regorafenib should be reduced in decrements of 40 mg; however, if a dosage of 80 mg daily is not tolerated, regorafenib should be permanently discontinued.1
If grade 3 or 4 toxicity occurs, regorafenib therapy should be interrupted.1 If the toxicity is grade 4, the manufacturer states that therapy should be permanently discontinued; the manufacturer states that therapy may be resumed following recovery from grade 4 toxicity only if the potential benefits of resuming therapy outweigh the risks.1, 13 When therapy is resumed following recovery from the first episode of grade 3 or 4 toxicity (except hepatotoxicity or infection), regorafenib should be administered at a reduced dosage of 120 mg daily; if grade 3 or 4 toxicity (except hepatotoxicity or infection) occurs at a dosage of 120 mg daily, therapy should be withheld again until recovery occurs and then may be resumed at a further reduced dosage of 80 mg daily.1 If the patient does not tolerate a dosage of 80 mg daily, regorafenib therapy should be permanently discontinued.1
For the first episode of grade 2 palmar-plantar erythrodysesthesia (hand-foot syndrome) of any duration, dosage of regorafenib should be reduced to 120 mg daily.1, 13 If grade 2 palmar-plantar erythrodysesthesia does not improve within 7 days of dosage reduction or if it recurs at a dosage of 120 mg daily, therapy should be withheld; when therapy is resumed, the dosage should be further reduced to 80 mg daily.1, 13 If the patient does not tolerate a dosage of 80 mg daily, regorafenib therapy should be permanently discontinued.1, 13 (See Dermatologic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
If grade 3 palmar-plantar erythrodysesthesia occurs, regorafenib therapy should be withheld for at least 7 days; following recovery, therapy may be resumed at a reduced dosage of 120 mg daily.1, 13 If grade 3 palmar-plantar erythrodysesthesia recurs at a dosage of 120 mg daily, therapy should be withheld again for at least 7 days; following recovery, therapy may be resumed at a further reduced dosage of 80 mg daily.1, 13 If the patient does not tolerate a dosage of 80 mg daily, regorafenib therapy should be permanently discontinued.1, 13
For recommended dosage modifications in patients experiencing grade 4 palmar-plantar erythrodysesthesia, see Grade 3 or 4 Toxicity under Dosage and Administration.1, 13
In patients who exhibit grade 3 serum aminotransferase (ALT and/or AST) elevations (i.e., exceeding 5 times the upper limit of normal [ULN], but not more than 20 times the ULN), regorafenib therapy should be interrupted; following recovery, therapy may be resumed at a reduced dosage of 120 mg daily only if the potential benefits of resuming therapy outweigh the risk of hepatotoxicity.1, 13 If grade 3 elevations in ALT or AST recur at a dosage of 120 mg daily, treatment with regorafenib should be permanently discontinued.1, 13
Following any occurrence of grade 4 ALT and/or AST elevations (i.e., exceeding 20 times the ULN), regorafenib therapy should be permanently discontinued.1, 13
Following any occurrence of grade 2 or higher AST and/or ALT elevations (i.e., exceeding 3 times the ULN) and bilirubin concentrations exceeding twice the ULN, regorafenib therapy should be permanently discontinued.1, 13
If symptomatic grade 2 hypertension occurs, regorafenib therapy should be interrupted.1 For recommended dosage modifications in patients with grade 3 or 4 hypertension, see Grade 3 or 4 Toxicity under Dosage and Administration.1
If grade 3 or 4 infection develops or worsening infection of any grade occurs, regorafenib therapy should be interrupted; following resolution of the infection, therapy may be resumed at the same dosage.1
No dosage adjustment is necessary in patients with mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN) or moderate (total bilirubin concentration exceeding 1.5 times, but not more than 3 times the ULN with any AST concentration) preexisting hepatic impairment; however, patients with hepatic impairment should be closely monitored for adverse effects.1 Use of regorafenib in patients with severe preexisting hepatic impairment (total bilirubin concentration exceeding 3 times the ULN) is not recommended because safety and efficacy have not been established in these patients.1
No dosage adjustment is necessary in patients with mild to severe renal impairment.1 The pharmacokinetics of regorafenib have not been studied in patients with end-stage renal disease requiring dialysis; therefore, the manufacturer states that an appropriate dosage for these patients has not been established.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Although hepatotoxicity and palmar-plantar erythrodysesthesia occur more frequently in Asian patients, the manufacturer states that no initial dosage adjustment is necessary in this population.1
A boxed warning about the risk of hepatoxicity is included in the prescribing information for regorafenib.1 Severe and sometimes fatal hepatotoxicity has been reported in patients receiving regorafenib, generally during the initial 2 months of therapy; hepatic toxicity is usually characterized by a hepatocellular pattern of injury.1, 2 In addition, hyperammonemic encephalopathy, including fatal cases, has been reported with regorafenib in the postmarketing setting.1 The risk of hyperammonemic encephalopathy appears increased in patients with hepatic dysfunction, liver metastases, or primary liver cancer.1
In the CORRECT study, fatal hepatic failure was reported more frequently in patients with metastatic colorectal cancer receiving regorafenib compared with those receiving placebo (1.6 versus 0.4%).1 Among patients receiving regorafenib for GI stromal tumor (GIST) in the GRID study, fatal hepatic failure occurred in 0.8% of patients.1 In the RESORCE study, the incidence of fatal hepatic failure was not increased in patients with hepatocellular carcinoma receiving regorafenib compared with those receiving placebo.1 In an analysis of pooled data from 3 trials involving patients with metastatic colorectal cancer, GIST, or hepatocellular carcinoma, liver function test abnormalities were reported more frequently in Asian patients receiving regorafenib compared with Caucasian patients.1
Serum aminotransferase (ALT and AST) and bilirubin concentrations should be evaluated prior to initiation of therapy, at least every 2 weeks for the first 2 months of therapy, and then monthly thereafter or more frequently as clinically indicated.1 If aminotransferase and/or bilirubin concentrations rise above pretreatment levels, liver function tests should be monitored weekly until the elevated concentrations have returned to baseline values or have decreased to less than 3 times the upper limit of normal (ULN).1 For patients who develop unexplained lethargy or changes in mental status, an ammonia level should be measured and appropriate clinical management initiated.1 Temporary interruption of therapy followed by dosage reduction or permanent drug discontinuance may be necessary depending on the severity and persistence of the toxicity (i.e., elevated liver function test results or hepatocellular necrosis).1 If hyperammonemic encephalopathy is confirmed, withhold regorafenib and consider permanent discontinuation.1
Other Warnings and Precautions
Infections, sometimes fatal, have been reported in patients receiving regorafenib.1 In clinical studies, infection was reported in 32% (grade 3 or greater in 9%) of patients receiving regorafenib compared with 17% of those receiving placebo.1 Urinary tract infections, nasopharyngitis, mucocutaneous and systemic fungal infections, and pneumonia were the most common infections, occurring in 5.7, 4, 3.3, and 2.6% of patients, respectively.1 Fatal infections, most commonly respiratory infections, occurred in 1% of regorafenib-treated patients compared with 0.3% of those receiving placebo.1
Temporary interruption of therapy may be necessary depending on the severity of the infection.1
Hemorrhage, sometimes fatal, has been reported in patients receiving regorafenib.1 In clinical studies, hemorrhage was reported more frequently in regorafenib-treated patients compared with patients receiving placebo (18.2 versus 9.5%); grade 3 or greater hemorrhage occurred in 3% of regorafenib-treated patients.1 Fatal hemorrhage (CNS bleeding or respiratory, GI, or genitourinary tract bleeding) was reported in 0.7% of patients receiving regorafenib.1
If severe or life-threatening hemorrhage occurs, regorafenib should be permanently discontinued.1 If regorafenib is used in patients receiving a coumarin-derivative anticoagulant (e.g., warfarin), the international normalized ratio (INR) should be monitored more frequently.1
GI Perforation and Fistula Formation
GI perforation occurred in 0.6% of 4518 patients receiving regorafenib in clinical trials; 8 deaths were reported.1 In placebo-controlled trials, GI fistula formation was reported in 0.8 or 0.2% of patients receiving regorafenib or placebo, respectively.1
Regorafenib should be permanently discontinued in patients with GI perforation or fistula formation.1
In clinical studies, skin reactions, including palmar-plantar erythrodysesthesia (hand-foot syndrome) and severe rash requiring dosage modification, occurred in 71.9% of patients receiving regorafenib and 25.5% of those receiving placebo.1 Palmar-plantar erythrodysesthesia was reported in 53% of patients receiving regorafenib and 8% of those receiving placebo;1 the onset generally occurred during the first cycle of therapy.1 Grade 3 palmar-plantar erythrodysesthesia, grade 3 rash, severe erythema multiforme, and severe Stevens-Johnson syndrome were reported more frequently in patients receiving regorafenib compared with those receiving placebo.1 Toxic epidermal necrolysis also occurred in patients receiving regorafenib in clinical trials.1 In an analysis of pooled data from 3 trials involving patients with metastatic colorectal cancer, GIST, or hepatocellular carcinoma, palmar-plantar erythrodysesthesia was reported more frequently in Asian patients receiving regorafenib compared with Caucasian patients.1
Dosage reduction, temporary interruption of therapy, or permanent drug discontinuance may be necessary depending on the severity and persistence of the toxicity; other symptomatic and supportive measures also should be employed.1
In the CORRECT study, hypertension was reported more frequently in patients with metastatic colorectal cancer receiving regorafenib compared with those receiving placebo (30 versus 8%).1 In the GRID study, hypertension occurred in 59% of patients with GIST receiving regorafenib compared with 27% of those receiving placebo.1 In the RESORCE study, hypertension occurred in 31% of patients with hepatocellular carcinoma receiving regorafenib compared with 6% of those receiving placebo.1 Hypertensive crisis has been reported.1 Onset of hypertension generally occurred during the first cycle of therapy.1 Blood pressure should be controlled before regorafenib therapy is initiated.1 Blood pressure should be monitored weekly during the first 6 weeks of regorafenib therapy and thereafter should be monitored every cycle, or more frequently, as clinically indicated.1 If hypertension is severe or uncontrolled, temporary or permanent discontinuance of therapy is recommended.1
In clinical studies, cardiac ischemia or infarction occurred more frequently in patients receiving regorafenib than in those receiving placebo (0.9 versus 0.2%).1 Therapy should be interrupted in patients who develop new or acute-onset cardiac ischemia or cardiac infarction.1 Upon resolution of acute cardiac ischemic events, therapy may be resumed if the potential benefits outweigh the risk of further cardiac ischemia.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients receiving regorafenib.1 This complication occurred in one of 4800 patients treated with regorafenib in clinical trials.1 RPLS is a syndrome of subcortical vasogenic edema that may manifest with headache, seizures, visual disturbances, confusion, or altered mental function.1 Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.1
The possible diagnosis of RPLS should be considered in any patient receiving regorafenib who presents with neurologic manifestations suggestive of RPLS.1 Regorafenib should be discontinued in patients who develop RPLS.1
The effect of regorafenib on wound healing has not been specifically studied to date; however, inhibitors of vascular endothelial growth factor receptor (VEGFR) may impair wound healing.1
The manufacturer recommends that regorafenib be discontinued at least 2 weeks prior to scheduled surgery.1 The decision to resume therapy postoperatively should be based on clinical assessment of the adequacy of wound healing.1 Do not resume regorafenib for at least 2 weeks following major surgery and until adequate wound healing occurs.1 The safety of resuming regorafenib after resolution of wound healing has not been established.1
Fetal/Neonatal Morbidity and Mortality
Regorafenib may cause fetal harm if administered to pregnant females;1 embryolethality and teratogenicity have been demonstrated in animals.1 Regorafenib produced developmental toxicity, including cardiovascular, genitourinary, and skeletal abnormalities, when administered to pregnant animals in dosages associated with exposure levels lower than those associated with the recommended human dosage.1 Pregnancy should be avoided during therapy and for 2 months after drug discontinuance.1 If regorafenib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
Regorafenib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1
Regorafenib and its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.1 Because of the potential for serious adverse reactions to regorafenib in nursing infants, women should be advised to discontinue nursing during regorafenib therapy.1 The effects of the drug on nursing infants or on milk production are unknown.1 Women may begin nursing 2 weeks after discontinuance of therapy.1
Females and Males of Reproductive Potential
Females and males of reproductive potential should use effective contraception during therapy and for 2 months after discontinuance of therapy.1
Results of animal studies suggest that regorafenib may impair male and female fertility.1 The effect of regorafenib on fertility in humans is not known.1
Safety and efficacy of regorafenib have not been established in pediatric patients younger than 18 years of age.1
Persistent growth and thickening of the femoral epiphyseal growth plate, as well as dose-dependent angiectasis and dentin alteration, have been observed in animals receiving repeated doses of regorafenib at exposure levels lower than those associated with the recommended human dosage.1
In clinical studies, 40% of patients were 65 years of age or older and 10% were 75 years of age or older.1 No overall differences in safety and efficacy were observed between geriatric patients and younger adults, but grade 3 or 4 hypertension occurred more frequently in geriatric patients.1
In a population pharmacokinetic analysis, no clinically meaningful differences in the mean systemic exposure to regorafenib and its active N -oxide (M-2) and N -oxide and N -desmethyl (M-5) metabolites were observed in patients with hepatocellular carcinoma and mild (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but no more than 1.5 times the ULN) or moderate (total bilirubin concentration exceeding 1.5 times, but not more than 3 times, the ULN with any AST concentration) hepatic impairment compared with patients with normal hepatic function; no dosage adjustment is required in patients with mild or moderate hepatic impairment.1 However, patients with mild or moderate hepatic impairment should be monitored closely for adverse effects.1 Regorafenib has not been studied in patients with severe hepatic impairment (total bilirubin concentration exceeding 3 times the ULN); therefore, use of the drug is not recommended in these patients.1
Following administration of regorafenib (160 mg daily for 21 days), systemic exposure to regorafenib and its active M-2 and M-5 metabolites in patients with severe renal impairment (creatinine clearance 15-29 mL/minute) was similar to that in patients with normal renal function; no dosage adjustment is recommended in patients with mild to severe renal impairment.1 However, regorafenib has not been studied in patients with end-stage renal disease requiring dialysis, and an appropriate dosage for these patients has not been established.1
In clinical trials, a higher incidence of palmar-plantar erythrodysesthesia (hand-foot syndrome) and liver function abnormalities were observed in Asian patients.1 No dosage adjustment is recommended based on race.1
The most common adverse reactions (≥20%) are pain (including GI and abdominal pain), palmar-plantar erythrodysesthesia (hand-foot syndrome), asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Metabolism of regorafenib to M-2 (an active N -oxide metabolite) is mediated by cytochrome P-450 isoenzyme 3A4 (CYP3A4); the enzyme responsible for conversion of M-2 to M-5 (an active N -oxide and N -desmethyl metabolite) has not been established to date.1, 12 Therefore, concomitant use of regorafenib with potent inhibitors of CYP3A4 may result in increased systemic exposure to the parent drug, decreased systemic exposure to M-2 and M-5, and an increased incidence of adverse effects.1 In healthy individuals, the potent CYP3A4 inhibitor ketoconazole (400 mg daily for 18 days) increased the area under the concentration-time curve (AUC) of regorafenib (single 160-mg dose administered 5 days after initiation of ketoconazole) by 33% and decreased the AUCs of both M-2 and M-5 by approximately 93%.1, 12 Concomitant use of regorafenib with potent inhibitors of CYP3A4 (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, voriconazole) should be avoided.1
Concomitant use of regorafenib with potent inducers of CYP3A4 may result in decreased systemic exposure to the parent drug, increased systemic exposure to M-5, and reduced regorafenib efficacy.1 In healthy individuals, the potent CYP3A4 inducer rifampin (600 mg daily for 9 days) decreased the AUC of regorafenib (single 160-mg dose administered 7 days after initiation of rifampin) by 50% and increased the AUC of M-5 by 264%; the AUC of M-2 was not substantially altered.1, 12 Concomitant use of regorafenib with potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided.1
Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro studies have suggested that regorafenib inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, and 3A4; that the active M-2 metabolite inhibits CYP isoenzymes 2C8, 2C9, 2D6, and 3A4; and that the active M-5 metabolite inhibits CYP2C8.1 In vitro studies also have suggested that regorafenib does not induce CYP isoenzymes 1A2, 2B6, 2C19, or 3A4.1 However, when patients with advanced solid tumors received a single dose of midazolam (2 mg; a CYP3A4 substrate), rosiglitazone (4 mg; a CYP2C8 substrate), warfarin sodium (10 mg; a CYP2C9 substrate), or omeprazole (40 mg; a CYP2C19 substrate) following 2 weeks of regorafenib administration (160 mg once daily), the AUCs of midazolam and rosiglitazone were not substantially altered, the AUC of warfarin was increased by 25%, and plasma concentrations of omeprazole measured 6 hours after administration were not substantially altered.1
Drugs Affected by Transport Systems
In vitro data indicate that regorafenib is an inhibitor of the efflux transporter breast cancer resistance protein (BCRP).12 Therefore, concomitant use of regorafenib with drugs that are substrates of BCRP may result in increased systemic exposure to the substrate drug.1 When regorafenib (160 mg once daily for 14 days) was administered prior to the BCRP substrate rosuvastatin (single 5-mg dose), peak plasma concentration and AUC of rosuvastatin were increased 4.6- and 3.8-fold, respectively.1 Patients receiving regorafenib concomitantly with BCRP substrates (e.g., atorvastatin, fluvastatin, methotrexate) should be closely monitored for signs of toxicity associated with the substrate drug.1
Although in vitro data also indicate that regorafenib is an inhibitor of the efflux transporter P-glycoprotein (P-gp),12 clinical data indicate that regorafenib does not alter the pharmacokinetics of digoxin (a P-gp substrate).16 No clinically meaningful interactions between regorafenib and P-gp substrates are expected.16
Drugs Affecting Transport Systems
In vitro studies indicate that the active M-2 and M-5 metabolites of regorafenib are substrates of P-gp and BCRP.16 Inhibitors or inducers of these efflux transporters may alter M-2 and M-5 exposure; however, the clinical importance of these in vitro findings is not known.16
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT)
In vitro studies indicate that regorafenib and its active metabolites competitively inhibit UGT1A1 and UGT1A9 at clinically relevant concentrations.1, 16 In patients receiving an irinotecan-containing regimen concomitantly with regorafenib, the AUCs of irinotecan and its active metabolite SN-38 (a UGT1A1 substrate) were increased by 28 and 44%, respectively, when a dose of irinotecan hydrochloride (180 mg/m2 as a 1.5-hour IV infusion) was given 5 days after completion of a series of 7 doses of regorafenib (160 mg orally once daily).1, 7
When regorafenib (single 160-mg dose) was administered concomitantly with neomycin sulfate (1 g orally 3 times daily for 5 days) in healthy individuals, the AUC of regorafenib was not substantially altered; however, the AUCs of M-2 and M-5 were decreased by 76 and 86%, respectively.1 The effect of other antibiotics on systemic exposure of regorafenib and its active metabolites has not been established.1
In patients receiving a fluorouracil-containing regimen concomitantly with regorafenib, the pharmacokinetics of fluorouracil were not substantially altered when fluorouracil (400 mg/m2 by IV injection, followed by continuous IV infusion of 2400 mg/m2 over 46 hours) was given 5 days after completion of a series of 7 doses of regorafenib (160 mg orally once daily).7
In patients receiving an irinotecan-containing regimen concomitantly with regorafenib, the AUCs of irinotecan and its active metabolite SN-38 were increased by 28 and 44%, respectively.1, 7
In patients receiving an oxaliplatin-containing regimen concomitantly with regorafenib, the AUCs of total and unbound platinum were increased by 39 and 17%, respectively, when oxaliplatin (85 mg/m2 as a 2-hour IV infusion) was given 5 days after completion of a series of 7 doses of regorafenib (160 mg orally once daily).7
When regorafenib is used in patients receiving a coumarin-derivative anticoagulant (e.g., warfarin), international normalized ratio (INR) should be monitored more frequently.1 When a single dose of warfarin sodium (10 mg; a CYP2C9 substrate) was administered following 2 weeks of therapy with regorafenib (160 mg once daily), the AUC of warfarin was increased by 25%.1
Regorafenib, an inhibitor of multiple receptor tyrosine kinases (RTKs), is an antineoplastic agent.1, 2, 3, 4, 5 Receptor tyrosine kinases are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase.1, 5 In vitro, regorafenib or its active metabolites (M-2 and M-5) exhibit inhibitory activity against vascular endothelial growth factor receptors (i.e., VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (i.e., PDGFR-α, PDGFR-β), fibroblast growth factor receptors (i.e., FGFR1, FGFR2), and tyrosine kinase with immunoglobulin and epidermal growth factor homology (i.e., TIE-2) at clinically relevant concentrations;1, 5, 6, 10 the drug also has a broad spectrum of inhibitory effects on other receptor kinases involved in normal cellular functions and pathologic processes (e.g., RET, c-Kit, DDR2, TrkA, EphA-2, Raf-1, b-Raf, mutant b-Raf, SAPK2, Ptk5, Bcr-Abl, CSF-1R).1, 5, 10 Regorafenib has been shown to inhibit tumor angiogenesis in vivo.1, 10 The drug also has demonstrated inhibition of tumor growth in mice bearing tumor xenografts, including human colorectal carcinoma, GI stromal tumor (GIST), and hepatocellular carcinoma.1, 10 In addition, regorafenib has demonstrated inhibition of tumor metastasis in xenograft models of human colorectal carcinoma in mice.1
When regorafenib is administered in dosages exceeding 60 mg daily, steady-state exposure to the drug, as measured by area under the serum concentration-time curve (AUC), increases in a less than dose-proportional manner.1, 5 Regorafenib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and uridine diphosphate-glucuronosyl transferase (UGT) 1A9.1, 9 The main circulating metabolites, M-2 (an N -oxide metabolite) and M-5 (an N -oxide and N -desmethyl metabolite), have been shown to be equipotent to regorafenib in biochemical and cellular assays.1, 5, 6, 9 Regorafenib and its active metabolites are highly bound (more than 99%) to plasma proteins.1 Regorafenib undergoes enterohepatic circulation.1 Following oral administration of a single 160-mg dose of regorafenib, the terminal half-life of regorafenib and M-2 were similar (28 and 25 hours, respectively); however, elimination of M-5 was slower, with a terminal half-life of approximately 51 hours.1, 6 Following oral administration of 120 mg of radiolabeled regorafenib (as an oral solution), approximately 71% of the dose was recovered in feces (47% of the dose as unchanged drug and 24% as metabolites) and 19% was recovered in urine within 12 days.1
Bioavailability of regorafenib and its active metabolites is affected by the presence of food and the fat content of the meal.9 Administration of a single 160-mg dose of regorafenib with a high-fat meal (945 calories and 54.6 g of fat) increased the AUC of regorafenib by 48% and decreased the AUCs of M-2 and M-5 by 20 and 51%, respectively, compared with administration in the fasted state.1 When the drug was administered with a low-fat meal (319 calories and 8.2 g of fat), the AUCs of regorafenib, M-2, and M-5 were increased by 36, 40, and 23%, respectively, compared with administration in the fasted state.1 In clinical trials establishing safety and efficacy, regorafenib was administered with a low-fat meal.1
Age, gender, ethnicity, and body weight do not have clinically important effects on the pharmacokinetics of regorafenib.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of regorafenib is restricted.24 Regorafenib can only be obtained through designated specialty pharmacies.24 Contact the manufacturer or consult the Stivarga® website for specific information.24
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 40 mg | Stivarga® |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Bayer Healthcare. Stivarga® (regorafenib) tablets prescribing information. Whippany, NJ; 2026 Feb. [Web]
2. Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet . 2013; 381:303-12. [PubMed 23177514]
3. Demetri GD, Reichardt P, Kang YK et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet . 2013; 381:295-302. [PubMed 23177515]
4. George S, Wang Q, Heinrich MC et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol . 2012; 30:2401-7. [PubMed 22614970]
5. Mross K, Frost A, Steinbild S et al. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res . 2012; 18:2658-67. [PubMed 22421192]
6. Strumberg D, Scheulen ME, Schultheis B et al. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study. Br J Cancer . 2012; 106:1722-7. [PubMed 22568966]
7. Schultheis B, Folprecht G, Kuhlmann J et al. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol . 2013; :. [PubMed 23493136]
8. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
9. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203085Orig1s000: Summary review. From FDA website. [Web]
10. Wilhelm SM, Dumas J, Adnane L et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer . 2011; 129:245-55. [PubMed 21170960]
12. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203085Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
13. Bayer Healthcare. Stivarga® (regorafenib) for professionals: Dosage and administration: Dose modifications. From Stivarga website. [Web]
14. Bruix J, Qin S, Merle P et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet . 2017; 389:56-66. [PubMed 27932229]
16. Bayer PLC. Stivarga 40 mg film-coated tablets summary of product characteristics. Reading, England; 2017 Aug.
17. Chiorean EG, Nandakumar G, Fadelu T et al. Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline. JCO Glob Oncol . 2020; 6:414-438. [PubMed 32150483]
18. Kang YK, George S, Jones RL et al. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study. J Clin Oncol . 2021; 39:3128-3139. [PubMed 34343033]
20. National Cancer Institute. Primary liver cancer treatment - health professional version. Revised April 17, 2025. [Web]
24. Bayer Healthcare Pharmaceuticals Inc. 3 ways to get Stivarga. From Stivarga patient website. [Web]
51. Gordan JD, Kennedy EB, Abou-Alfa GK et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update. J Clin Oncol . 2024; 42:1830-50.
60. Casali PG, Blay JY, Abecassis N et al. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol . 2022; 33:20-33.
61. National Cancer Institute. Gastrointestinal Stromal Tumors Treatment - health professional version. Updated December 13, 2024. [Web]
62. Wu CE, Tzen CY, Wang SY et al. Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View. Cancers (Basel) . 2019; 11 [PubMed 31100836]