Sorafenib tosylate, an inhibitor of several serine/threonine and receptor tyrosine kinases, is an antineoplastic agent.1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17
Sorafenib tosylate is used for the treatment of unresectable hepatocellular carcinoma and is designated an orphan drug by FDA for the treatment of this cancer.1, 3, 18, 20, 21, 22
Efficacy and safety of sorafenib tosylate for the treatment of unresectable hepatocellular carcinoma is based principally on the results of a randomized, double-blind, placebo-controlled phase 3 study (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol [SHARP] trial) in patients with previously untreated advanced hepatocellular carcinoma.1, 18 In this study, 602 patients were randomized in a 1:1 ratio to receive either sorafenib (400 mg orally twice daily) or placebo.1, 18 Treatment was continued until disease progression, death, or unacceptable toxicity occurred.18
Patients were enrolled in the study if they were not eligible for or had disease progression after surgical or locoregional therapies; approximately 70% of patients enrolled in the study had macroscopic vascular invasion, extrahepatic spread, or both.18 The majority of enrolled patients had mild (Child-Pugh class A) hepatic impairment (97%) and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (54%) or 1 (38%).18 Chronic hepatitis C virus (HCV) infection, alcohol consumption, or chronic hepatitis B virus (HBV) infection was the cause of hepatocellular carcinoma in 28, 26, or 18% of patients, respectively.18 The median duration of treatment was 5.3 months for patients receiving sorafenib and 4.3 months for those receiving placebo.18
The primary measure of efficacy was overall survival;1 secondary end points included time to progression (based on independent radiologic review) and disease control rate.18 A planned second interim analysis indicated that patients receiving sorafenib had a longer median overall survival than those receiving placebo (10.7 versus 7.9 months; hazard ratio for death: 0.69).1, 18 Final analysis of the time to disease progression (which occurred at an earlier time point than the survival analysis) indicated that patients receiving sorafenib had a longer median time to progression compared with those receiving placebo (5.5 versus 2.8 months).1, 18 Patients receiving sorafenib had higher disease control rates compared with those receiving placebo (43 versus 32%).18 The proportion of patients with disease stabilization was slightly higher among those receiving sorafenib compared with those receiving placebo (71 versus 67%, respectively); however, partial response rates were low (2 versus 1%, respectively) and none of the patients achieved a complete response.18 Subgroup analysis according to disease etiology (HCV, HBV, alcohol consumption), tumor burden (presence or absence of macroscopic vascular invasion and/or extrahepatic spread), ECOG performance status (0-2), tumor stage (Barcelona Clinic Liver Cancer [BCLC] stage), and prior therapy (resection/ablation or chemoembolization) suggested that sorafenib consistently improved median overall survival across all subgroups; an effect on time to progression was not apparent in the small subgroup of HBV-positive patients.19
Efficacy of sorafenib also was demonstrated in a supportive phase 3 study conducted in the Asia-Pacific area (i.e., China, South Korea, Taiwan).20 In this study, 271 adults with previously untreated advanced hepatocellular carcinoma were randomized in a 2:1 ratio to receive either sorafenib (400 mg orally twice daily) or placebo.20 In contrast to the SHARP trial, most patients in this study were HBV-positive (73%) and had an ECOG performance status of 1 (69%).20 Although absolute overall survival, time to progression, and disease control were poorer in this study as compared to the SHARP trial, patients in this study who received sorafenib had a longer median overall survival (6.5 versus 4.2 months), longer median time to progression (2.8 versus 1.4 months), and higher disease control rate (35.3 versus 15.8%) than those who received placebo.20
Sorafenib also has been used in combination with transarterial chemoembolization (TACE) in patients with intermediate-advanced hepatocellular carcinoma and as monotherapy following surgical resection†.30, 31, 32, 33 Additional studies are needed to more fully evaluate the efficacy and safety of sorafenib for the treatment of hepatocellular carcinoma in patients with more severe (i.e., Child-Pugh class B) hepatic impairment as monotherapy or in combination with other therapies and as adjuvant therapy† .18, 20, 22, 24, 30, 31, 32, 33
For the treatment of early stage hepatocellular carcinoma, liver transplantation, surgical resection, and ablation offer a potential cure and high rates of complete response; however, survival is usually less than 6 months in patients with untreated advanced stage hepatocellular carcinoma.34 Treatment of hepatocellular carcinoma is complicated by the presence of underlying liver disease, the extent and location of tumor, comorbidities, and performance status; therefore, the American Society of Clinical Oncology (ASCO) states that the risk of potential toxicities and potential benefits from treatment should be considered when selecting therapy.34, 51
The ASCO guideline on systemic therapy for advanced hepatocellular carcinoma states that lenvatinib or sorafenib 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 and/or bevacizumab is contraindicated.51 ASCO also states that tyrosine kinase inhibitors (i.e., cabozantinib, lenvatinib, regorafenib, sorafenib) may be used as second-line therapy† following first-line therapy with atezolizumab in combination with bevacizumab.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
Sorafenib tosylate is used for the treatment of advanced renal cell carcinoma and is designated an orphan drug by FDA for the treatment of this cancer.1, 3, 4, 5, 14, 15, 16, 17 Safety and efficacy of sorafenib tosylate in the treatment of advanced renal cell carcinoma were established in 2 randomized, controlled clinical trials (one phase 2 and one phase 3).1, 4, 5, 15
In the phase 3 trial, patients with unresectable and/or metastatic clear cell renal carcinoma who had received one prior systemic (e.g., cytokine) therapy were randomized to receive sorafenib 400 mg twice daily or placebo.1, 4, 7, 10, 11, 12, 14, 15 Patients receiving sorafenib had a longer median progression-free survival (167 versus 84 days), an increased rate of progression-free survival at 12 weeks (79 versus 50%), and a decreased risk of progression compared with those receiving placebo.1, 4, 7, 10, 11, 12, 14, 15, 16 A similar benefit on progression-free survival was observed in patients receiving sorafenib regardless of prior cytokine therapy.36 In the final overall survival analysis that included patients who crossed over from placebo to sorafenib therapy, survival was similar between sorafenib and placebo (17.8 versus 15.2 months, respectively); however, a significant difference in overall survival (17.8 versus 14.3 months) was observed when crossover data were censored.37
The phase 2 trial included patients with metastatic malignancies, including individuals with untreated or previously treated renal cell carcinoma.1, 2, 5, 6, 7, 8, 10, 11, 12 Following a 12-week run-in induction period during which all patients received sorafenib 400 mg twice daily, tumor response was assessed and those with stable disease (i.e., less than 25% change from baseline in bidimensional tumor measurements) were randomized to receive either sorafenib 400 mg twice daily or placebo for an additional 12 weeks, those with tumor shrinkage (at least 25% reduction from baseline) continued to receive sorafenib in an open-label arm of the study, and those with tumor growth (at least 25% increase from baseline) discontinued therapy with the drug.1, 2, 5, 7, 8, 11, 12 Of the 202 patients with renal cell carcinoma who were enrolled in the run-in induction phase, 65 were randomized to receive either sorafenib or placebo and 79 were assigned to receive open-label treatment with the drug.1, 14 Patients in the placebo group who experienced disease progression were allowed to cross over to open-label sorafenib.1, 2, 7, 8 In the subgroup of patients randomized to receive sorafenib or placebo, those receiving sorafenib had a higher rate of progression-free survival at 24 weeks (50 versus 18%) and a longer median progression-free survival (163 versus 41 days) than did those receiving placebo.1, 5, 6, 7, 10, 11, 12, 14
Prognosis is generally poor in patients with metastatic renal cell carcinoma, including those who have undergone complete tumor resection.55 First-line therapy with vascular endothelial growth factor receptor (VEGFR) inhibitors has been shown to provide benefits in patients with advanced renal cell carcinoma; however, relapsed or refractory renal cell carcinoma eventually develops in most patients.52 Combination regimens (e.g., immune checkpoint inhibitor in combination with a tyrosine kinase inhibitor) have generally become a standard for the treatment of advanced renal cell carcinoma.53
Some experts also state that subsequent monotherapy with a tyrosine kinase inhibitor (e.g., sunitinib, pazopanib) may be offered to patients who experience a treatment-limiting immune-mediated adverse effect following combination therapy with an immune checkpoint inhibitor or as a second-line option following disease progression during immune checkpoint inhibitor-based therapy; however, certain regimens (e.g., nivolumab, lenvatinib and everolimus combination therapy, cabozantinib, axitinib, everolimus) may be recommended over sorafenib in the second-line setting.54
Differentiated Thyroid Carcinoma
Sorafenib tosylate is used for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment.1 The drug has been designated an orphan drug by the FDA for the treatment of medullary, anaplastic, and recurrent or metastatic follicular or papillary thyroid cancer.3
Differentiated thyroid cancer, specifically papillary and follicular (including Hürthle cell) thyroid cancer, is the most common type of thyroid cancer.42 Differentiated thyroid cancer is generally treated with surgery and radioactive iodine therapy.42
Efficacy and safety of sorafenib tosylate for the treatment of differentiated thyroid carcinoma are based principally on a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (DECISION) in patients with locally advanced or metastatic, progressive differentiated thyroid carcinoma refractory to radioactive iodine treatment.1, 43 In this study, 417 patients were randomized in a 1:1 ratio to receive either sorafenib (400 mg orally twice daily) or placebo.1, 43 Treatment was continued until disease progression, unacceptable toxicity, noncompliance, or withdrawal of consent occurred.1, 43 Crossover to open-label sorafenib occurred in 77% of placebo-treated patients following investigator-determined disease progression.1
Patients were enrolled in the study if they had actively progressing disease defined as progression within 14 months of enrollment.1 Approximately 96% of patients enrolled in the study had metastatic disease; the most common sites of metastases were the lungs (86%) followed by lymph nodes (51%) and bone (27%).1, 43 The majority of enrolled patients had a baseline ECOG performance status of 0 (62%) or 1 (34%).1, 43 Histologic subtypes were papillary, follicular, and poorly differentiated carcinoma in approximately 57, 25, and 10% of patients, respectively.43 The median duration of treatment was 10.6 months in patients receiving sorafenib and 6.5 months in those receiving placebo.43
The primary measure of efficacy was progression-free survival.43 Median progression-free survival was 10.8 or 5.8 months in patients receiving sorafenib or placebo, respectively, which corresponds to a 41% reduction in the risk of disease progression or death (hazard ratio of 0.59).1, 43 Median time to progression was prolonged in patients receiving sorafenib compared with those receiving placebo (11.1 versus 5.7 months, respectively).43 No significant difference in overall survival was observed between the treatment groups; median overall survival was 42.8 months in patients receiving sorafenib and 39.4 months in patients receiving placebo.1 The objective response rate was 12.2 or 0.5% in patients receiving sorafenib or placebo, respectively; none of the patients achieved complete response.43 In a post-hoc analysis, stable disease for 6 months or more was observed in 41.8 or 33.2% of patients who received sorafenib or placebo, respectively.43 Results of a subgroup analysis (based on geographic region, age, histology, site of metastases, fluorodeoxyglucose [FDG] uptake, number of target or non-target lesions, target lesion size, sex, cumulative radioactive iodine [RAI] dosage) suggested that the effect of sorafenib on progression-free survival was consistent across all subgroups.43 Although thyroglobulin concentrations may be a pharmacodynamic biomarker of tumor response or progression,44 exploratory analyses of the DECISION trial suggested that median progression-free survival was improved in patients receiving sorafenib regardless of baseline thyroglobulin concentrations.43
The American Thyroid Association (ATA) published a guideline on the management of patients with thyroid nodules and differentiated thyroid carcinoma in 2015.45 The basic goals of initial therapy for patients with differentiated thyroid carcinoma are to improve overall and disease-specific survival, reduce the risk of persistent/recurrent disease and associated morbidity, and permit accurate disease staging and risk stratification, while minimizing treatment-related morbidity and unnecessary therapy.45 In patients with metastatic disease, ATA states that the preferred hierarchy of treatment is surgical excision of locoregional disease in potentially curable patients, iodine I 131 therapy for RAI-responsive disease, directed treatment modalities (e.g., external beam radiation therapy, thermal ablation), TSH-suppressive thyroid hormone therapy for patients with stable or slowly progressive asymptomatic disease, and systemic therapy with kinase inhibitors, especially for patients with significantly progressive macroscopic refractory disease.45
At the time of publication of the ATA guideline, limited evidence of efficacy was available for certain kinase inhibitors (e.g., sorafenib, lenvatinib, vandetanib); however, a 2019 guideline published by international experts states that lenvatinib and sorafenib should be considered the standard first-line systemic therapy in patients with radioactive iodine-refractory differentiated thyroid carcinoma.46
Sorafenib also has been studied in patients with acute myeloid leukemia (AML) harboring fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations who have undergone allogeneic hematopoietic stem cell transplant (HSCT)†, 47, 48, 49 advanced or metastatic GI stromal tumor†, 50, 56, 57 and recurrent or metastatic angiosarcoma†.58, 59
Because administration with a high-fat meal may decrease oral bioavailability of sorafenib, the manufacturer recommends that sorafenib tosylate be administered orally at least 1 hour before or 2 hours after a meal.1
If a dose is missed, skip the missed dose and take the next dose at the regularly scheduled time.1
Store sorafenib tablets in a dry place at controlled room temperature (20-25ºC).1 Excursions are permitted to 15-30ºC.1
Dosage of sorafenib tosylate is expressed in terms of sorafenib.1
For the treatment of unresectable hepatocellular carcinoma, the recommended adult dosage of sorafenib is 400 mg twice daily.1 Therapy should be continued for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1
For the treatment of advanced renal cell carcinoma, the recommended adult dosage of sorafenib is 400 mg twice daily.1, 2, 4, 5, 15 Therapy should be continued for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1
Differentiated Thyroid Carcinoma
For the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment, the recommended adult dosage of sorafenib is 400 mg twice daily.1 Therapy should be continued for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If dosage modification is required, the dosage of sorafenib should be reduced as described in Table 1 in patients with hepatocellular carcinoma, renal cell carcinoma, or differentiated thyroid carcinoma.1
Dosage Reduction Level | Hepatocellular Carcinoma (Starting Dosage = 400 mg twice daily) | Renal Cell Carcinoma (Starting Dosage = 400 mg twice daily) | Differentiated Thyroid Carcinoma (Starting Dosage = 400 mg twice daily) |
|---|---|---|---|
First | Restart at 400 mg once daily | Restart at 400 mg once daily | Restart at 400 mg in the morning and 200 mg in the evening (approximately 12 hours apart) OR 200 mg in the morning and 400 mg in the evening (approximately 12 hours apart) |
Second | Restart at 200 mg once daily OR 400 mg every other day | Restart at 200 mg once daily OR 400 mg every other day | Restart at 200 mg twice daily |
Third | Discontinue drug | Discontinue drug | Restart at 200 mg once daily |
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of sorafenib may be necessary in patients experiencing certain adverse effects (see Table 2) or cutaneous toxicity (see Table 3).1
Adverse Reaction and Severity | Modification |
|---|---|
Cardiac ischemia and/or infarction: Grade 2 or higher | Permanently discontinue therapy |
Congestive heart failure: Grade 3 | Interrupt therapy; when toxicity resolves or improves to grade 1 or less, resume at dosage reduced by one dose level; however, if recovery does not occur within 30 days of withholding therapy, discontinue sorafenib (unless the patient is deriving clinical benefit). Discontinue therapy if more than 2 dosage reductions are necessary |
Congestive heart failure: Grade 4 | Permanently discontinue therapy |
Hemorrhage: Grade 2 or higher requiring medical intervention | Permanently discontinue therapy |
Hypertension: Grade 2 (symptomatic/persistent) | Interrupt therapy; when diastolic BP resolves or improves to <90 mm Hg, resume at dosage reduced by one dose level; if necessary, reduce dosage by another dose level. Discontinue therapy if more than 2 dosage reductions are necessary |
Hypertension: Grade 2 symptomatic increase in diastolic BP by >20 mm Hg or BP >140/90 mm Hg if previously normal | Interrupt therapy; when diastolic BP resolves or improves to <90 mm Hg, resume at dosage reduced by one dose level; if necessary, reduce dosage by another dose level. Discontinue therapy if more than 2 dosage reductions are necessary |
Hypertension: Grade 3 | Interrupt therapy; when diastolic BP resolves or improves to <90 mm Hg, resume at dosage reduced by one dose level; if necessary, reduce dosage by another dose level. Discontinue therapy if more than 2 dosage reductions are necessary |
Hypertension: Grade 4 | Permanently discontinue therapy |
GI Perforation: Any grade | Permanently discontinue therapy |
QT Prolongation: >500 msec or ≥60 msec increase from baseline | Interrupt therapy and correct electrolyte abnormalities (e.g., magnesium, potassium, calcium); resume therapy if appropriate |
Hepatotoxicity: Grade 3 or higher ALT concentrations in absence of other etiologya | Permanently discontinue therapy |
Hepatotoxicity: AST/ALT concentrations >3 times the ULN with bilirubin concentrations >2 times the ULN in absence of other etiologya | Permanently discontinue therapy |
Other Adverse Effects: Grade 2 | Continue therapy at dosage reduced by one dose level |
Other Adverse Effects: Grade 3 | 1st occurrence: Interrupt therapy; if toxicity resolves to grade 2 or less within 7 days, resume at dosage reduced by one dose level; if toxicity does not improve to grade 2 or less within 7 days, resume at dosage reduced by two dose levels 2nd or 3rd occurrence: Interrupt therapy; when toxicity resolves to grade 2 or less, resume at dosage reduced by two dose levels 4th occurrence: Interrupt therapy; when toxicity resolves to grade 2 or less, resume at dosage reduced by two dose levels in patients with hepatocellular carcinoma or renal cell carcinoma and by 3 dose levels in patients with differentiated thyroid carcinoma |
Other Adverse Effects: Grade 4 | Permanently discontinue therapy |
a In addition, any grade increased alkaline phosphatase in the absence of known bone pathology and grade 2 or worse increased bilirubin; any one of the following: INR of ≥1.5, ascites and/or encephalopathy in the absence of underlying cirrhosis or other organ failure considered to be due to drug-induced liver injury.1
Cutaneous Toxicity Grade | Occurrence | Recommended Dosage Modification in Patients with Hepatocellular Carcinoma or Renal Cell Carcinoma | Recommended Dosage Modification in Patients with Differentiated Thyroid Carcinoma |
|---|---|---|---|
Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient's normal activities | 1st occurrence | Continue sorafenib therapy and consider topical therapy for symptomatic relief | Decrease sorafenib dosage to 600 mg daily |
Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient's normal activities | No improvement within 7 days at reduced dosage or 2nd or 3rd occurrence | Interrupt therapy until toxicity resolves to grade 0 or 1 When resuming therapy, reduce sorafenib dosage by one dose level | Interrupt therapy until toxicity completely resolves or improves to grade 1 When resuming therapy, reduce sorafenib dosage by one dose level for 2nd occurrence and by 2 dose levels for 3rd occurrence |
Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient's normal activities | 4th occurrence | Discontinue therapy | Discontinue therapy |
Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living | 1st occurrence | Interrupt therapy until toxicity resolves to grade 0 or 1 When resuming therapy, reduce sorafenib dosage by one dose level (e.g., to 400 mg once daily or 400 mg every other day) | Interrupt therapy until toxicity completely resolves or improves to grade 1 When resuming therapy, reduce sorafenib dosage by one dose level |
Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living | 2nd occurrence | Interrupt therapy until toxicity resolves to grade 0 or 1 When resuming therapy, reduce sorafenib dosage by one dose level (e.g., to 400 mg once daily or 400 mg every other day) | Interrupt therapy until toxicity completely resolves or improves to grade 1 When resuming therapy, reduce sorafenib dosage by 2 dose levels |
Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living | 3rd occurrence | Discontinue therapy | Discontinue therapy |
Following improvement of grade 2 or 3 cutaneous toxicity to grade 0 or 1 for at least 28 days or a reduced sorafenib dosage, the dosage may be increased one dose level from the reduced dosage.1 Approximately 50% of patients requiring a dosage reduction for cutaneous toxicity are expected to meet the criteria for resumption of the higher dosage and about 50% of patients resuming the previous dosage are expected to tolerate the higher dosage without recurrent grade 2 or higher cutaneous toxicity.1
No dosage adjustment is necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.1 The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh class C) hepatic impairment.1
No dosage adjustment is necessary in patients with mild to severe renal impairment who are not receiving dialysis.1 The pharmacokinetics of sorafenib have not been studied in patients with renal impairment requiring dialysis.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
In the phase 3 trial of sorafenib in patients with unresectable hepatocellular carcinoma, cardiac ischemia or infarction occurred in 2.7% of patients receiving sorafenib compared with 1.3% of those receiving placebo.1, 18 In the phase 3 trial in patients with advanced renal cell carcinoma, cardiac ischemia or infarction occurred more frequently in patients receiving sorafenib than in those receiving placebo (2.9 versus 0.4%).1, 15 In a clinical trial of sorafenib in patients with differentiated thyroid carcinoma, cardiac ischemia or infarction occurred in 1.9% of patients receiving sorafenib and in 0% of those receiving placebo.1 In multiple clinical trials, congestive heart failure was reported in 1.9% of sorafenib-treated patients.1 Temporary or permanent discontinuance of sorafenib should be considered in patients who develop cardiovascular events.1
In several clinical trials, congestive heart failure was reported in 1.9% of patients receiving sorafenib.1
In the phase 3 trial of sorafenib in patients with unresectable hepatocellular carcinoma, hypertension was reported in 9.4% of patients receiving sorafenib compared with 4.3% of those receiving placebo.1 In the phase 3 trial in patients with advanced renal cell carcinoma, hypertension was reported more frequently in patients receiving sorafenib compared with those receiving placebo (16.9 versus 1.8%).1, 4, 10, 15 In a clinical trial of sorafenib in patients with differentiated thyroid carcinoma, hypertension was reported in 40.6% of patients receiving sorafenib and in 12.4% of those receiving placebo.1 Hypertension usually was mild or moderate in severity, occurred early in the course of treatment, and was managed with standard antihypertensive therapy.1, 12, 15 Permanent discontinuance of sorafenib therapy because of hypertension was necessary in 1 patient in each of the clinical trials.1 Blood pressure should be monitored weekly during the first 6 weeks of sorafenib therapy and thereafter should be monitored periodically and treated, if required, in accordance with established medical practice.1 If hypertension is severe or persistent despite initiation of antihypertensive therapy, temporary or permanent discontinuance of sorafenib should be considered.1
Sorafenib may prolong the QT interval, which may increase the risk of ventricular arrhythmias.1 In a small multicenter, open-label, nonrandomized trial evaluating the effects of sorafenib (400 mg twice daily) on the QT interval in patients with advanced cancer, no large (i.e., exceeding 20 msec) increases in the corrected QT (QTc) interval were observed.1 Following the first 28-day treatment cycle (cycle 1), the maximum mean change in QTc interval was 8.5 msec, which was observed at 6 hours following the first dose of cycle 2.1 Sorafenib should be avoided in patients with congenital long QT syndrome.1 ECGs and serum electrolytes (potassium, calcium, and magnesium) should be monitored in patients with congestive heart failure, bradyarrhythmias, and in those who are receiving drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmic agents).1 Electrolyte (magnesium, potassium, calcium) abnormalities should be corrected.1 Sorafenib therapy should be interrupted if QT interval is >500 msec or an increase of ≥60 msec from baseline occurs.1
Sorafenib may increase the risk of bleeding.1, 15 In the phase 3 trial of sorafenib in patients with unresectable hepatocellular carcinoma, the incidence of bleeding from esophageal varices was similar in patients receiving sorafenib compared with those receiving placebo (2.4 versus 4%);1, 18 similarly, fatal hemorrhage from any site occurred in 2.4% of patients receiving sorafenib and 4% of those receiving placebo.1 In the phase 3 trial in patients with advanced renal cell carcinoma, bleeding (regardless of causality) was reported in 15.3 or 8.2% of patients receiving sorafenib or placebo, respectively;1, 15 grade 3 and 4 bleeding were reported in 2 and 0%, respectively, of patients receiving sorafenib compared with 1.3 and 0.2%, respectively, of patients receiving placebo.1 Fatal hemorrhage occurred in one patient in each treatment group in this study.1 In a clinical trial of sorafenib in patients with differentiated thyroid carcinoma, hemorrhage occurred in 17.4% of patients receiving sorafenib and in 9.6% of those receiving placebo; the incidence of grade 3 bleeding was 1% and 1.4% in those receiving sorafenib and placebo, respectively.1
Permanent discontinuance of sorafenib should be considered if any bleeding episode requires medical intervention.1 Because of the potential risk of bleeding, treat tracheal, bronchial, and esophageal infiltration with local therapy prior to initiating sorafenib in patients with differentiated thyroid carcinoma.1
Patients concurrently receiving sorafenib and warfarin should be regularly monitored for changes in PT or INR and for clinical bleeding episodes.1
Palmar-plantar erythrodysesthesia (commonly referred to as hand-foot syndrome) and rash are common adverse effects of sorafenib.1, 2, 4, 5, 8, 9, 10, 11, 12, 15, 18 Permanent discontinuance of therapy because of palmar-plantar erythrodysesthesia occurred in 1.3, 0.7, and 5.3% of sorafenib-treated patients with unresectable hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma trials, respectively.1 Rash and hand-foot syndrome usually are grade 1 or 2 and generally appear during the first 6 weeks of treatment with sorafenib.1, 15 Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary interruption of therapy, and/or dosage modification of sorafenib; in severe or persistent cases, permanent discontinuance of sorafenib therapy may be necessary.1
Cases of severe and possibly life-threatening dermatologic toxicities, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving sorafenib.1 If Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, sorafenib therapy should be discontinued.1
GI perforation, sometimes associated with apparent intra-abdominal tumor, has been reported in less than 1% of patients receiving sorafenib.1 Sorafenib therapy should be permanently discontinued if GI perforation occurs.1
Drugs that inhibit the VEGF signaling pathway, like sorafenib, have the potential to impair wound healing.1 Sorafenib should be withheld for at least 10 days prior to elective surgery and should not be administered for at least 2 weeks following major surgery and until adequate healing has occurred.1 The safety of resuming sorafenib therapy after resolution of wound healing complications has not been established.1
Increased Mortality in Squamous Cell Carcinoma of the Lung
Subset analysis of data from 2 randomized controlled trials in patients with previously untreated advanced (stage IIIB or IV) non-small cell lung cancer revealed an increased risk of mortality in patients with squamous cell carcinoma receiving sorafenib in combination with carboplatin and paclitaxel (hazard ratio of 1.81) and in those receiving sorafenib in combination with gemcitabine and cisplatin (hazard ratio of 1.22) compared with those receiving the corresponding dual regimen (i.e., therapy with carboplatin and paclitaxel or with gemcitabine and cisplatin, respectively).1
Sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell carcinoma of the lung.1 In addition, the manufacturer states that use of sorafenib in combination with gemcitabine and cisplatin is not recommended in patients with squamous cell carcinoma of the lung.1
Safety and efficacy of sorafenib in patients with non-small cell lung cancer have not been established.1
Serious or fatal drug-induced hepatitis characterized by a hepatocellular pattern of hepatic injury with substantially elevated serum aminotransferase concentrations may occur; increased serum concentrations of bilirubin and increased INR also may occur.1 The incidence of severe drug-induced liver injury (aminotransferase concentrations >20 ULN or with significant clinical sequelae such as elevated INR, ascites, fatal, or transplantation) was 0.06% (2 of 3357 patients) in a global monotherapy database.1
Liver function tests should be monitored regularly in patients receiving sorafenib.1 Sorafenib therapy should be discontinued if substantially elevated serum aminotransferase concentrations occur and other possible causes (i.e., viral hepatitis, malignancy progression) have been ruled out.1
Fetal/Neonatal Morbidity and Mortality
Sorafenib may cause fetal harm if administered to pregnant women; teratogenicity and embryolethality have been demonstrated in animals.1 Although there are no adequate and well-controlled studies in humans, sorafenib has been shown to have teratogenic and embryolethal effects (i.e., postimplantation loss, resorptions, skeletal retardation, retarded fetal weight) in rats and rabbits when given in dosages lower than the usual human dosage.1 Pregnancy should be avoided during therapy.1 If sorafenib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.1
Verify pregnancy status of females of reproductive potential prior to initiation of therapy.1 Females of reproductive potential receiving the drug should use an effective contraceptive method during treatment and for at least 6 months following discontinuance of sorafenib therapy.1 Male patients with female partners of reproductive potential and pregnant partners should use an effective contraceptive method during treatment and for at least 3 months following discontinuance of sorafenib therapy.1
Sorafenib impairs exogenous thyroid suppression.1 In the differentiated thyroid carcinoma clinical study, elevation of TSH above 0.5 mU/L was observed in 41% of patients who received sorafenib and in 16% of those who received placebo.1
Thyroid function should be monitored prior to initiation and at least monthly during sorafenib therapy.1 Hypothyroidism should be treated according to standard medical practice.1
Sorafenib may cause fetal harm if administered to a pregnant female based on its mechanism of action and animal findings.1
Sorafenib is distributed into milk in rats; it is not known whether the drug or its metabolites are distributed into milk in humans.1 It is also not known if the drug has effects on the breast-fed infant or on milk production.1 Because of the potential for serious adverse reactions to sorafenib in breast-fed infants, females should not breast-feed during treatment with sorafenib and for 2 weeks following discontinuance of the drug.1
Females and Males of Reproductive Potential
Females of reproductive potential should be advised to use effective contraceptive methods while receiving sorafenib and for at least 6 months after discontinuance of the drug.1
Male patients with female partners of reproductive potential and pregnant partners should use an effective contraceptive method during sorafenib treatment and for at least 3 months following discontinuance of the drug.1
Males should be advised that sorafenib may impair fertility.1
The pharmacokinetics of sorafenib have not been studied in pediatric patients younger than 18 years of age.1, 14
In clinical trials evaluating sorafenib in patients with unresectable hepatocellular carcinoma or advanced renal cell carcinoma, 59 or 32%, respectively, of patients were 65 years of age or older, and 19 or 4%, respectively, were 75 years of age or older.1 No substantial differences in safety and efficacy relative to younger adults have been observed, but increased sensitivity to the drug cannot be ruled out.1
Systemic exposure to sorafenib in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment, including both patients with hepatocellular carcinoma and individuals without such disease, is similar to that observed in individuals with normal hepatic function.1 In patients with hepatocellular carcinoma, systemic exposure and peak plasma concentrations of the drug were slightly higher in those with moderate (Child-Pugh class B) hepatic impairment compared with those with mild (Child-Pugh class A) hepatic impairment; however, the differences were not clinically meaningful.21, 23
Limited safety and efficacy data are available for patients with hepatocellular carcinoma and moderate (Child-Pugh class B) hepatic impairment.18, 20 In a phase 2 study in patients with hepatocellular carcinoma, median overall survival was shorter in patients with moderate (Child-Pugh class B) hepatic impairment than in those with mild (Child-Pugh class A) hepatic impairment (3.2 versus 9.5 months, respectively).23 Shorter median overall survival in patients with moderate hepatic impairment also has been reported from several prospective and retrospective studies of sorafenib use for hepatocellular carcinoma.25, 26, 27
The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh class C) hepatic impairment.1
Mild (creatinine clearance 50-80 mL/minute), moderate (creatinine clearance 30 to <50 mL/minute), and severe (creatinine clearance <30 mL/minute) renal impairment does not affect the pharmacokinetics of sorafenib.1
Pharmacokinetic parameters of sorafenib have not been evaluated in patients with renal impairment requiring dialysis.1
The most common adverse reactions (≥20%) are diarrhea, fatigue, infection, alopecia, palmar-plantar erythrodysesthesia (hand-foot skin reaction), rash, decreased weight, decreased appetite, nausea, GI and abdominal pain, hypertension, and hemorrhage.1
Sorafenib undergoes oxidative metabolism by cytochrome P450 (CYP) 3A4 and glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 1A9.1
In vitro studies using human hepatic microsomes indicate that sorafenib competitively inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.1, 7, 24 Sorafenib is unlikely to induce CYP1A2 or CYP3A4.1 Sorafenib also inhibits glucuronidation by UGT1A1 and UGT1A9 in vitro.1 In vitro data also indicate that sorafenib is an inhibitor of the efflux transporter P-glycoprotein (P-gp).1, 24
Drugs Affecting Hepatic Microsomal Enzymes
Sorafenib is partially metabolized by CYP3A4; however, when the potent CYP3A4 inhibitor ketoconazole (400 mg daily for 7 days) was administered concomitantly with sorafenib (single 50-mg dose) in healthy individuals, mean systemic exposure to sorafenib was unchanged.1 These data suggest that clinically important interactions with drugs that inhibit CYP3A4 are unlikely.28
Concomitant use of sorafenib with inducers of CYP3A4 may result in increased metabolism of and decreased systemic exposure to sorafenib.1, 24 In healthy individuals, the potent CYP3A4 inducer rifampin (600 mg daily for 5 days) decreased systemic exposure to sorafenib (single 400-mg dose) by 37%.1 Concomitant use of sorafenib with potent inducers of CYP3A4 (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided when possible.1
Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro studies using human hepatic microsomes indicate that sorafenib competitively inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.1, 7, 24 However, concomitant administration of sorafenib with cyclophosphamide (a CYP2B6 substrate) or paclitaxel (a CYP2C8 substrate) did not result in clinically important changes in enzyme inhibition, suggesting that sorafenib, when administered at the recommended dosage, may not result in clinically important inhibition of CYP2B6 or CYP2C8.28 In addition, sorafenib does not appear to alter systemic exposure to dextromethorphan (a CYP2D6 substrate), midazolam (a CYP3A4 substrate), or omeprazole (a CYP2C19 substrate),1, 24, 28 suggesting that clinically important interactions with drugs that are metabolized by these isoenzymes also are unlikely.24, 28 When warfarin (a CYP2C9 substrate) was administered concomitantly with sorafenib, mean changes from baseline in prothrombin time (PT)/international normalized ratio (INR) did not appear to be greater in patients receiving sorafenib as compared with placebo,24, 28 suggesting that the risk for clinically important inhibition of CYP2D6 by sorafenib also may be low (see Warfarin under Drug Interactions).28
The manufacturer states that sorafenib is unlikely to induce CYP isoenzymes 1A2 or 3A4.1, 24
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase
In vitro studies indicate that sorafenib inhibits glucuronidation by the uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and 1A9 pathways;1, 24, 28 sorafenib may increase systemic exposure to UGT1A1 or UGT1A9 substrates.1 Caution is advised when sorafenib is used concomitantly with drugs predominantly metabolized by the UGT1A1 or UGT1A9 pathway.1, 28
Drugs Affecting Gastric Acidity
Because the aqueous solubility of sorafenib is dependent on pH, drugs that increase the pH of the upper GI tract (e.g., proton-pump inhibitors) may potentially decrease the solubility of sorafenib.1 However, concomitant administration of the proton-pump inhibitor omeprazole (40 mg once daily for 5 days) with a single dose of sorafenib did not result in clinically important changes in systemic exposure to sorafenib.1 The manufacturer states that dosage adjustment of sorafenib is not necessary when sorafenib is administered concurrently with drugs affecting gastric acidity.1
Substrates of P-Glycoprotein Transport System
In vitro data indicate that sorafenib is an inhibitor of the efflux transporter P-glycoprotein (P-gp).1, 24 Concomitant use of sorafenib with drugs that are substrates of P-gp (e.g., digoxin) may result in increased systemic exposure to the substrate drug.1, 24
In healthy individuals, neomycin (1 g orally 3 times daily for 5 days) decreased the mean systemic exposure to sorafenib (single 400-mg dose) by 54%.1 Bacterial glucuronidases in the GI tract may cleave sorafenib conjugates, allowing reabsorption of unconjugated drug; neomycin interferes with this enterohepatic circulation process, thereby reducing bioavailability of sorafenib.28 Avoid concomitant use of sorafenib and neomycin1
The effect of other antibiotics on the pharmacokinetics of sorafenib has not been established.1
When docetaxel was administered concomitantly with sorafenib, systemic exposure and peak plasma concentration of docetaxel were increased by 36-80 and 16-32%, respectively.24, 28 Caution is advised.28
When irinotecan was administered concomitantly with sorafenib, systemic exposure to irinotecan and its active metabolite SN-38 was increased by 26-42 and 67-120%, respectively.24, 28 Caution is advised.28
When doxorubicin was used concomitantly with sorafenib, systemic exposure to doxorubicin was increased by 21%.28
Concomitant use of capecitabine with sorafenib did not substantially alter systemic exposure to sorafenib but increased systemic exposure to capecitabine and its active metabolite fluorouracil by 15-50 and 0-52%, respectively.28
Concomitant use of paclitaxel and carboplatin with continuous sorafenib therapy increased systemic exposure to sorafenib and to paclitaxel and its major metabolite 6-hydroxypaclitaxel (a metabolite formed by CYP2C829 ) by 47, 29, and 50%, respectively, but did not alter the pharmacokinetics of carboplatin.28
Sorafenib does not appear to affect the pharmacokinetics of cisplatin, cyclophosphamide, gemcitabine, or oxaliplatin.24, 28
Drugs that Prolong the QT Interval
Sorafenib can prolong the QT interval.1 Avoid concomitant use with other drugs that can prolong the QT interval (e.g., class 1a and III antiarrhythmic agents).1
When warfarin (a CYP2C9 substrate) was administered concomitantly with sorafenib, mean changes from baseline in PT/INR did not appear to be greater in patients receiving sorafenib as compared with placebo.24, 28 However, infrequent bleeding events or elevations in INR have been reported in some patients receiving concomitant therapy with warfarin and sorafenib.1 Patients concurrently receiving sorafenib and warfarin should be regularly monitored for changes in PT, INR, or clinical bleeding episodes.1
Sorafenib tosylate, an inhibitor of several serine/threonine and receptor tyrosine kinases, is an antineoplastic agent.1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17 Serine/threonine and receptor tyrosine kinases are involved in 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, apoptosis, metastasis), based on the respective kinase.1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15 Although the exact mechanism of antineoplastic activity of sorafenib has not been fully elucidated, sorafenib appears to inhibit signal transduction pathways involving multiple intracellular (e.g., c-Raf, b-Raf, mutant b-Raf) and cell surface kinases (e.g., c-Kit, Flt-3, RET, RET/PTC, vascular endothelial growth factor receptor [VEGFR]-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor [PDGFR]-β) in vitro.1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17 In vivo, sorafenib inhibited angiogenesis and/or growth of human hepatocellular carcinoma, renal cell carcinoma, differentiated thyroid carcinoma, and several other human tumor xenografts in immunocompromised mice.1
Sorafenib is metabolized mainly in the liver via oxidation by cytochrome P-450 (CYP) isoenzyme 3A4, as well as via glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT) 1A9.1, 7 At least 8 metabolites of sorafenib have been identified.1 The main circulating metabolite, a pyridine N -oxide derivative, is pharmacologically active and accounts for approximately 9-16% of total plasma concentrations of the drug.1 Approximately 77% of an oral dose of sorafenib is excreted in feces and 19% is eliminated in urine; unchanged sorafenib, which accounts for 51% of a dose, is recovered in feces but not in urine.1 The pharmacokinetics of sorafenib do not appear to be affected by age or gender; however, systemic exposure to the drug was 30% lower in Asians than in Caucasians.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.
Sorafenib can only be obtained through designated specialty pharmacies.60 Contact the manufacturer for more information.60
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg (of sorafenib)* | ||
SORAfenib Tosylate Film-coated Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Bayer HealthCare Pharmaceuticals Inc. Nexavar® (sorafenib tosylate) tablets prescribing information. Wayne, NJ: 2020 Jul. [Web]
2. Ahmad T, Eisen T. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res . 2004; 10:6388S-92S. [PubMed 15448036]
3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2013 Sept 16. [Web]
4. Escudier B, Szczylik C, Eisen T et al. Randomized phase III trial of the raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). Orlando, FL. 2005 13-17 May. Abstract LBA 4510.
5. Ratain MJ, Eisen T, Stadler WM et al. Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). Orlando, FL. 2005 13-17 May. Abstract LBA 4544.
6. Favaro JP, George DJ. Targeted therapy in renal cell carcinoma. Expert Opin Investig Drugs . 2005; 14:1251-8. [PubMed 16185167]
7. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol . 2005; 23:6771-90. [PubMed 16170185]
8. Cooney MM, Remick SC, Vogelzang NJ. Promising systemic therapy for renal cell carcinoma. Curr Treat Options Oncol . 2005; 6:357-65. [PubMed 16107239]
9. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther . 2005; 315:971-9. [PubMed 16002463]
10. Schöffski P, Dumez H, Clement P et al. Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol . 2006 (Advance access [doi:10.1093/annonc/mdj133]); :.
11. Zakarija A, Soff G. Update on angiogenesis inhibitors. Curr Opin Oncol . 2005; 17:578-83. [PubMed 16224236]
12. Gollob JA. Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer . 2005; 4:167-74. [PubMed 16425993]
13. Wilhelm SM, Carter C, Tang L et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res . 2004; 64:7099-109. [PubMed 15466206]
14. Bayer, West Haven, CT: Personal communication.
15. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med . 2007; 356:125-34. [PubMed 17215530]
16. Brugarolas J. Renal-cell carcinoma—molecular pathways and therapies. N Engl J Med . 2007; 356:185-7. [PubMed 17215538]
17. Govindarajan R, Adusumilli J, Baxter DL et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol . 2006; 24:e48. [PubMed 17008686]
18. Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med . 2008; 359:378-90. [PubMed 18650514]
19. Bruix J, Raoul JL, Sherman M et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol . 2012; 57:821-9. [PubMed 22727733]
20. Cheng AL, Kang YK, Chen Z et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol . 2009; 10:25-34. [PubMed 19095497]
21. Abou-Alfa GK, Schwartz L, Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol . 2006; 24:4293-300. [PubMed 16908937]
22. Yau T, Chan P, Ng KK et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer . 2009; 115:428-36. [PubMed 19107763]
23. Abou-Alfa GK, Amadori D, Santoro A et al. Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis. Gastrointest Cancer Res . 2011; 4:40-4. [PubMed 21673874]
24. Keating GM, Santoro A. Sorafenib: a review of its use in advanced hepatocellular carcinoma. Drugs . 2009; 69:223-40. [PubMed 19228077]
25. Pinter M, Sieghart W, Hucke F et al. Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib. Aliment Pharmacol Ther . 2011; 34:949-59. [PubMed 21883324]
26. Chiu J, Tang YF, Yao TJ et al. The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits. Cancer . 2012; 118:5293-301. [PubMed 22517493]
27. Hollebecque A, Cattan S, Romano O et al. Safety and efficacy of sorafenib in hepatocellular carcinoma: the impact of the Child-Pugh score. Aliment Pharmacol Ther . 2011; 34:1193-201. [PubMed 21958438]
28. Bayer Pharma AG. Nexavar® (sorafenib tosylate) tablets summary of product characteristics. Berlin, Germany; 2011 Jul 21.
29. Pfizer Inc. Paclitaxel injection prescribing information. New York, NY; 2011 Jun.
30. Xie Y, Tian H, Xiang B et al. Transarterial chemoembolization plus sorafenib versus sorafenib for intermediate-advanced hepatocellular carcinoma: A meta-analysis comparing clinical outcomes. Medicine (Baltimore) . 2021; 100:e26958. [PubMed 34414963]
31. Huang S, Li D, Zhuang L et al. A meta-analysis of the efficacy and safety of adjuvant sorafenib for hepatocellular carcinoma after resection. World J Surg Oncol . 2021; 19:168. [PubMed 34112190]
32. Chen A, Li S, Yao Z et al. Adjuvant transarterial chemoembolization to sorafenib in unresectable hepatocellular carcinoma: A meta-analysis. J Gastroenterol Hepatol . 2021; 36:302-310. [PubMed 32652685]
33. Cheng Z, He L, Guo Y et al. The combination therapy of transarterial chemoembolisation and sorafenib is the preferred palliative treatment for advanced hepatocellular carcinoma patients: a meta-analysis. World J Surg Oncol . 2020; 18:243. [PubMed 32917226]
34. National Cancer Institute. Adult primary liver cancer treatment - health professional version. Revised August 23, 2021. Accessed 2021 Sept 17. [Web]
36. Negrier S, Jäger E, Porta C et al. Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a subanalysis of TARGET. Med Oncol . 2010; 27:899-906. [PubMed 19757215]
37. Escudier B, Eisen T, Stadler WM et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol . 2009; 27:3312-8. [PubMed 19451442]
42. Jasim S, Ozsari L, Habra MA. Multikinase inhibitors use in differentiated thyroid carcinoma. Biologics . 2014; 8:281-91. [PubMed 25506209]
43. Brose MS, Nutting CM, Jarzab B et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet . 2014; 384:319-28. [PubMed 24768112]
44. Brose MS, Schlumbeger M, Jeffers M et al. Analysis of Biomarkers and Association With Clinical Outcomes in Patients With Differentiated Thyroid Cancer: Subanalysis of the Sorafenib Phase III DECISION Trial. Clin Cancer Res . 2019; 25:7370-7380. [PubMed 31558473]
45. Haugen BR, Alexander EK, Bible KC et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid . 2016; 26:1-133. [PubMed 26462967]
46. Filetti S, Durante C, Hartl D et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol . 2019; 30:1856-1883. [PubMed 31549998]
47. Burchert A, Bug G, Fritz LV et al. Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN). J Clin Oncol . 2020; 38:2993-3002. [PubMed 32673171]
48. Xuan L, Wang Y, Huang F et al. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol . 2020; 21:1201-1212. [PubMed 32791048]
49. Bazarbachi A, Bug G, Baron F et al. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica . 2020; 105:1507-1516. [PubMed 32241850]
50. Park SH, Ryu MH, Ryoo BY et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs . 2012; 30:2377-83. [PubMed 22270258]
51. Gordan JD, Kennedy EB, Abou-Alfa GK et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol . 2020; 38:4317-4345. [PubMed 33197225]
52. Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med . 2017; 376:354-366. [PubMed 28121507]
53. Schmidinger M, Resch I, Fajkovic H et al. Dual immune check point blockade or immune check point-tyrosine kinase inhibitor combination: as a first-line treatment in metastatic renal cell carcinoma. Curr Opin Urol . 2021; 31:270-275. [PubMed 33742987]
54. Powles T, Albiges L, Bex A et al. ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma. Ann Oncol . 2021; 32:1511-1519. [PubMed 34597799]
55. National Cancer Institute. Renal cell cancer treatment - health professional version. Revised March 17, 2021. Accessed 2021 Nov 22. [Web]
56. Montemurro M, Gelderblom H, Bitz U et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis. Eur J Cancer . 2013; 49:1027-31. [PubMed 23140824]
57. Italiano A, Cioffi A, Coco P et al. Patterns of care, prognosis, and survival in patients with metastatic gastrointestinal stromal tumors (GIST) refractory to first-line imatinib and second-line sunitinib. Ann Surg Oncol . 2012; 19:1551-9. [PubMed 22065192]
58. Maki RG, D'Adamo DR, Keohan ML et al. Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol . 2009; 27:3133-40. [PubMed 19451436]
59. Ray-Coquard I, Italiano A, Bompas E et al. Sorafenib for patients with advanced angiosarcoma: a phase II Trial from the French Sarcoma Group (GSF/GETO). Oncologist . 2012; 17:260-6. [PubMed 22285963]
60. Bayer. Nexavar®: Specialty Pharmacy Providers (SPPs). Updated 2021 Mar. Accessed 2022 Mar. [Web]