Sorafenib

NEXAVAR is a kinase inhibitor indicated for the treatment of

• Unresectable hepatocellular carcinoma ( 1.1 )
• Advanced renal cell carcinoma ( 1.2 )
• Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment ( 1.3 )

1.1 Hepatocellular Carcinoma NEXAVAR ® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

1.2 Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

1.3 Differentiated Thyroid Carcinoma NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.

Tablets:

• 200 mg sorafenib, round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side.
• 200 mg sorafenib, round, faceted biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side. Tablets: 200 mg ( 3 )

• NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR.
• NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer [see Warnings and Precautions ( 5.8 )] .
• NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR. ( 4 )
• NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. ( 4 )

• Cardiovascular Events : Consider temporary or permanent discontinuation of NEXAVAR. ( 2.2 , 5.1 )
• Hemorrhage: Discontinue NEXAVAR if needed. ( 5.2 )
• Hypertension: Monitor blood pressure weekly during the first 6 weeks and periodically thereafter. Consider temporary or permanent discontinuation for severe or persistent hypertension despite antihypertensive therapy. ( 5.3 )
• Dermatologic Toxicities : Interrupt and/or decrease dose. Discontinue for severe or persistent reactions, or if Stevens-Johnson syndrome and toxic epidermal necrolysis is suspected. ( 5.4 )
• Gastrointestinal Perforation : Discontinue NEXAVAR. ( 5.5 )
• Risk of Impaired Wound Healing : Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established. ( 5.7 )
• QT Prolongation : Monitor electrocardiograms and electrolytes in patients at increased risk for ventricular arrhythmias. Correct electrolytes. Interrupt if QTc greater than 500 msec or increases greater than 60 msec from baseline. ( 2.2 , 5.9 , 12.2 )
• Drug-Induced Liver Injury : Monitor liver function tests regularly; discontinue for unexplained transaminase elevations. ( 5.10 )
• Embryo-Fetal Toxicity : NEXAVAR may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 )
• Impairment of Thyroid Stimulating Hormone Suppression (TSH) in DTC : Monitor TSH monthly and adjust thyroid replacement therapy in patients with thyroid cancer. ( 5.12 )

5.1 Cardiovascular Events In the SHARP (HCC) study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR-treated patients compared with 1.3% in those receiving placebo; in the TARGET (RCC) study, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR-treated group (2.9%) compared with patients receiving placebo (0.4%), and in the DECISION (DTC) study, the incidence of cardiac ischemia/infarction was 1.9% in the NEXAVAR-treated group compared with 0% in patients receiving placebo. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. In multiple clinical trials, congestive heart failure has been reported in 1.9% of NEXAVAR-treated patients (N=2276) [see Adverse Reactions ( 6.2 )] . Consider temporary or permanent discontinuation of NEXAVAR in patients who develop cardiovascular events [see Dosage and Administration ( 2.2 )].

5.2 Hemorrhage An increased risk of bleeding may occur following NEXAVAR administration. In the SHARP (HCC) study, the rates of bleeding from esophageal varices (2.4% and 4%) and of bleeding with a fatal outcome from any site (2.4% and 4%) were similar in NEXAVAR-treated patients and those receiving placebo, respectively . In the TARGET (RCC) study, bleeding was reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients receiving placebo. The incidence of Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in those receiving placebo. There was one fatal hemorrhage in each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study, bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in NEXAVAR-treated patients and in those receiving placebo. If any bleeding necessitates medical intervention, consider permanent discontinuation of NEXAVAR [see Dosage and Administration ( 2.2 )] . Due to the potential risk of bleeding, treat tracheal, bronchial, and esophageal infiltration with local therapy prior to administering NEXAVAR in patients with DTC.

5.3 Hypertension In the SHARP (HCC) study, hypertension was reported in 9.4% of NEXAVAR-treated patients and 4.3% of patients receiving placebo. In the TARGET (RCC) study, hypertension was reported in 16.9% of NEXAVAR-treated patients and 1.8% of patients receiving placebo. In the DECISION (DTC) study, hypertension was reported in 40.6% of NEXAVAR-treated patients and 12.4% of patients receiving placebo. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR-treated patients in the SHARP (HCC) study, 1 of 451 NEXAVAR-treated patients in the TARGET (RCC) study, and 1 of 207 NEXAVAR-treated patients in the DECISION (DTC) study. Monitor blood pressure weekly during the first 6 weeks of NEXAVAR. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR [see Dosage and Administration ( 2.2 )] .

5.4 Dermatologic Toxicities Hand-foot skin reaction and rash represent the most common adverse reactions attributed to NEXAVAR. Rash and hand-foot skin reaction are usually Grade 1 and 2 and generally appear during the first six weeks of treatment with NEXAVAR. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 NEXAVAR-treated patients with HCC, 3 (0.7%) of 451 NEXAVAR-treated patients with RCC, and 11 (5.3%) of 207 NEXAVAR-treated patients with DTC. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose reduction of NEXAVAR, or in severe or persistent cases, permanent discontinuation of NEXAVAR [see Dosage and Administration ( 2.2 )] . There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue NEXAVAR if SJS or TEN are suspected.

5.5 Gastrointestinal Perforation Gastrointestinal perforation has been reported in less than 1% of patients taking NEXAVAR. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, permanently discontinue NEXAVAR.

5.6 Increased Risk of Bleeding with Concomitant Use of Warfarin Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes.

5.7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, NEXAVAR has the potential to adversely affect wound healing. Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established.

5.8 Increased Mortality Observed with NEXAVAR Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of NEXAVAR compared to those treated with carboplatin/paclitaxel alone (HR 1.81; 95% CI 1.19, 2.74) and gemcitabine/cisplatin alone (HR 1.22; 95% CI 0.82, 1.80). The use of NEXAVAR in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. NEXAVAR in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. […]

The following clinically significant adverse reactions are discussed elsewhere in the labeling:

• Cardiovascular events [see Warnings and Precautions ( 5.1 )]
• Hemorrhage [see Warnings and Precautions ( 5.2 )]
• Hypertension [see Warnings and Precautions ( 5.3 )]
• Dermatologic toxicities [see Warnings and Precautions ( 5.4 )]
• Gastrointestinal perforation [see Warnings and Precautions ( 5.5 )]
• QT interval prolongation [see Warnings and Precautions ( 5.9 ) and Clinical Pharmacology ( 12.2 )]
• Drug-induced liver injury [see Warnings and Precautions ( 5.10 )]
• Impairment of TSH suppression in DTC [see Warnings and Precautions ( 5.12 )] The most common adverse reactions (≥20%) are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described reflect exposure to NEXAVAR in 955 patients who participated in placebo-controlled studies in hepatocellular carcinoma (N=297), advanced renal cell carcinoma (N=451), or differentiated thyroid carcinoma (N = 207). The most common adverse reactions (≥20%), which were considered to be related to NEXAVAR, in patients with HCC, RCC or DTC are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. Hepatocellular Carcinoma Table 4 shows the percentage of patients in the SHARP (HCC) study experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the NEXAVAR-treated group than in those receiving placebo. Table 4: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – SHARP (HCC) Adverse Reaction 1 NEXAVAR N=297 Placebo N=302 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Any Adverse Reaction 98 39 6 96 24 8 Gastrointestinal Diarrhea 55 10 <1 25 2 0 Anorexia 29 3 0 18 3 <1 Nausea 24 1 0 20 3 0 Vomiting 15 2 0 11 2 0 Constipation 14 0 0 10 0 0 Constitutional symptoms Fatigue 46 9 1 45 12 2 Weight loss 30 2 0 10 1 0 Pain Pain, abdomen 31 9 0 26 5 1 Dermatology/skin Hand-foot skin reaction 21 8 0 3 <1 0 Rash/desquamation 19 1 0 14 0 0 Alopecia 14 0 0 2 0 0 Pruritus 14 <1 0 11 <1 0 Dry skin 10 0 0 6 0 0 Hepatobiliary/pancreas Liver dysfunction 11 2 1 8 2 1 1 Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Hypertension was reported in 9% of patients treated with NEXAVAR and 4% of those receiving placebo. Grade 3 hypertension was reported in 4% of NEXAVAR-treated patients and 1% of those receiving placebo. Hemorrhage/bleeding was reported in 18% of those receiving NEXAVAR and 20% of patients receiving placebo. The rates of Grade 3 and 4 bleeding were also higher in patients receiving placebo (Grade 3 – 3% NEXAVAR and 5% placebo and Grade 4 – 2% NEXAVAR and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in NEXAVAR-treated patients and 4% of patients receiving placebo. Renal failure was reported in <1% of patients treated with NEXAVAR and 3% of patients receiving placebo. Clinical pancreatitis was reported in 1 of 297 NEXAVAR-treated patients (Grade 2). The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the NEXAVAR-treated patients and those receiving placebo (32% of NEXAVAR-treated patients and 35% of patients receiving placebo). Laboratory test abnormalities reported in SHARP are presented in Table 5. Table 5: Laboratory Test Abnormalities Reported in SHARP (HCC) Laboratory Parameter 1 NEXAVAR N=297 Placebo N=302 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hypoalbuminemia 59 0 47 0 Elevated Lipase 40 9 37 9 Lymphopenia 47 NR 42 NR Thrombocytopenia 46 4 41 <1 Elevated INR 42 4 34 2 Hypophosphatemia 35 11 11 2 Elevated Amylase 34 2 29 2 Hypocalcemia 27 2.4 15 1 Hypokalemia 10 <1 6 <1 1- Laboratory parameters graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). NR = not reported Renal Cell Carcinoma Table 6 shows the percentage of patients in the TARGET (RCC) study experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in NEXAVAR-treated patients arm than in those receiving placebo. The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the NEXAVAR-treated patients and patients receiving placebo (10% and 8%, respectively). Clinical pancreatitis was reported in 3 of 451 NEXAVAR-treated patients (one Grade 2 and two Grade 4). Table 6: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – TARGET (RCC) Adverse Reaction 1 NEXAVAR N=451 Placebo N=451 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Any Adverse Reactions 95 31 7 86 22 6 Gastrointestinal symptoms Diarrhea 43 2 0 13 <1 0 Nausea 23 <1 0 19 <1 0 Anorexia 16 <1 0 13 1 0 Vomiting 16 <1 0 12 1 0 Constipation 15 <1 0 11 <1 0 Dermatology/skin Rash/desquamation 40 <1 0 16 <1 0 Hand-foot skin reaction 30 6 0 7 0 0 Alopecia 27 <1 0 3 0 0 Pruritus 19 <1 0 6 0 0 Dry skin 11 0 0 4 0 0 Constitutional symptoms Fatigue 37 5 <1 28 3 <1 Weight loss 10 <1 0 6 0 0 Cardiovascular, General Hypertension 17 3 <1 2 <1 0 Hemorrhage/bleeding Hemorrhage – all sites 15 2 0 8 1 <1 Pulmonary Dyspnea 14 3 <1 12 2 <1 Neurology Neuropathy-sensory 13 <1 0 6 <1 0 Pain Pain, abdomen 11 2 0 9 2 0 Pain, headache 10 <1 0 6 <1 0 Pain, joint 10 2 0 6 <1 0 1 Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Laboratory test abnormalities reported in TARGET are presented in Table 7. Table 7: Laboratory Test Abnormalities Reported in TARGET (RCC) Laboratory Parameter 1 NEXAVAR N=451 Placebo N=451 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hypophosphatemia 45 13 11 3 Anemia 44 2 49 4 Elevated Lipase 41 12 30 7 Elevated Amylase 30 1 23 3 Lymphopenia 23 13 13 7 Neutropenia 18 5 10 2 Thrombocytopenia 12 1 5 0 Hypocalcemia 12 2 8 <1 Hypokalemia 5 1 <1 <1 1 Laboratory parameters graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Differentiated Thyroid Carcinoma The safety of NEXAVAR was evaluated in DECISION in 416 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) treatment randomized to receive 400 mg twice daily NEXAVAR (n=207) or matching placebo (n=209) until disease progression or intolerable toxicity in a double-blind trial [see Clinical Studies ( 14.3 )]. The data described below reflect a median exposure to NEXAVAR for 46 weeks (range 0.3 to 135). The population exposed to NEXAVAR was 50% male, and had a median age of 63 years. Dose interruptions for adverse reactions were required in 66% of patients receiving NEXAVAR and dose reductions were required in 64% of patients. Adverse reactions that resulted in treatment discontinuation were reported in 14% of NEXAVAR-treated patients compared to 1.4% of patients receiving placebo. […]

• Strong CYP3A Inducers: Avoid strong CYP3A4 inducers. ( 7.1 )

7.1 Effect of Other Drugs on NEXAVAR Strong CYP3A4 Inducers The concomitant use of NEXAVAR with rifampin, a strong CYP3A4 inducer decreased the mean AUC of sorafenib, which may decrease the antitumor activity [see Clinical Pharmacology ( 12.3 )] . Avoid concomitant use of NEXAVAR with strong CYP3A4 inducers, when possible, because these drugs can decrease the systemic exposure to sorafenib. Neomycin The concomitant use of NEXAVAR with neomycin decreased the mean AUC of sorafenib, which may decrease the antitumor activity. Avoid concomitant use of NEXAVAR with neomycin. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied [see Clinical Pharmacology ( 12.3 )].

7.2 Concomitant Use of Warfarin The concomitant use of NEXAVAR and warfarin may increase the risk of bleeding or increased the INR. Monitor INR and for clinical bleeding episodes in patients taking warfarin while receiving NEXAVAR [see Warnings and Precautions ( 5.6 )].

7.3 Drugs That Prolong the QT Interval NEXAVAR is associated with QTc interval prolongation. Avoid coadministration of NEXAVAR with medicinal products with a known potential to prolong QT/QTc interval [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.2 )] .

• Lactation : Advise women not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , NEXAVAR may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of sorafenib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicities at maternal exposures that were significantly lower than human exposures at the recommended dose of 400 mg twice daily (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In animal reproduction studies, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight) when administered orally to pregnant rats and rabbits during the period of organogenesis. The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m 2 /day on a body surface area basis). Adverse intrauterine development effects were seen at doses >0.2 .mg/kg/day (1.2 mg/m 2 /day) in rats and ≥0.3 mg/kg/day (≥3.6 mg/m 2 /day) in rabbits. These doses result in exposures (AUC) that are approximately 0.008 times the AUC in patients at the recommended dose.

8.2 Lactation Risk Summary There are no data on the presence of sorafenib or its metabolites in human milk, or its effects on the breast-fed child or on milk production. Sorafenib was present in milk of lactating rats (see Data) . Because of the potential for serious adverse reactions in a breastfed child from NEXAVAR, advise women not to breastfeed during treatment with NEXAVAR and for 2 weeks after the last dose. Data Animal Data Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into milk. The milk to plasma AUC ratio was approximately 5:1.

8.3 Females and Males of Reproductive Potential NEXAVAR may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of NEXAVAR. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of NEXAVAR. Males Based on genotoxicity and findings in animal reproduction studies, advise males with female partners of reproductive potential and pregnant partners to use effective contraception during treatment with NEXAVAR and for 3 months following the last dose of NEXAVAR [see Use in Specific Populations ( 8.1 ), Nonclinical Toxicology ( 13.1 )] . Infertility Males Based on findings in animal studies, NEXAVAR may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use The safety and effectiveness of NEXAVAR have not been established in pediatric patients. Juvenile Animal Toxicity Data Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥600 mg/m 2 (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m 2 /day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m 2 /day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less.

8.5 Geriatric Use In total, 59% of HCC patients treated with NEXAVAR were age 65 years or older and 19% were 75 and older. In total, 32% of RCC patients treated with NEXAVAR were age 65 years or older and 4% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment No dose adjustment is necessary for patients with mild, moderate or severe renal impairment who are not on dialysis. The pharmacokinetics of sorafenib have not been studied in patients who are on dialysis [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment No dose adjustment is necessary for patients with mild or moderate hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology ( 12.3 )].

Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, RET, RET/PTC, VEGFR-1, VEGFR- 2, VEGFR- 3, and PDGFR-ß). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of HCC, RCC, and DTC human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.