1.1 Gastrointestinal Stromal Tumor

SUTENT is indicated for the treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.

1.2 Advanced Renal Cell Carcinoma

SUTENT is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC).

1.3 Adjuvant Treatment of Renal Cell Carcinoma

SUTENT is indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.

1.4 Advanced Pancreatic Neuroendocrine Tumors

SUTENT is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.

2.1 Recommended Dosage for GIST and Advanced RCC

The recommended dosage of SUTENT for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or unacceptable toxicity. SUTENT may be taken with or without food.

2.2 Recommended Dosage for Adjuvant Treatment of RCC

The recommended dosage of SUTENT for the adjuvant treatment of RCC is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2), for nine 6-week cycles. SUTENT may be taken with or without food.

2.3 Recommended Dosage for pNET

The recommended dosage of SUTENT for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. SUTENT may be taken with or without food.

2.4 Dosage Modifications for Adverse Reactions

To manage adverse reactions, the recommended dosage modifications are provided in Table 1. Table 2 provides the recommended dosage reductions of SUTENT for adverse reactions.

2.5 Dosage Modification for Drug Interactions

2.6 Dosage Modification for End-Stage Renal Disease Patients on Hemodialysis

No starting dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis. However, given the decreased exposure compared to patients with normal renal function, subsequent doses may be increased gradually up to 2-fold based on safety and tolerability [see Clinical Pharmacology (12.3)].

5.1 Hepatotoxicity

SUTENT can cause severe hepatotoxicity, resulting in liver failure or death. In the pooled safety population, liver failure occurred in <1% of patients in clinical trials. Liver failure include jaundiced, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure.

Monitor liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) at baseline, during each cycle, and as clinically indicated. Interrupt SUTENT for Grade 3 hepatotoxicity until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose.

Discontinue SUTENT in patients with Grade 4 hepatotoxicity, in patients without resolution of Grade 3 hepatotoxicity, in patients who subsequently experience severe changes in liver function tests and in patients who have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 × upper limit of normal (ULN) or with >5 × ULN and liver metastases has not been established.

5.2 Cardiovascular Events

Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported.

In pooled safety population, 3% of patients experienced heart failure; 71% of the patients with heart failure were reported as recovered. Fatal cardiac failure was reported in <1% of patients.

In the adjuvant treatment of RCC study, 11 patients experienced Grade 2 decreased ejection fraction (left ventricular ejection fraction [LVEF] 40% to 50% and a 10% to 19% decrease from baseline). In 3 of these 11 patients, the ejection fractions arm did not return to ≥50% or baseline by the time of last measurement. No patients who received SUTENT were diagnosed with CHF.

Patients who presented with cardiac events within 12 months prior to SUTENT administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from SUTENT clinical studies. Patients with prior anthracycline use or cardiac radiation were also excluded from some studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing left ventricular dysfunction.

Consider monitoring LVEF at baseline and periodically as clinically indicated. Carefully monitor patients for clinical signs and symptoms of congestive heart failure (CHF). Discontinue SUTENT in patients who experience clinical manifestations of CHF. Interrupt SUTENT and/or reduce the dose in patients without clinical evidence of CHF who have an ejection fraction of greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline ejection fraction was not obtained.

5.3 QT Interval Prolongation and Torsade de Pointes

SUTENT can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes was observed in <0.1% of patients.

Monitor patients who are at higher risk of developing QT interval prolongation, including patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Consider periodic monitoring of electrocardiograms and electrolytes (i.e., magnesium, potassium) during treatment with SUTENT.

Monitor QT interval more frequently when SUTENT is concomitantly administered with strong CYP3A4 inhibitors or drugs known to prolong QT interval. Consider dose reducing SUTENT [see Dosage and Administration (2.5), Drug Interactions (7.2)].

5.4 Hypertension

In the pooled safety population, 29% of patients experienced hypertension. Grade 3 hypertension was reported in 7% of patients, and Grade 4 hypertension was reported in 0.2%.

Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. In cases of Grade 3 hypertension, withhold SUTENT until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose. Discontinue SUTENT in patients with who develop Grade 4 hypertension.

5.5 Hemorrhagic Events and Viscus Perforation

Hemorrhagic events, some of which were fatal, have involved the gastrointestinal tract, respiratory tract, tumor, urinary tract, and brain. In the pooled safety population, 30% of patients experienced hemorrhagic events, including Grade 3 or 4 in 4.2% of patients. Epistaxis was the most common hemorrhagic event and gastrointestinal hemorrhage was the most common Grade 3–5 event.

Tumor-related hemorrhage was observed in patients treated with SUTENT. These events may occur suddenly, and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Pulmonary hemorrhage, some with a fatal outcome, was observed in patients treated with SUTENT for metastatic RCC, GIST, and metastatic lung cancer. SUTENT is not approved for use in patients with lung cancer.

Serious, sometimes fatal, gastrointestinal complications including gastrointestinal perforation, have been reported in patients with intra-abdominal malignancies treated with SUTENT.

Include serial complete blood counts (CBCs) and physical examinations with the clinical assessment of hemorrhagic events. Interrupt SUTENT for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose.

Discontinue SUTENT in patients without resolution of Grade 3 or 4 hemorrhagic events.

5.6 Tumor Lysis Syndrome

Tumor Lysis Syndrome (TLS), some fatal, occurred in clinical trials and has been reported in postmarketing experience, primarily in patients with RCC or GIST. Patients generally at risk of TLS are those with high tumor burden prior to treatment. Monitor these patients for TLS and manage as appropriate.

5.7 Thrombotic Microangiopathy

Thrombotic Microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, occurred in clinical trials and in postmarketing experience of SUTENT as monotherapy and administered in combination with bevacizumab. SUTENT is not approved for use in combination with bevacizumab.

Discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after SUTENT was discontinued.

5.8 Proteinuria

Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes.

Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt SUTENT and dose reduce for 24-hour urine protein of 3 or more grams. Discontinue SUTENT for patients with nephrotic syndrome or repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been evaluated.

5.9 Dermatologic Toxicities

Severe cutaneous adverse reactions have been reported, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. Permanently discontinue SUTENT for these severe cutaneous adverse reactions.

Necrotizing fasciitis, including fatal cases, has been reported in patients treated with SUTENT, including of the perineum and secondary to fistula formation. Discontinue SUTENT in patients who develop necrotizing fasciitis.

5.10 Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in <1% of patients, some of which were fatal. Patients can present with hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness. Magnetic resonance imaging is necessary to confirm the diagnosis. Discontinue SUTENT in patients developing RPLS.

5.11 Thyroid Dysfunction

Hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through postmarketing experience of SUTENT.

Monitor thyroid function at baseline, periodically during treatment and as clinically indicated. Monitor patients closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during treatment with SUTENT. Initiate and/or adjust therapies for thyroid dysfunction as appropriate.

5.12 Hypoglycemia

SUTENT can result in symptomatic hypoglycemia, which may lead to loss of consciousness, or require hospitalization. In the pooled safety population, hypoglycemia occurred in 2% of the patients treated with SUTENT. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with SUTENT for advanced RCC (Study 3) and GIST (Study 1) (n=577) and in approximately 10% of the patients treated with SUTENT for pNET (Study 6) (n=83). For patients being treated with SUTENT for pNET, pre-existing abnormalities in glucose homeostasis were not present in all patients who experienced hypoglycemia. Reductions in blood glucose levels may be worse in patients with diabetes.

Check blood glucose levels at baseline, regularly during treatment, as clinically indicated and after discontinuation of SUTENT. In patients with diabetes, assess if antidiabetic therapies need to be adjusted to minimize the risk of hypoglycemia.

5.13 Osteonecrosis of the Jaw

Osteonecrosis of the Jaw (ONJ) occurred in patients treated with SUTENT. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease/invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to initiation of SUTENT and periodically during SUTENT therapy. Advise patients regarding good oral hygiene practices. Withhold SUTENT treatment for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold SUTENT for development of ONJ until complete resolution. The safety of resumption of SUTENT after resolution of osteonecrosis of the jaw has not been established.

5.14 Impaired Wound Healing

Impaired wound healing has been reported in patients who received SUTENT [see Adverse Reactions (6.2)].

Withhold SUTENT for at least 3 weeks 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 SUTENT after resolution of wound healing complications has not been established.

5.15 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, SUTENT can cause fetal harm when administered to pregnant woman. Administration of sunitinib to pregnant rats and rabbits during the period of organogenesis resulted in teratogenicity at approximately 5.5 and 0.3 times the combined systemic exposure [combined area under the curve (AUC) of sunitinib plus its active metabolite] in patients administered the recommended daily dose (RDD) of 50 mg, respectively.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with SUTENT and for 4 weeks following the final dose [see Use in Specific Populations (8.1, 8.3)].

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 pooled safety population described in the Warnings and Precautions reflect exposure to SUTENT in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET. In this pooled safety population, the most common adverse reactions (≥25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of SUTENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

•

Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia1.

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Gastrointestinal disorders: esophagitis.

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Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis.

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Immune system disorders: hypersensitivity reactions, including angioedema.

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Infections and infestations: serious infection (with or without neutropenia)1. The infections most commonly observed with SUTENT include respiratory, urinary tract, skin infections, and sepsis/septic shock.

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Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression1; myopathy and/or rhabdomyolysis with or without acute renal failure1.

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Renal and urinary disorders: renal impairment and/or failure1.

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Respiratory disorders: pulmonary embolism1, pleural effusion1.

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Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive de-challenges.

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Vascular disorders: arterial (including aortic) aneurysms, dissections1, and rupture1; arterial thromboembolic events1. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction.

•

General disorders and administration site conditions: impaired wound healing.

1

including some fatalities

7.1 Effect of Other Drugs on SUTENT

7.2 Drugs that Prolong QT Interval

SUTENT is associated with QTc interval prolongation [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)]. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

8.1 Pregnancy

8.2 Lactation

There is no information regarding the presence of sunitinib and its metabolites in human milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma (see Data). Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose.

8.3 Females and Males of Reproductive Potential

SUTENT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of SUTENT in pediatric patients have not been established. Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to <17 years of age (n=29) with refractory solid tumors. In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to <17 years of age (n=27) with high-grade glioma or ependymoma. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. Sunitinib was poorly tolerated in pediatric patients. The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation. No responses were reported in patients in either of the trials.

Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults.

The effect on open tibial growth plates in pediatric patients who received SUTENT has not been adequately studied. See Juvenile Animal Toxicity Data below.

8.5 Geriatric Use

Of the 7527 patients with GIST, RCC (advanced and adjuvant), or pNET who received SUTENT, 32% were 65 years and older, and 7% were 75 years and older. Patients aged 65 years of age and older had a higher incidence of Grade 3 or 4 adverse reactions (67%) than younger patients (60%).

In the GIST study, 73 (30%) of the patients who received SUTENT were 65 years and older. In the mRCC study, 152 (41%) of patients who received SUTENT were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

In the pNET study, 22 (27%) of the patients who received SUTENT were 65 years and older. Clinical studies of SUTENT did not include sufficient numbers of patients with pNET to determine if patients 65 years of age and older respond differently than younger patients.

8.6 Hepatic Impairment

No dose adjustment is required in patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment [see Clinical Pharmacology (12.3)]. SUTENT was not studied in patients with severe (Child-Pugh Class C) hepatic impairment.

8.7 Renal Impairment

No dose adjustment is recommended in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis [see Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with end-stage renal disease (ESRD) on hemodialysis [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.

Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors.

Sunitinib AUC and Cmax increase proportionately over a dose range of 25 mg to 100 mg (0.5 to 2 times the approved RDD of 50 mg). The pharmacokinetics were similar in healthy subjects and in patients with a solid tumor, including patients with GIST and RCC. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 63 to 101 ng/mL.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of sunitinib has been evaluated in 2 species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice, gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at sunitinib daily doses of ≥25 mg/kg/day in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day [approximately 0.9 times the combined AUC (combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg]. At the high dose of 3 mg/kg/day (approximately 8 times the combined AUC in patients administered the RDD of 50 mg), the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal gland.

Sunitinib did not cause genetic damage when tested in in vitro assays [bacterial mutation (Ames test), human lymphocyte chromosome aberration] and an in vivo rat bone marrow micronucleus test.

In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Preimplantation loss was observed in females administered 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). No adverse effects on fertility were observed at doses ≤1.5 mg/kg/day (approximately equal to the combined AUC in patients administered the RDD of 50 mg). In addition, effects on the female reproductive system were identified in a 3-month oral repeat-dose monkey study (2, 6, 12 mg/kg/day). Ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (approximately 0.4 times the combined AUC in patients administered the RDD of 50 mg). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day (approximately 0.8 times the combined AUC in patients administered the RDD of 50 mg) in a 9-month monkey study (0.3, 1.5, and 6 mg/kg/day administered daily for 28 days followed by a 14-day respite).

In a male fertility study, no reproductive effects were observed in male rats dosed with 1, 3, or 10 mg/kg/day oral sunitinib for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤10 mg/kg/day (approximately ≥26 times the combined AUC in patients administered the RDD of 50 mg).

14.1 Gastrointestinal Stromal Tumor

Study 1

Study 1 (NCT#00075218) was a 2-arm, international, randomized, double-blind, placebo-controlled trial of SUTENT in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The objective was to compare time-to-tumor progression (TTP) in patients receiving SUTENT plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Patients were randomized (2:1) to receive either 50 mg SUTENT or placebo orally, once daily, on Schedule 4/2 until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label SUTENT and patients randomized to SUTENT were permitted to continue treatment per investigator judgment.

At the time of a prespecified interim analysis, the intent-to-treat (ITT) population included 312 patients. Two hundred seven (207) patients were randomized to the SUTENT arm and 105 patients were randomized to the placebo arm. Demographics were comparable between the SUTENT and placebo groups with regard to age (69% versus 72% <65 years for SUTENT versus placebo, respectively), sex (male: 64% versus 61%), race (White: 88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and performance status (ECOG 0: 44% versus 46%, ECOG 1: 55% versus 52%, and ECOG 2: 1% versus 2%). Prior treatment included surgery (94% versus 93%) and radiotherapy (8% versus 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% versus 4%), progression within 6 months of starting treatment (17% versus 16%), or progression beyond 6 months (78% versus 80%) balanced.

The planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. There was a statistically significant advantage for SUTENT over placebo in TTP, meeting the primary endpoint. Efficacy results are summarized in Table 10 and the Kaplan-Meier curve for TTP is shown in Figure 1.

Table 10. GIST Efficacy Results From Study 1 (Double-Blind Treatment Phase)

Efficacy Parameter	SUTENT (N=207)	Placebo (N=105)	p-value (log-rank test)	HR (95% CI)
Abbreviations: CI=confidence interval; GIST=gastrointestinal stromal tumor; HR=hazard ratio; N=number of patients; PR=partial response.
* Time from randomization to progression; deaths prior to documented progression were censored at time of last radiographic evaluation. † A comparison is considered statistically significant if the p-value is <0.00417 (O'Brien Fleming stopping boundary). ‡ Time from randomization to progression or death due to any cause. § Pearson chi-square test.
Time-to-tumor progression* [median, weeks (95% CI)]	27.3 (16.0, 32.1)	6.4 (4.4, 10.0)	<0.0001†	0.33 (0.23, 0.47)
Progression-free survival‡ [median, weeks (95% CI)]	24.1 (11.1, 28.3)	6.0 (4.4, 9.9)	<0.0001	0.33 (0.24, 0.47)
Objective response rate (PR) [%, (95% CI)]	6.8 (3.7, 11.1)	0	0.006§

Figure 1. Kaplan-Meier Curve of TTP in GIST Study 1 (Intent-to-Treat Population)

Abbreviations: CI=confidence interval; GIST=gastrointestinal stromal tumor; N=number of patients; TTP=time-to-tumor progression.

The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the SUTENT arm and 118 patients randomized to the placebo arm. After the primary endpoint was met at the interim analysis, the study was unblinded, and patients on the placebo arm were offered open-label SUTENT treatment. Ninety-nine (99) of the patients initially randomized to placebo crossed over to receive SUTENT in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the SUTENT arm and 64.9 weeks for the placebo arm [hazard ratio (HR)=0.876, 95% confidence interval (CI) (0.679, 1.129)].

14.2 Renal Cell Carcinoma

Treatment-Naïve

Study 3 (NCT#00083889) was a multi-center, international, randomized study comparing single-agent SUTENT with interferon alfa was conducted in patients with treatment-naïve RCC. The objective was to compare PFS in patients receiving SUTENT versus patients receiving interferon alfa. Other endpoints included ORR, OS, and safety. Seven hundred fifty (750) patients were randomized (1:1) to receive either 50 mg SUTENT once daily on Schedule 4/2 or to receive interferon alfa administered subcutaneously at 9 million international units (MIU) 3 times a week. Patients were treated until disease progression or withdrawal from the study.

The ITT population included 750 patients, 375 randomized to SUTENT and 375 randomized to interferon alfa. Demographics were comparable between the SUTENT and interferon alfa groups with regard to age (59% versus 67% <65 years for SUTENT versus interferon alfa, respectively), sex (male: 71% versus 72%), race (White: 94% versus 91%, Asian: 2% versus 3%, Black: 1% versus 2%, remainder not reported), and performance status (ECOG 0: 62% versus 61%, ECOG 1: 38% each arm, ECOG 2: 0 versus 1%). Prior treatment included nephrectomy (91% versus 89%) and radiotherapy (14% each arm). The most common site of metastases present at screening was the lung (78% versus 80%, respectively), followed by the lymph nodes (58% versus 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% versus 77%, respectively).

There was a statistically significant advantage for SUTENT over interferon alfa in the endpoint of PFS (see Table 11 and Figure 2). In the prespecified stratification factors of lactate dehydrogenase (LDH) (>1.5 ULN versus ≤1.5 ULN), ECOG performance status (0 versus 1), and prior nephrectomy (yes versus no), the hazard ratio favored SUTENT over interferon alfa. The ORR was higher in the SUTENT arm (see Table 11).

Table 11. Treatment-Naïve RCC Efficacy Results (Interim Analysis) from Study 3

Efficacy Parameter	SUTENT (N=375)	Interferon Alfa (N=375)	p-value (log-rank test)	HR (95% CI)
Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NA=not applicable; RCC=renal cell carcinoma.
* Assessed by blinded core radiology laboratory; 90 patients' scans had not been read at time of analysis. † A comparison is considered statistically significant if the p-value is <0.0042 (O'Brien Fleming stopping boundary). ‡ Pearson chi-square test.
Progression-free survival* [median, weeks (95% CI)]	47.3 (42.6, 50.7)	22.0 (16.4, 24.0)	<0.000001†	0.415 (0.320, 0.539)
Objective response rate* [%, (95% CI)]	27.5 (23.0, 32.3)	5.3 (3.3, 8.1)	<0.001‡	NA

Figure 2. Kaplan-Meier Curve of PFS in Treatment-Naïve RCC Study 3 (Intent-to-Treat Population)

Abbreviations: CI=confidence interval; IFN-α=interferon-alfa; N=number of patients; PFS=progression-free survival; RCC=renal cell carcinoma.

At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the SUTENT arm and 94.9 weeks for the interferon alfa arm (HR=0.821; 95% CI: 0.673, 1.001). The median OS for the interferon alfa arm includes 25 patients who discontinued interferon alfa treatment because of disease progression and crossed over to treatment with SUTENT as well as 121 patients (32%) on the interferon alfa arm who received post-study cancer treatment with SUTENT.

Adjuvant Treatment

In the adjuvant treatment setting, SUTENT was investigated in S-TRAC (NCT#00375674), a multi-center, international, randomized, double-blind, placebo-controlled, trial in patients with high risk of recurrent RCC following nephrectomy. Patients were required to have clear cell histology and high risk of recurrence defined as ≥T3 and/or N+ tumors. Six hundred fifteen (615) patients were randomized 1:1 to receive either 50 mg SUTENT once daily on Schedule 4/2 or placebo. Patients were treated for 9 cycles (approximately 1 year), or until disease recurrence, unacceptable toxicity, or withdrawal of consent.

Demographics were generally comparable between the SUTENT and placebo arms with regard to age (median age 58 years), sex (73% male), and race (84% White, 12% Asian and 4% Other). At randomization, most patients had an ECOG performance status of 0 (74% SUTENT and 72% placebo). The remainder of the patients had an ECOG performance status of 1; 1 patient on SUTENT had a performance status of 2.

The major efficacy outcome measure was disease-free survival (DFS) in patients receiving SUTENT versus placebo as assessed by blinded independent central review (BICR). Overall survival was an additional endpoint. There was a statistically significant improvement in DFS in patients who were treated with SUTENT compared to placebo (Table 13 and Figure 3). Prespecified subgroup analyses are presented in Table 14. At the time of the DFS analysis, overall survival data were not mature, with 141/615 (23%) patient deaths.

Table 13. Disease-free Survival Results as Assessed by BICR in Adjuvant RCC (Intent to Treat Population) from S-TRAC

	SUTENT N=309	Placebo N=306	p-value*	HR* (95% CI)
Abbreviations: BICR=blinded independent central review; CI=confidence interval; DFS=disease-free survival; HR=hazard ratio; N=number of patients; RCC=renal cell carcinoma.
* P-value based on log-rank test stratified by University of California Los Angeles Integrated Staging System (UISS) prognostic group; HR based on a Cox proportional hazard model stratified by UISS prognostic group
Median DFS [years (95% CI)]	6.8 (5.8, NR)	5.6 (3.8, 6.6)	0.03	0.76 (0.59, 0.98)
DFS Events	113 (36.6%)	144 (47.1%)
5 Year DFS Rate	59.3%	51.3%

Table 14. Disease-free Survival by Baseline Disease Characteristics

	Number of Events/ Total n/N		Median DFS [years (95% CI)]		HR* (95% CI)
	SUTENT	Placebo	SUTENT	Placebo
Abbreviations: CI=confidence interval; DFS=disease-free survival; HR=hazard ratio; N=number of patients; n=number of events; NR=not reached
* HR based on a Cox proportional hazards model † T3 Intermediate: T3, N0 or NX, M0, any Fuhrman's grade, ECOG PS 0 OR T3, N0 or NX, M0, Fuhrman's grade 1, ECOG PS ≥ 1 ‡ T3 High: T3, N0 or NX, M0, Fuhrman's grade ≥ 2, ECOG PS ≥ 1 § T4/Node Positive: T4, N0 or NX, M0, any Fuhrman's grade, any ECOG PS OR Any T, N1–2, M0, any Fuhrman's grade, any ECOG PS
T3 Intermediate†	35/115	46/112	NR (5.2, NR)	6.4 (4.7, NR)	0.82 (0.53, 1.28)
T3 High‡	63/165	79/166	6.8 (5.0, NR)	5.3 (2.9, NR)	0.77 (0.55, 1.07)
T4/Node Positive§	15/29	19/28	3.5 (1.2, NR)	1.7 (0.4, 3.0)	0.62 (0.31, 1.23)

Figure 3. Kaplan-Meier Curve of Disease-free Survival as Assessed by BICR (Intent-to-Treat Population)

Abbreviations: BICR=blinded independent central review; CI=confidence interval; N=number of patients.

14.3 Pancreatic Neuroendocrine Tumors

Study 6 (NCT#00428597) was a multi-center, international, randomized, double-blind, placebo-controlled study of single-agent SUTENT conducted in patients with unresectable pNET. Patients were required to have documented RECIST-defined disease progression within the prior 12 months and were randomized (1:1) to receive either 37.5 mg SUTENT (N=86) or placebo (N=85) once daily without a scheduled off-treatment period. The primary objective was to compare PFS in patients receiving SUTENT versus patients receiving placebo. Other endpoints included OS, ORR, and safety. Use of somatostatin analogs was allowed in the study.

Demographics were comparable between the SUTENT and placebo groups. Additionally, 49% of SUTENT patients had nonfunctioning tumors vs 52% of placebo patients, and 92% patients in both arms had liver metastases. A total of 66% of SUTENT patients received prior systemic therapy compared with 72% of placebo patients and 35% of SUTENT patients had received somatostatin analogs compared with 38% of placebo patients. Patients were treated until disease progression or withdrawal from the study. Upon disease progression or study closure, patients were offered access to SUTENT in a separate extension study.

As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the prespecified interim analysis. This may have led to an overestimate of the magnitude of PFS effect. A clinically significant improvement for SUTENT over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring SUTENT was observed in all subgroups of baseline characteristics evaluated. OS data were not mature at the time of the analysis. There were 9 deaths in the SUTENT arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring SUTENT over placebo was observed. Efficacy results are summarized in Table 15 and the Kaplan-Meier curve for PFS is in Figure 4.

Figure 4. Kaplan-Meier Curve of PFS in the pNET Study 6

Abbreviations: CI=confidence interval; N=number of patients; PFS=progression-free survival; pNET=pancreatic neuroendocrine tumors.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Hepatotoxicity

Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.1)].

Cardiovascular Events

Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.2)].

QT Prolongation and Torsade de Pointes

Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately in the event of syncope, pre-syncopal symptoms, and cardiac palpitations [see Warnings and Precautions (5.3)].

Hypertension

Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.4)].

Hemorrhagic Events

Advise patients that SUTENT can cause severe bleeding. Advise patients to immediately contact their healthcare provider for bleeding or symptoms of bleeding [see Warnings and Precautions (5.5)].

Gastrointestinal Disorders

Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during SUTENT treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking SUTENT [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

Dermatologic Effects and Toxicities

Advise patients that depigmentation of the hair or skin may occur during treatment with SUTENT due to the drug color (yellow). Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Severe dermatologic toxicities including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, erythema multiforme, and necrotizing fasciitis have been reported. Advise patients to immediately inform their healthcare provider if severe dermatologic reactions occur [see Warnings and Precautions (5.9), Adverse Reactions (6.1)].

Reversible Posterior Leukoencephalopathy Syndrome

Inform patients of the signs and symptoms of reversible posterior leukoencephalopathy syndrome. Advise patients to contact their healthcare provider if they develop symptoms of reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10)].

Thyroid Dysfunction

Advise patients that SUTENT can cause thyroid dysfunction. Advise patient to contact their healthcare provider if symptoms of abnormal thyroid function occur [see Warnings and Precautions (5.11)].

Hypoglycemia

Advise patients that SUTENT can cause severe hypoglycemia and may be more severe in patients with diabetes taking antidiabetic medications. Inform patients of the signs, symptoms, and risks associated with hypoglycemia. Advise patients to immediately inform their healthcare provider if severe signs or symptoms of hypoglycemia occur [see Warnings and Precautions (5.12)].

Osteonecrosis of the Jaw

Advise patients regarding good oral hygiene practices and to inform their healthcare provider of any planned dental procedures. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see Warnings and Precautions (5.13)].

Impaired Wound Healing

Advise patients that SUTENT impairs wound healing. Advise patients to inform their healthcare provider of any planned surgical procedures [see Warnings and Precautions (5.14)].

Concomitant Medications

Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements [see Drug Interactions (7)].

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment and for 4 weeks after receiving the last dose of SUTENT [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 7 weeks after receiving the last dose of SUTENT [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise patients that SUTENT may impair male and female fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Missed Dose

Advise patients that miss a dose of SUTENT by less than 12 hours to take the missed dose right away. Advise patients that miss a dose of SUTENT by more than 12 hours to take the next scheduled dose at its regular time.