Sutent Drug Information

Generic name: SUNITINIB MALATE

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Uses of Sutent

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.

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

Adjuvant Treatment of Renal Cell Carcinoma SUTENT is indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.

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.

Dosage & Administration of Sutent

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.

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.

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.

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. Table 1.

Recommended Dosage Reductions of SUTENT for Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis Any Grade • Permanently discontinue. Reversible posterior leukoencephalopathy syndrome

Dosage Modification for Drug Interactions Strong CYP3A4 Inhibitors Select an alternate concomitant medication with no or minimal enzyme inhibition potential. If coadministration of SUTENT with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction for SUTENT to a minimum dosage as follows: • GIST and RCC: 37.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) • pNET: 25 mg orally once daily Strong CYP3A4 Inducers Select an alternate concomitant medication with no or minimal enzyme induction potential. If coadministration of SUTENT with a strong CYP3A4 inducer cannot be avoided, consider a dose increase for SUTENT to a maximum dosage as follows: • GIST and RCC: 87.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) • pNET: 62.5 mg orally once daily If the dose of SUTENT is increased, monitor patients carefully for adverse reactions.

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.

Table 1. Recommended Dosage Reductions of SUTENT for Adverse Reactions
Indications	GIST	RCC		pNET
Indications	GIST	Advanced RCC	Adjuvant RCC	pNET
First dose reduction	37.5 mg once daily	37.5 mg once daily	37.5 mg once daily	25 mg once daily
Second dose reduction	25 mg once daily	25 mg once daily	NA	NA

Table 2. Recommended Dosage Modifications for SUTENT for Adverse Reactions
Adverse Reaction	Severity	Dosage Modifications for SUTENT
Hepatotoxicity [see Warnings and Precautions (5.1) ]	Grade 3	• Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. • For recurring Grade 3 permanently discontinue.
Hepatotoxicity [see Warnings and Precautions (5.1) ]	Grade 4	• Permanently discontinue.
Cardiovascular events [see Warnings and Precautions (5.2) ]	Asymptomatic cardiomyopathy (left ventricular ejection fraction greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline was not obtained)	• Withhold until resolution to Grade 0 to 1 or baseline. • Resume at reduced dose.
Cardiovascular events [see Warnings and Precautions (5.2) ]	Clinically manifested congestive heart failure (CHF)	• Permanently discontinue.
Hypertension [see Warnings and Precautions (5.4) ]	Grade 3	• Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose.
Hypertension [see Warnings and Precautions (5.4) ]	Grade 4	• Permanently discontinue.
Hemorrhagic events [see Warnings and Precautions (5.5) ]	Grade 3 or 4	• Withhold until resolution to Grade 0 to 1 or baseline. • Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction.
Thrombotic microangiopathy [see Warnings and Precautions (5.7) ]	Any Grade	• Permanently discontinue.
Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8) ]	3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome	• Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose.
	Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions	• Permanently discontinue.
Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9) ]	Any Grade	• Permanently discontinue.
Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10) ]	Any Grade	• Permanently discontinue.
Osteonecrosis of the jaw [see Warnings and Precautions (5.13) ]	Any Grade	• The safety of resumption of SUTENT after osteonecrosis has not been established. • Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction.
Impaired wound healing [see Warnings and Precautions (5.14) ]	Any Grade	• The safety of resumption of SUTENT after resolution of wound healing has not been established. • Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction.

Side Effects of Sutent

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.

Gastrointestinal Stromal Tumor The safety of SUTENT was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received SUTENT 50 mg daily on Schedule 4/2 (n=202) or placebo (n=102). Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the SUTENT arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received SUTENT.

Table 3 summarizes the adverse reactions for Study 1. Table 3. Adverse Reactions Reported in ≥10% of GIST Patients Who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received SUTENT.

Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label SUTENT.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received SUTENT. Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received SUTENT. Advanced Renal Cell Carcinoma The safety of SUTENT was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received SUTENT 50 mg daily on Schedule 4/2 (n=375) or interferon alfa 9 million International Units (MIU) (n=360).

Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received SUTENT. Table 5 summarizes the adverse reactions for Study 3. Table 5.

Table 6. Laboratory Abnormalities Reported in ≥ 1 1 0 Long-Term Safety in RCC The long-term safety of SUTENT in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings. Prolonged treatment with SUTENT did not appear to be associated with new types of adverse reactions.

There appeared to be no increase in the yearly incidence of adverse reactions at later time points. Hypothyroidism increased during the second year of treatment with new cases reported up to year 4. Adjuvant Treatment of RCC The safety of SUTENT was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received SUTENT 50 mg daily on Schedule 4/2 (n=306) or placebo (n=304).

Adverse reactions leading to permanent discontinuation in >2% of patients include hand-foot syndrome and fatigue/asthenia. Table 7 summarizes the adverse reactions in S-TRAC. Table 7.

Advanced Pancreatic Neuroendocrine Tumors The safety of SUTENT was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received SUTENT 37.5 mg once daily (n=83) or placebo (n=82). Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received SUTENT. Table 8 summarizes the adverse reactions in Study 6.

Table 8. Adverse Reactions Reported in ≥10% of Patients With pNET Who Received SUTENT and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study Table 9 summarizes the laboratory abnormalities in Study 6. Table 9.

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 thrombocytopenia including some fatalities. • Gastrointestinal disorders: esophagitis. • Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis. • Immune system disorders: hypersensitivity reactions, including angioedema. • Infections and infestations: serious infection (with or without neutropenia). The infections most commonly observed with SUTENT include respiratory, urinary tract, skin infections, and sepsis/septic shock. • Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression; myopathy and/or rhabdomyolysis with or without acute renal failure. • Renal and urinary disorders: renal impairment and/or failure. • Respiratory disorders: pulmonary embolism, pleural effusion. • Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive de-challenges. • Vascular disorders: arterial (including aortic) aneurysms, dissections, and rupture; arterial thromboembolic events. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction. • General disorders and administration site conditions: impaired wound healing.

Table 3. Adverse Reactions Reported in ≥10% of GIST Patients Who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1
Adverse Reaction	GIST
	SUTENT (N=202)		Placebo (N=102)
	All Grades %	Grade 3–4 %	All Grades %	Grade 3–4 %
Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients.
Any Adverse Reaction	94	56	97	51
Gastrointestinal
Diarrhea	40	4	27	0
Mucositis/stomatitis	29	1	18	2
Constipation	20	0	14	2
Metabolism/Nutrition
Anorexia Includes decreased appetite.	33	1	29	5
Asthenia	22	5	11	3
Dermatology
Skin discoloration	30	0	23	0
Rash	14	1	9	0
Hand-foot syndrome	14	4	10	3
Neurology
Altered taste	21	0	12	0
Cardiac
Hypertension	15	4	11	0
Musculoskeletal
Myalgia/limb pain	14	1	9	1

Table 4. Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1
Laboratory Abnormality	GIST
	SUTENT (N=202)		Placebo (N=102)
	All Grades %	Grade 3–4, Grade 4 laboratory abnormalities in patients on SUTENT included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). %	All Grades %	Grade 3–4, Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%). %
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; GIST=gastrointestinal stromal tumor; LVEF=left ventricular ejection fraction; N=number of patients.
Any Laboratory Abnormality		34		22
Hematology
Neutrophils decreased	53	10	4	0
Lymphocytes decreased	38	0	16	0
Platelets decreased	38	5	4	0
Hemoglobin decreased	26	3	22	2
Gastrointestinal
AST/ALT increased	39	2	23	1
Lipase increased	25	10	17	7
Alkaline phosphatase increased	24	4	21	4
Amylase increased	17	5	12	3
Total bilirubin increased	16	1	8	0
Indirect bilirubin increased	10	0	4	0
Renal/Metabolic
Creatinine increased	12	1	7	0
Potassium decreased	12	1	4	0
Sodium increased	10	0	4	1
Cardiac
Decreased LVEF	11	1	3	0

Table 5. Adverse Reactions Reported in ≥10% of Patients With RCC Who Received SUTENT or Interferon Alfa Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 3
Adverse Reaction	Treatment-Naïve RCC
	SUTENT (N=375)		Interferon Alfa (N=360)
	All Grades %	Grade 3–4 Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). %	All Grades %	Grade 3–4 Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). %
Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.
Any Adverse Reaction	99	77	99	55
Gastrointestinal
Diarrhea	66	10	21	<1
Nausea	58	6	41	2
Mucositis/stomatitis	47	3	5	<1
Vomiting	39	5	17	1
Dyspepsia	34	2	4	0
Abdominal pain Includes flank pain.	30	5	12	1
Constipation	23	1	14	<1
Dry mouth	13	0	7	<1
Oral pain	14	<1	1	0
Flatulence	14	0	2	0
GERD/reflux esophagitis	12	<1	1	0
Glossodynia	11	0	1	0
Hemorrhoids	10	0	2	0
Constitutional
Fatigue	62	15	56	15
Asthenia	26	11	22	6
Fever	22	1	37	<1
Weight decreased	16	<1	17	1
Chills	14	1	31	0
Chest Pain	13	2	7	1
Influenza like illness	5	0	15	<1
Metabolism/Nutrition
Anorexia Includes decreased appetite.	48	3	42	2
Neurology
Altered taste Includes ageusia, hypogeusia, and dysgeusia.	47	<1	15	0
Headache	23	1	19	0
Dizziness	11	<1	14	1
Hemorrhage/Bleeding
Bleeding, all sites	37	4 Includes 1 patient with Grade 5 gastric hemorrhage.	10	1
Cardiac
Hypertension	34	13	4	<1
Edema peripheral	24	2	5	1
Ejection fraction decreased	16	3	5	2
Dermatology
Rash	29	2	11	<1
Hand-foot syndrome	29	8	1	0
Skin discoloration/yellow skin	25	<1	0	0
Dry skin	23	<1	7	0
Hair color changes	20	0	<1	0
Alopecia	14	0	9	0
Erythema	12	<1	1	0
Pruritus	12	<1	7	<1
Musculoskeletal
Pain in extremity/limb discomfort	40	5	30	2
Arthralgia	30	3	19	1
Back pain	28	5	14	2
Respiratory
Cough	27	1	14	<1
Dyspnea	26	6	20	4
Nasopharyngitis	14	0	2	0
Oropharyngeal pain	14	<1	2	0
Upper respiratory tract infection	11	<1	2	0
Endocrine
Hypothyroidism	16	2	1	0
Psychiatric
Insomnia	15	<1	10	0
Depression Includes depressed mood.	11	0	14	1

Table 6. Laboratory Abnormalities Reported in ≥10% of RCC Patients Who Received SUTENT or Interferon Alfa in Study 3
Laboratory Abnormality	Treatment-Naïve RCC
	SUTENT (N=375)		Interferon Alfa (N=360)
	All Grades Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. %	Grade 3–4, Grade 4 laboratory abnormalities in patients on SUTENT included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%). %	All Grades %	Grade 3–4, Grade 4 laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%). %
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; RCC=renal cell carcinoma.
Hematology
Hemoglobin decreased	79	8	69	5
Neutrophils decreased	77	17	49	9
Platelets decreased	68	9	24	1
Lymphocytes decreased	68	18	68	26
Renal/Metabolic
Creatinine increased	70	<1	51	<1
Creatine kinase increased	49	2	11	1
Uric acid increased	46	14	33	8
Calcium decreased	42	1	40	1
Phosphorus decreased	31	6	24	6
Albumin decreased	28	1	20	0
Glucose increased	23	6	15	6
Sodium decreased	20	8	15	4
Glucose decreased	17	0	12	<1
Potassium increased	16	3	17	4
Calcium increased	13	<1	10	1
Potassium decreased	13	1	2	<1
Sodium increased	13	0	10	0
Gastrointestinal
AST increased	56	2	38	2
Lipase increased	56	18	46	8
ALT increased	51	3	40	2
Alkaline phosphatase increased	46	2	37	2
Amylase increased	35	6	32	3
Total bilirubin increased	20	1	2	0
Indirect bilirubin increased	13	1	1	0

Table 7. Adverse Reactions Reported in ≥10% of Patients With RCC Who Received SUTENT and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in S-TRAC
Adverse Reaction	Adjuvant Treatment of RCC
	SUTENT (N=306)		Placebo (N=304)
	All Grades %	Grade 3–4 %	All Grades %	Grade 3–4 %
Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.
Any Adverse Reaction	99	60	88	15
Gastrointestinal
Mucositis/Stomatitis Includes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain.	61	6	15	0
Diarrhea	57	4	22	<1
Nausea	34	2	15	0
Dyspepsia	27	1	7	0
Abdominal pain Includes abdominal pain, abdominal pain lower, and abdominal pain upper.	25	2	9	<1
Vomiting	19	2	7	0
Constipation	12	0	11	0
Constitutional
Fatigue/Asthenia	57	8	34	2
Localized edema Includes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema.	18	<1	<1	0
Pyrexia	12	<1	6	0
Dermatology
Hand-foot syndrome	50	16	10	<1
Rash Includes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic.	24	2	12	0
Hair color changes	22	0	2	0
Skin discoloration/Yellow skin	18	0	1	0
Dry skin	14	0	6	0
Cardiac
Hypertension Includes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis.	39	8	14	1
Edema/Peripheral edema	10	<1	7	0
Neurology
Altered taste Includes ageusia, hypogeusia, and dysgeusia.	38	<1	6	0
Headache	19	<1	12	0
Endocrine
Hypothyroidism/TSH increased	24	<1	4	0
Hemorrhage/Bleeding
Bleeding events, all sites Includes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria.	24	<1	5	<1
Metabolism/Nutrition
Anorexia/Decreased appetite	19	<1	5	0
Musculoskeletal
Pain in extremity	15	<1	7	0
Arthralgia	11	<1	10	0

Table 8. Adverse Reactions Reported in ≥10% of Patients With pNET Who Received SUTENT and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 6
Adverse Reaction	pNET
	SUTENT (N=83)		Placebo (N=82)
	All Grades %	Grade 3–4 Grade 4 adverse reactions in patients on SUTENT included fatigue (1%). %	All Grades %	Grade 3–4 %
Abbreviations: N=number of patients; pNET=pancreatic neuroendocrine tumors.
Any Adverse Reaction	99	54	95	50
Gastrointestinal
Diarrhea	59	5	39	2
Stomatitis/oral syndromes Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth.	48	6	18	0
Nausea	45	1	29	1
Abdominal pain Includes abdominal discomfort, abdominal pain, and abdominal pain upper.	39	5	34	10
Vomiting	34	0	31	2
Dyspepsia	15	0	6	0
Constitutional
Asthenia	34	5	27	4
Fatigue	33	5	27	9
Weight decreased	16	1	11	0
Dermatology
Hair color changes	29	1	1	0
Hand-foot syndrome	23	6	2	0
Rash	18	0	5	0
Dry skin	15	0	11	0
Cardiac
Hypertension	27	10	5	1
Hemorrhage/Bleeding
Bleeding events Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.	22	0	10	4
Epistaxis	21	1	5	0
Neurology
Dysgeusia	21	0	5	0
Headache	18	0	13	1
Psychiatric
Insomnia	18	0	12	0
Musculoskeletal
Arthralgia	15	0	6	0

Table 9. Laboratory Abnormalities Reported in ≥10% of Patients With pNET Who Received SUTENT in Study 6
	pNET
Laboratory Abnormality	SUTENT		Placebo
	All Grades The denominator used to calculate the rate varied from 52 to 82 for SUTENT and 39 to 80 for Placebo based on the number of patients with a baseline value and at least one post-treatment value. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. %	Grade 3–4, Grade 4 laboratory abnormalities in patients on SUTENT included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%), and total bilirubin (1%). %	All Grades %	Grade 3–4, Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%). %
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; N=number of patients; pNET=pancreatic neuroendocrine tumors.
Gastrointestinal
AST increased	72	5	70	3
Alkaline phosphatase increased	63	10	70	11
ALT increased	61	4	55	3
Total bilirubin increased	37	1	28	4
Amylase increased	20	4	10	1
Lipase increased	17	5	11	4
Hematology
Neutrophils decreased	71	16	16	0
Hemoglobin decreased	65	0	55	1
Platelets decreased	60	5	15	0
Lymphocytes decreased	56	7	35	4
Renal/Metabolic
Glucose increased	71	12	78	18
Albumin decreased	41	1	37	1
Phosphorus decreased	36	7	22	5
Calcium decreased	34	0	19	0
Sodium decreased	29	2	34	3
Creatinine increased	27	5	28	5
Glucose decreased	22	2	15	4
Potassium decreased	21	4	14	0
Magnesium decreased	19	0	10	0
Potassium increased	18	1	11	1

Warnings & Cautions for Sutent

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, aspartate aminotransferase, 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.

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 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.

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.

Hypertension In the pooled safety population, 29% of patients experienced hypertension. 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.

Hemorrhagic Events and Viscus Perforation

Hemorrhagic events, some of which were fatal, have involved the gastrointestinal tract, respiratory tract, tumor, urinary tract, and brain. 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. Discontinue SUTENT in patients without resolution of Grade 3 or 4 hemorrhagic events.

Tumor Lysis Syndrome (TLS) 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.

Thrombotic Microangiopathy (TMA) 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.

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.

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.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

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.

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.

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. 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.

Osteonecrosis of the Jaw (ONJ) 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.

Impaired Wound Healing

Impaired wound healing has been reported in patients who received SUTENT. 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.

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 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.

Drug Interactions with Sutent

Effect of Other Drugs on SUTENT Strong CYP3A4 Inhibitors Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations. Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider a dose reduction for SUTENT when it is co-administered with strong CYP3A4 inhibitors.

Strong CYP3A4 Inducers Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations. Consider a dose increase for SUTENT when it must be co-administered with CYP3A4 inducers.

Drugs that Prolong QT Interval SUTENT is associated with QTc interval prolongation. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

Pregnancy Safety for Sutent

Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, SUTENT can 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 developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 and 0.3 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses (RDD) of 50 mg, respectively (see Data ).

Advise females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is respectively. Embryolethality was observed at 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). In embryo-fetal developmental toxicity studies, oral sunitinib was administered to pregnant rats mg/kg/day and rabbits mg/kg/day during the period of organogenesis.

No adverse fetal effects were observed in rats at doses ≤3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg). Sunitinib (0.3, 1, 3 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥1 mg/kg/day (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg).

At 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg), reduced neonate body weights were observed at birth and persisted in the offspring of both sexes during the preweaning period and in males during postweaning period. No adverse developmental effects were observed at doses ≤1 mg/kg/day.

Pediatric Use of Sutent

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. The no-effect level (NOEL) was 1.5 mg/kg/day in monkeys treated intermittently for 8 cycles, but was not identified in monkeys treated continuously for 3 months. Additionally, tooth caries were present in rats at >5 mg/kg.

The incidence and severity of physeal dysplasia were dose related and reversible upon cessation of treatment; however, findings in the teeth were not. In rats, the NOEL in bones was ≤2 mg/kg/day.

Overdosage Information for Sutent

Treatment of overdose with SUTENT should consist of general supportive measures. There is no specific antidote for overdosage with SUTENT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage.

Cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of SUTENT, or without adverse reactions. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection, and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

Clinical Studies of Sutent

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 patients were randomized to the SUTENT arm and 105 patients were randomized to the placebo arm. 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.

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 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.

Figure 1 Study 2 Study 2 was an open-label, multi-center, single-arm, dose-escalation study conducted in patients with GIST following progression on, or intolerance to imatinib. Partial responses (PR) were observed in 5 of 55 patients 9.1% PR rate; 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. The ITT population included 750 patients, 375 randomized to SUTENT and 375 randomized to interferon alfa. Prior treatment included nephrectomy (91% versus 89%) and radiotherapy (14% each arm).

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. 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.

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. Figure 2 Cytokine-Refractory The use of single-agent SUTENT in the treatment of cytokine-refractory RCC was investigated in 2 single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy.

In Study 4 (NCT#00077974), failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by response evaluation criteria in solid tumors (RECIST) or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (interferon alfa, interleukin-2, or interferon alfa plus interleukin-2; patients who were treated with interferon alfa alone must have received treatment for at least 28 days). In Study 5 (NCT#00054886), failure of prior cytokine therapy was defined as disease progression or unacceptable treatment-related toxicity. The endpoint for both studies was ORR.

Duration of response (DR) was also evaluated. One hundred and six patients were enrolled into Study 4 and 63 patients were enrolled into Study 5. Patients received 50 mg SUTENT on Schedule 4/2.

Therapy was continued until the patients met withdrawal criteria or had progressive disease. The baseline age, sex, race, and ECOG performance statuses of the patients were comparable between Studies 4 and 5. Approximately 86%–94% of patients in the 2 studies were White.

Men comprised 65% of the pooled population. The median age was 57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG performance status <2 at the screening visit.

The baseline malignancy and prior treatment history of the patients were comparable between Studies 4 and 5. Across the 2 studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 4 were required to have a histological clear-cell component.

Most patients enrolled in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in Study 4. All patients had received 1 previous cytokine regimen. Metastatic disease present at the time of study entry included lung metastases in 81% of patients.

Patients with known brain metastases or leptomeningeal disease were excluded from both studies. The ORR and DR data from Studies 4 and 5 are provided in Table 12. There were 36 PRs in Study 4 as assessed by a core radiology laboratory for an ORR of There were 23 PRs in Study 5 as assessed by the investigators for an ORR of The majority (>90%) of objective disease responses were observed during the first 4 cycles; the latest reported response was observed in Cycle 10.

Table 12. Objective response rate 34.0 Assessed by blinded core radiology laboratory. 36.5 Assessed by investigators. Duration of response NR Data not mature enough to determine upper confidence limit. 54 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 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.

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 Table 14.

Disease-free Survival by Baseline Disease Characteristics 1.7 0.62 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. Figure 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.

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.

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. 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. Table 15. pNET Efficacy Results from Study 6 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. Figure 4

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-to-tumor progression Time from randomization to progression; deaths prior to documented progression were censored at time of last radiographic evaluation. [median, weeks (95% CI)]	27.3 (16.0, 32.1)	6.4 (4.4, 10.0)	<0.0001 A comparison is considered statistically significant if the p-value is <0.00417 (O'Brien Fleming stopping boundary).	0.33 (0.23, 0.47)
Progression-free survival Time from randomization to progression or death due to any cause. [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 Pearson chi-square test.

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.
Progression-free survival Assessed by blinded core radiology laboratory; 90 patients' scans had not been read at time of analysis. [median, weeks (95% CI)]	47.3 (42.6, 50.7)	22.0 (16.4, 24.0)	<0.000001 A comparison is considered statistically significant if the p-value is <0.0042 (O'Brien Fleming stopping boundary).	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 Pearson chi-square test.	NA

Table 12. Cytokine-Refractory RCC Efficacy Results from Study 4 and Study 5
Efficacy Parameter	Study 4 (N=106)	Study 5 (N=63)
Abbreviations: CI=confidence interval; N=number of patients; NR=not reached; RCC=renal cell carcinoma.
Objective response rate [%, (95% CI)]	34.0 Assessed by blinded core radiology laboratory. (25.0, 43.8)	36.5 Assessed by investigators. (24.7, 49.6)
Duration of response [median, weeks (95% CI)]	NR Data not mature enough to determine upper confidence limit. (42.0, )	54 (34.3, 70.1)

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 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	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.
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 HR based on a Cox proportional hazards model (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
T3 Intermediate 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	35/115	46/112	NR (5.2, NR)	6.4 (4.7, NR)	0.82 (0.53, 1.28)
T3 High T3 High: T3, N0 or NX, M0, Fuhrman's grade ≥ 2, ECOG PS ≥ 1	63/165	79/166	6.8 (5.0, NR)	5.3 (2.9, NR)	0.77 (0.55, 1.07)
T4/Node Positive 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	15/29	19/28	3.5 (1.2, NR)	1.7 (0.4, 3.0)	0.62 (0.31, 1.23)

Table 15. pNET Efficacy Results from Study 6
Efficacy Parameter	SUTENT (N=86)	Placebo (N=85)	p-value	HR (95% CI)
Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NA=not applicable; pNET=pancreatic neuroendocrine tumors.
Progression-free survival [median, months (95% CI)]	10.2 (7.4, 16.9)	5.4 (3.4, 6.0)	0.000146 2-sided unstratified log-rank test.	0.427 (0.271, 0.673)
Objective response rate [%, (95% CI)]	9.3 (3.2, 15.4)	0	0.0066 Fisher's Exact test.	NA

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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