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SUTENT® (sunitinib malate) Slide Kit

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    SUTENT® (sunitinib malate) Slide Kit SUTENT® (sunitinib malate) Slide Kit Presentation Transcript

    • SUTENT ® (sunitinib malate) Slide Kit .
    • Contents
      • Slide
      • Indications 3
      • Dosing 4
      • Mechanism of Action in RCC 6
      • Mechanism of Action in GIST 8
      • SUTENT in RCC 10
      • SUTENT in Imatinib-Resistant or -Intolerant GIST 25
      • Some Strategies for Managing Adverse Reactions 40
      • Important Safety Information 46
    • SUTENT Is Approved for 2 Hard-to-Treat Tumor Types
      • SUTENT is indicated for the treatment of advanced renal cell carcinoma (RCC)
      • SUTENT is also indicated for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate
    • SUTENT Dosing
    • SUTENT Efficacy and Safety Were Demonstrated Using a 50-mg Starting Dose
      • No dose adjustment is recommended based on age, race, gender, body weight, creatinine clearance, ECOG performance status score, or hepatic impairment (Child-Pugh Class A or B)
      SUTENT dose may be easily adjusted in 12.5-mg increments
    • Mechanism of Action in RCC
    • SUTENT Inhibits Multiple Signaling Pathways Resulting in a Dual-Action Antiproliferative and Antiangiogenic Effect 1
      • Overexpression of multiple growth factors drives RCC progression
      1. Data on file. Pfizer Inc. 2. Bergers G, et al. J Clin Invest. 2003;111:1287-1295. 3. Sulzbacher I, et al. Am J Clin Pathol. 2003;120:107-112. 4. Tsuchiya N, et al. Tohoku J Exp Med. 2001;195:101-113 . 5. Mendel DB, et al. Clin Cancer Res. 2003;9:327-337. (Bergers et al 2 ; Sulzbacher et al 3 ; Tsuchiya et al 4 )
      • Sunitinib simultaneously inhibits all known PDGF and VEGF receptors, which play a role in both tumor cell proliferation and angiogenesis
      • Sunitinib induces tumor regression and inhibits angiogenesis and metastatic progression 2,5
      • A correlation between the mechanism of action and the clinical efficacy of SUTENT has not been established.
    • Mechanism of Action in GIST
    • SUTENT Inhibits Multiple Signaling Pathways
      • SUTENT simultaneously inhibits PDGF, VEGF, and KIT receptors for an antiproliferative and antiangiogenic effect 1
      • Sunitinib demonstrated direct antiproliferative activity by inhibiting PDGF  and KIT receptors
      • Sunitinib demonstrated antiangiogenic activity by inhibiting PDGF receptors on pericytes and VEGF receptors on endothelial cells in preclinical studies 2,4
      • In preclinical studies, sunitinib induced tumor regression and inhibited angiogenesis and metastatic progression
      • A correlation between the mechanism of action and the clinical efficacy of SUTENT has not been established.
      1. Data on file. Pfizer Inc. 2. Bergers G, et al. J Clin Invest. 2003;111:1287-1295. 3. Heinrich MC, et al. J Clin Oncol. 2003;21:4342-4349. 4. Mendel DB, et al. Clin Cancer Res . 2003;9:327-337 . (Bergers et al 2 ; Heinrich et al 3 )
    • SUTENT in RCC
    • NCCN Recommends SUTENT for 1st-Line Treatment of Metastatic Renal Cell Carcinoma (mRCC)
      • SUTENT has a category 1 recommendation for 1st-line treatment of patients with predominantly clear-cell mRCC regardless of MSKCC risk group 1 *
      • “… sunitinib has been given category 1 recommendation for first line treatment of patients with relapsed or medically unresectable stage IV renal cancer with predominant clear cell and for non-clear cell histology it is a category 2A recommendation.”
      • — NCCN guidelines v.2.2010
      NCCN = National Comprehensive Cancer Network. *Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups are classified based on 5 prognostic factors that impact survival (poor performance status, high serum lactate dehydrogenase [LDH], low serum hemoglobin, high corrected serum calcium, and time from initial diagnosis to treatment). Favorable risk=0 factors; intermediate risk=1-2 factors; poor risk=≥3 factors. 2 1. National Comprehensive Cancer Network ® . NCCN Clinical Practice Guidelines in Oncology™. Kidney cancer. V.2.2010. 2. Motzer RJ, et al. J Clin Oncol. 2002;20:289-296 .
    • Phase 3, Randomized, Multicenter Trial Compares SUTENT With IFN  as 1st-Line Therapy in mRCC
      • Patient accrual ran from August 2004 through October 2005
      • Data were analyzed at 3 time points
        • First analysis: November 2005
        • Second analysis: June 2007
        • Third analysis: February 2008
      • Primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST), overall survival (OS), patient-reported outcomes, and safety.
      *Efficacy assessed by a blinded core radiology laboratory (independent assessment) . Data on file. Pfizer Inc.
    • Patient Baseline Characteristics Were Well Balanced Between the Arms 1,2 Totals may not equal 100% because of rounding and/or missing data. ECOG = Eastern Cooperative Oncology Group. *Data are missing for 17 patients in the IFN  group. 1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 2. Data on file. Pfizer Inc.
    • Patient Baseline Characteristics Were Well Balanced Between the Arms 1,2 (cont’d)
      • In both treatment arms (SUTENT and IFN  ):
        • The majority of patients were white (94% and 91%)
        • Few patients had previous radiotherapy (14% and 14%)
      Totals may not equal 100% because of rounding and/or missing data. *Data are missing for 17 patients in the IFN  group. † MSKCC risk groups are classified based on 5 prognostic factors that impact survival (poor performance status, high serum LDH, low serum hemoglobin, high corrected serum calcium, and time from initial diagnosis to treatment). Favorable risk=0 factors; intermediate risk=1-2 factors; poor risk=≥3 factors. 1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 2. Data on file. Pfizer Inc.
    • SUTENT More Than Doubled Single-Agent Median PFS vs IFN 
      • Median PFS was 11 months vs 5 months (with IFN  )
      • 58% reduced risk of progression or death (HR=0.42)
      • The median duration of treatment with SUTENT was 11 months (48 weeks) vs 4 months (18 weeks) with IFN  1
      1. Data on file. Pfizer Inc. Progression-Free Survival
    • Median PFS Across MSKCC Risk Groups
      • Factors that constitute these risk groups were prespecified. The PFS efficacy analysis according to these risk factors was analyzed retrospectively. As with any retrospective analysis, there may be interpretive limitations.
      Data on file. Pfizer Inc. Progression-Free Survival by MSKCC Risk Group Favorable (HR=0.476; 95% Cl: 0.329, 0.688) Intermediate (HR=0.538; 95% Cl: 0.415, 0.698) Poor (HR=0.679; 95% Cl: 0.3305, 1.398)
    • SUTENT Achieved a Median OS of Single-Agent More Than 2 Years *Stratification factors: ECOG performance status score, LDH, and prior nephrectomy. Data on file. Pfizer Inc. Overall Survival
    • Poststudy Treatments * P <.0001. Data on file. Pfizer Inc.
      • 6% of the patients in the IFN  arm crossed over to SUTENT during the study; poststudy, 33% of the patients in the IFN  arm received SUTENT
    • 5-Fold Higher Objective Response Rate With SUTENT vs IFN  PR=partial response. Data on file. Pfizer Inc. Objective Response Rates
      • Response was defined by RECIST and assessed by blinded core review at 2 different time points (November 2005 and June 2007)
      (n=375) (n=375) First analysis (n=375) (n=375) Second analysis
    • Treatment-Emergent ARs Reported in ≥10% of Treatment-Naïve mRCC Patients* * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia (<1%), asthenia (<1%), dehydration (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). ‡ Grade 4 ARs in patients on IFNα included dyspnea (1%), fatigue (1%), and depression (<1%). § Includes flank pain.
    • Treatment-Emergent ARs Reported in ≥10% of Treatment-Naïve mRCC Patients* (cont’d) * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia (<1%), asthenia (<1%), dehydration (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). ‡ Grade 4 ARs in patients on IFNα included dyspnea (1%), fatigue (1%), and depression (<1%). § Includes ageusia, hypogeusia, and dysgeusia. || Includes decreased appetite. ¶ Includes one patient with grade 5 gastric hemorrhage. # Includes depressed mood.
    • Laboratory Abnormalities Reported in ≥10% of Treatment-Naïve mRCC Patients* *Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Grade 4 laboratory abnormalities in patients on SUTENT included uric acid (12%), lipase (3%), amylase (1%), neutrophils (1%), ALT (<1%), calcium decreased (<1%), phosphorus (<1%), potassium increased (<1%), sodium decreased (<1%), and hemoglobin (<1%). ‡ Grade 4 laboratory abnormalities in patients on IFN  included uric acid (8%), lipase (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%).
    • Important Safety Information Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Given the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or SUTENT ® (sunitinib malate). Left ventricular ejection fraction declines to below the lower limit of normal have occurred. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies. SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including torsades de pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered. Hypertension may occur. Monitor blood pressure and treat as needed.
    • Important Safety Information (cont’d) There have been rare (<1%) reports of subjects with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None resulted in a fatal outcome. Hemorrhagic events including tumor-related hemorrhage have occurred. Perform serial complete blood counts (CBCs) and physical examinations. In an ongoing clinical trial of patients with metastatic non–small cell lung cancer (NSCLC), fatal pulmonary hemorrhage occurred in 2 patients, both with squamous cell histology. SUTENT is not approved for use in patients with NSCLC. Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice. Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection. CBCs and serum chemistries should be performed at the beginning of each treatment cycle. Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers.
    • SUTENT in Imatinib-Resistant or -Intolerant GIST
    • Routine Monitoring and Imaging Are Essential to Identifying Disease Progression in Patients With GIST
      • Medical imaging is currently the best method for assessing response to therapy and detecting disease progression in patients with GIST 1-4
      • However, assessing response using current criteria and technology can still be challenging 3-5
      1. Therasse P, et al. J Natl Cancer Inst . 2000;92:205-216. 2. Cancer Therapy Evaluation Program, NCI. Response Evaluation Criteria in Solid Tumors (RECIST) quick reference. 3. Choi H, et al. J Clin Oncol. 2007;25:1753-1759. 4. Demetri GD. Cancer: Principles & Practice of Oncology. 7th ed. 2004:1050-1060. 5. Blay J-Y, et al. Ann Oncol. 2005;16:566-578. 6. National Comprehensive Cancer Network ® . NCCN Clinical Practice Guidelines in Oncology™. Soft tissue sarcoma. V.2.2008. 7. Phongkitkarun S, et al. World J Gastroenterol. 2008;14:892-898. 8. Benjamin RS, et al. J Clin Oncol. 2007;25:1760-1764. 9. Boyar MS, Taub RN. Cancer Invest. 2007;25:328-335.
    • Routine Monitoring and Imaging Are Essential to Identifying Disease Progression in Patients With GIST
      • Primary resistance to imatinib occurs in up to 14% of patients with GIST 2-10
        • Primary resistance is defined as disease progression within 6 months of imatinib treatment 8,9,11-14
      • Secondary resistance to imatinib occurs in more than 40% of patients with GIST 3,5,6,8,9,12
        • Secondary resistance is defined as initial benefit from imatinib treatment followed by disease progression after 6 months and occurs after a median duration of response of 29 months and a median overall time to tumor progression of 24 months (400- and 600-mg dosing groups) 11,12,15
      • About 5% of patients with GIST are intolerant of imatinib therapy 16
      • When disease progression or intolerance to imatinib occurs, imatinib therapy may no longer be appropriate 1
      1. National Comprehensive Cancer Network ® . NCCN Clinical Practice Guidelines in Oncology™. Soft tissue sarcoma. V.2.2008. 2. Boyar MS, Taub RN. Cancer Invest. 2007;25:328-335. 3. Verweij J, et al. Lancet. 2004;364:1127-1134. 4. Demetri GD, et al. N Engl J Med. 2002;347:472-480. 5. Antonescu CR, et al. Clin Cancer Res. 2005;11:4182-4190. 6. Siddiqui MA, Scott LJ. Drugs. 2007;67:805-820. 7. Sciot R, Debiec-Rychter M. Semin Diagn Pathol. 2006;23:84-90. 8. Sleijfer S, et al. Oncologist. 2007;12:719-726. 9. Van Glabbeke M, et al. J Clin Oncol. 2005;23:5795-5804. 10. Connolly EM, et al. Br J Surg. 2003;90:1178-1186. 11. Blay J-Y, et al. Ann Oncol. 2005;16:566-578. 12. Heinrich MC, et al. J Clin Oncol. 2006;24:4764-4774. 13. Badalamenti G, et al. Ann Oncol. 2007;18(suppl 6):vi136-vi140. 14. Rubin BP, Duensing A. Lab Invest. 2006;86:981-986. 15. Blanke CD, et al. J Clin Oncol . 2008;26:620-625. 16. Gleevec [package insert]. 2007. Some patients are intolerant of or develop primary resistance to imatinib, while others may develop secondary resistance 1
    • Understanding Primary and Secondary Mutations in GIST
      • Exons are genetic segments containing sequences that code for proteins, such as KIT and PDGFR  1
      • Exon mutations can result in structurally and functionally abnormal receptors that can lead to continual (“constitutive”) activation and tumor development 2,3
      • A primary mutation refers to a mutation that occurs prior to GIST treatment 4-6
      • A secondary mutation refers to a mutation that occurs in addition to the primary mutation and emerges during the course of treatment 4-6
      1. National Institutes of Health National Human Genome Research Institute glossary. 2. Demetri GD. Cancer: Principles & Practice of Oncology. 7th ed. 2004:1050-1060. 3. National Library of Medicine. Your guide to understanding genetic conditions. 4. Antonescu CR, et al. Clin Cancer Res. 2005;11:4182-4190. 5. Heinrich MC, et al. J Clin Oncol. 2006;24:4764-4774. 6. Lasota J, Miettinen M. Histopathology . 2008;53:245-266.
    • Primary Mutations in KIT or PDGFR  Are Common in Patients With GIST 1. Corless CL, et al . J Clin Oncol. 2004;22:3813-3825. 2. Heinrich MC, et al. J Clin Oncol. 2003;21:4342-4349. 3. Debiec-Rychter M, et al. Eur J Cancer 2006;42:1093-1103. 4. Hopkins TG, et al. Eur J Surg Oncol. 2008;34:844-850. 5. Braconi C, et al. Ann Oncol. 2008;19:706-710. 6. Corless CL, et al. J Clin Oncol. 2005;23:5357-5364. 7. Steigen SE, et al. APMIS. 2007;115:289-298. 8. De Giorgi U, Verweij J. Mol Cancer Ther. 2005;4:495-501. 9. Antonescu CR, et al. Clin Cancer Res. 2005;11:4182-4190.
    • Receptor Mutations Are Common in Patients With GIST and Can Lead to the Development of Drug Resistance
      • Primary resistance is commonly associated with primary exon 9 mutations in patients with GIST 1-5 *
      • Secondary resistance is commonly associated with primary exon 11 mutations in patients with GIST 2,3,5-8†
      • Secondary resistance is associated with the emergence of secondary mutations
        • In one study (N=43), 67% of patients who developed secondary resistance had secondary mutations 2
      *Defined as disease progression within 6 months of imatinib treatment. 1-4,9,10 † Defined as initial benefit from imatinib treatment followed by disease progression after 6 months and occurs after a median duration of response of 29 months and a median time to tumor progression of 24 months (400- and 600-mg dosing groups). 2,9,11 1. Sleijfer S, et al. Oncologist. 2007;12:719-726. 2. Heinrich MC, et al. J Clin Oncol. 2006;24:4764-4774. 3. Badalamenti G, et al. Ann Oncol. 2007;18(suppl 6):vi136-vi140. 4. Rubin BP, Duensing A. Lab Invest. 2006;86:981-986. 5. De Giorgi U, Verweij J. Mol Cancer Ther. 2005;4:495-501. 6. Wardelmann E, et al. Clin Cancer Res. 2006;12:1743-1749. 7. Fletcher JA, Rubin BP. Curr Opin Genet Dev. 2007;17:3-7. 8. Antonescu CR, et al. Clin Cancer Res. 2005;11:4182-4190. 9. Blay J-Y, et al. Ann Oncol. 2005;16:566-578. 10. Van Glabbeke M, et al. J Clin Oncol. 2005;23:5795-5804. 11. Blanke CD, et al. J Clin Oncol . 2008;26:620-625.
    • Primary and Secondary Mutations Are Associated With the Development of Resistance 1-6 1. Antonescu CR, et al. Clin Cancer Res. 2005;11:4182-4190. 2. Sleijfer S, et al. Oncologist. 2007;12:719-726. 3. Heinrich MC, et al. J Clin Oncol. 2006;24:4764-4774. 4. Lasota J, Miettinen M. Histopathology. 2008;53:245-266. 5. Wardelmann E, et al. Clin Cancer Res. 2006;12:1743-1749. 6. Wardelmann E, et al. Lancet Oncol. 2005;6:249-251.
    • Phase 3, Randomized, Multicenter Trial Evaluated SUTENT in the Treatment of Imatinib-Resistant or -Intolerant GIST
      • Primary endpoint
      • Time to tumor progression (TTP)
      • Secondary endpoints
      • Progression-free survival
      • Objective response rate
      • Overall survival
      • Clinical benefit rate
      • Duration of response
      *Starting dosage was 50 mg once daily, 4 weeks on/2 weeks off. Patients received SUTENT or placebo + best supportive care. Data on file. Pfizer Inc.
    • Patient Characteristics Were Well-Balanced Between the Arms *Total does not equal 100% due to rounding. † n = 205. 1. Data on file. Pfizer Inc.
    • 4-Fold Increase in TTP and a 67% Reduced Risk of Progression
      • Duration of PFS was consistent with TTP
      • 67% reduced risk of progression
      • Significant improvement in PFS for SUTENT (24.1 weeks [5.6 months]) vs placebo (6 weeks [1.4 months]) (hazard ratio=0.33; 95% CI: 0.24, 0.47; P <.0001)
      • OS data were not mature at the time of this analysis
      Time to Tumor Progression
    • Consistent Efficacy Across Patient Subgroups Data on file. Pfizer Inc. Risk of Progression Across Patient Subgroups Diagnosis ≥6 months = initial diagnosis of GIST made at least 6 months prior to initiation of SUTENT. Subgroup analysis of baseline factors was evaluated using Cox proportional hazards analysis.
    • Treatment-Emergent ARs (≥10%) With SUTENT and More Common Than With Placebo* *Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † Includes decreased appetite. Oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on SUTENT versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on SUTENT versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on SUTENT versus 2 (2%) on placebo.
    • Treatment-Emergent Laboratory Abnormalities (≥10%) With SUTENT or Placebo* LVEF = left ventricular ejection fraction. *Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. † 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%). ‡ Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).
    • Important Safety Information Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Given the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or SUTENT ® (sunitinib malate). Left ventricular ejection fraction declines to below the lower limit of normal have occurred. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies. SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including torsades de pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered. Hypertension may occur. Monitor blood pressure and treat as needed. There have been rare (<1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None resulted in a fatal outcome. Hemorrhagic events including tumor-related hemorrhage have occurred. Perform serial complete blood counts (CBCs) and physical examinations. In an ongoing clinical trial of patients with metastatic non–small cell lung cancer (NSCLC), fatal pulmonary hemorrhage occurred in 2 patients, both with squamous cell histology. SUTENT is not approved for use in patients with NSCLC. Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice.
    • Important Safety Information (cont’d) Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection. CBCs and serum chemistries should be performed at the beginning of each treatment cycle. Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers.
    • Some Strategies Used in Clinical Trials for Managing SUTENT Adverse Reactions
    • Few Patients Discontinued Therapy Due to ARs *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.
    • Patient Management Strategies for Hypertension in the SUTENT Phase 3 Clinical Trial
      • Hypertension may occur. Monitor blood pressure and treat as needed
      *Imatinib-resistant or -intolerant. Data on file. Pfizer Inc. Patient management strategies for hypertension included:
      • Incidence of severe (>200 mm Hg systolic or 110 mm Hg diastolic) hypertension
        • mRCC trial: SUTENT vs IFN  (5% vs 1%)
        • GIST* trial: SUTENT vs placebo (4% vs 1%)
      • Incidence of hypertension
        • mRCC trial: SUTENT vs IFN  (all grades: 30% vs 4%; grade 3/4: 10% vs <1%)
        • GIST* trial: SUTENT vs placebo (all grades: 15% vs 11%; grade 3/4: 4% vs 0%)
    • Patient Management Strategies for Hypothyroidism in the SUTENT Phase 3 Clinical Trial
      • Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice
      *Imatinib-resistant or -intolerant. † Recurring grade 3 toxicity requires SUTENT dose reduction. 1. Data on file. Pfizer Inc. 2. Desai J, et al. Ann Intern Med . 2006;145:660-664. Patient management strategies for hypothyroidism included:
      • Incidence of hypothyroidism 1
        • mRCC trial: SUTENT vs IFN  (all grades: 3% vs <1%; no grade 3/4)
        • GIST* trial: SUTENT vs placebo (all grades: 4% vs 1%; grade 3/4: <1% vs 0%)
      • Hypothyroidism has been effectively managed 2†
        • All patients receiving hormone-replacement therapy effectively normalized their serum thyroid-stimulating hormone (sTSH) in a subset of patients from a phase 1/2 GIST* trial
    • Some Patient Management Strategies for Hand-Foot Syndrome *Recurring grade 3 toxicity requires SUTENT dose reduction. † There is no classification of grade 4 hand-foot syndrome in the Common Terminology Criteria for Adverse Events. 3 1. Data on file. Pfizer Inc. 2. American Society of Clinical Oncology (ASCO ® ). People Living With Cancer Web site. Managing side effects: hand-foot syndrome (palmar-plantar erythrodysesthesia). 3. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). August 9, 2006. Additional recommendations The American Society of Clinical Oncology (ASCO ® ) suggests preventing or managing symptoms by 2 :
          • Avoiding prolonged exposure of hands and feet to hot water or other heat sources
          • Avoiding activities that cause unnecessary force or friction on the feet
          • Cooling hands and feet with ice packs or cool compresses in 15- to 20-minute intervals
          • Elevating hands and feet when sitting or lying down
          • Applying mild skin-care creams
      Patient management strategies for hand-foot syndrome used in the SUTENT phase 3 clinical trial included 1 :
    • Some Patient Management Strategies for Fatigue *Recurring grade 3 toxicity requires SUTENT dose reduction. 1. Data on file. Pfizer Inc. 2. National Comprehensive Cancer Network ® (NCCN). Clinical Practice Guidelines in Oncology™. Cancer-related fatigue. V.1.2008. 3. Wood LS. Community Oncol . 2006;3:558-562. Additional recommendations National Comprehensive Cancer Network ® (NCCN) and current literature recommend ruling out and/or treating potential underlying causes or contributing factors, including 2,3 : Patient management strategies for fatigue used in the SUTENT phase 3 clinical trial included 1 :
          • Anemia
          • Nutrition (anorexia, gastrointestinal problems)
          • Pain
          • Depression/emotional distress
          • Sleep disturbances
          • Hypothyroidism
          • Patient activity level
          • Other medications (including over-the-counter and herbal products)
    • Important Safety Information Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. Given the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or SUTENT ® (sunitinib malate). Left ventricular ejection fraction declines to below the lower limit of normal have occurred. Monitor patients for signs and symptoms of congestive heart failure (CHF) and, in the presence of clinical manifestations, discontinuation is recommended. Patients who presented with cardiac events, pulmonary embolism, or cerebrovascular events within the previous 12 months were excluded from clinical studies. SUTENT has been shown to prolong QT interval in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including torsades de pointes, which has been seen in <0.1% of patients. Monitoring with on-treatment electrocardiograms and electrolytes should be considered. Hypertension may occur. Monitor blood pressure and treat as needed. There have been rare (<1%) reports of subjects with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None resulted in a fatal outcome. Hemorrhagic events including tumor-related hemorrhage have occurred. Perform serial complete blood counts (CBCs) and physical examinations. In an ongoing clinical trial of patients with metastatic non–small cell lung cancer (NSCLC), fatal pulmonary hemorrhage occurred in 2 patients, both with squamous cell histology. SUTENT is not approved for use in patients with NSCLC. Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice. Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress such as surgery, trauma, or severe infection.
    • Important Safety Information (cont’d)
      • CBCs and serum chemistries should be performed at the beginning of each treatment cycle.
      • Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers.
      • The most common ARs occurring in ≥20% of patients receiving SUTENT for treatment-naïve metastatic RCC (all grades, vs IFN  ) were fatigue (58% vs 55%), diarrhea (58% vs 20%), nausea (49% vs 38%), altered taste (44% vs 14%), mucositis/stomatitis (43% vs 4%), anorexia (38% vs 40%), bleeding, all sites (30% vs 8%), hypertension (30% vs 4%), vomiting (28% vs 14%), dyspepsia (28% vs 4%), rash (27% vs 11%), abdominal pain (22% vs 12%), asthenia (21% vs 24%), and hand-foot syndrome (21% vs 1%). The most common grade 3/4 ARs (occurring in ≥5% of SUTENT patients) were hypertension (10% vs <1%), fatigue (9% vs 14%), asthenia (7% vs 6%), diarrhea (6% vs 0%), and hand-foot syndrome (5% vs 0%).
      • The most common grade 3/4 lab abnormalities occurring in ≥8% of patients with treatment-naïve metastatic RCC receiving SUTENT (vs IFN  ) included lipase (16% vs 6%), uric acid (12% vs 8%), neutrophils (12% vs 7%), lymphocytes (12% vs 22%), and platelets (8% vs 0%).
      • The most common ARs occurring in ≥20% of patients with GIST and more commonly with SUTENT than placebo (all grades, vs placebo) were diarrhea (40% vs 27%), anorexia (33% vs 29%), skin discoloration (30% vs 23%), mucositis/stomatitis (29% vs 18%), asthenia (22% vs 11%), altered taste (21% vs 12%), and constipation (20% vs 14%). The most common grade 3/4 ARs (occurring in ≥4% of SUTENT patients) were asthenia (5% vs 3%), hand-foot syndrome (4% vs 3%), diarrhea (4% vs 0%), and hypertension (4% vs 0%).
      • The most common grade 3/4 lab abnormalities occurring in ≥5% of patients with GIST receiving SUTENT (vs placebo) included lipase (10% vs 7%), neutrophils (10% vs 0%), amylase (5% vs 3%), and platelets (5% vs 0%).
      SUU00237BJ © 2009 Pfizer Inc. All rights reserved. October 2009 Please see full prescribing information.