SUTENT® (sunitinib malate) Slide Kit

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  • The dose of SUTENT may be adjusted in 12.5-mg increments in any patient, based on individual safety and tolerability.
    Dose adjustments are recommended when administered with CYP3A4 inhibitors or inducers.*
    Patients should not take St. John’s Wort while taking SUTENT
    Patients should not eat grapefruit or drink grapefruit juice while taking SUTENT
  • RCC is a high PDGF- and VEGF-expressing tumor
    RCC comprises approximately 85% of all kidney cancers1
    Individuals with von Hippel-Lindau (VHL) disease are at increased risk of developing RCC. The most common mutations in clear-cell RCC are in the VHL gene2
    The VHL protein plays an important role in the regulation of cell growth of human kidney cells and regulates hypoxia-inducible factors (HIFs)3
    In the absence of normal VHL function, hypoxia-inducible factor alpha (HIF) accumulates3
    This leads to transcription and overexpression of numerous targets, including PDGF and VEGF4
    PDGF=platelet-derived growth factor; VEGF=vascular endothelial growth factor.
    Slide references: 1. Data on file. Pfizer Inc, New York, NY. 2. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287-1295. 3. Sulzbacher I, Birner P, Träxler M, Marberger M, Haitel A. Expression of platelet-derived growth factor- receptor is associated with tumor progression in clear cell renal cell carcinoma. Am J Clin Pathol. 2003;120:107-112. 4. Tsuchiya N, Sato K, Akao T, et al. Quantitative analysis of gene expressions of vascular endothelial growth factor-related factors and their receptors in renal cell carcinoma. Tohoku J Exp Med. 2001;195:101-113. 5. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9:327-337.
    Notes references: 1. Motzer RJ, ed. Advances in the treatment of renal cell carcinoma [CME]. Gainesville, Fla: University of Florida College of Medicine; 2004. 2. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor–targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23:1028-1043. 3. Cockman ME, Masson N, Mole DR, et al. Hypoxia inducible factor- binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem. 2000;275:25733-25741. 4. Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Negative regulation of hypoxia-inducible genes by the von Hippel-Lindau protein. Proc Natl Acad Sci U S A. 1996;93:10595-10599.
  • KIT or platelet-derived growth factor receptor alpha (PDGFR) mutations have been observed in 93% of patients with GIST1
    KIT normally regulates cell proliferation; mutations can therefore drive unregulated proliferation and tumor growth2
    PDGFR mutations have similar biological consequences as KIT mutations and can drive GIST progression3
    Slide references: 1. Data on file. Pfizer Inc, New York, NY. 2. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelialcells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287-1295.3. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349.4. Mendel DB, Laird AD, Xin X, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship.Clin Cancer Res. 2003;9:327-337.
    Notes references: 1. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349. 2. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-580. 3. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-710.
  • Slide references: 1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™. Kidney cancer. V.1.2009. Available at: http://www.nccn.org. Accessed October 1, 2008. 2. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-296.
  • Patients were treated with either 50-mg SUTENT once daily in cycles of 4 weeks on/2 weeks off, or 9 MIU IFN 3 times per week (administered subcutaneously) until disease progression or study withdrawal.
    Primary endpoint
    Progression-free survival (PFS)
    Secondary endpoints
    Overall survival (OS)
    Objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
    Patient-reported outcomes
    Safety
    Slide and notes reference: Data on file. Pfizer Inc, New York, NY.
  • Slide references: 1. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124. 2. Data on file. Pfizer Inc, New York, NY.
  • Slide references: 1. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124. 2. Data on file. Pfizer Inc, New York, NY.
  • Median PFS was reached at the first analysis (November 2005).
    All scans were confirmed by an independent central review committee.
    Slide reference: 1. Data on file. Pfizer Inc, New York, NY.
  • Slide reference: Data on file. Pfizer Inc, New York, NY.
  • Median OS was event driven and met at the third analysis (February 2008).
    Both the stratified and unstratified analyses were preplanned; however, the unstratified analysis was the primary analysis specified in the statistical analysis plan.
    At the time of the third analysis (February 2008), 52 patients (14%) remained on assigned treatment with SUTENT vs 6 patients (2%) with IFN.
    Slide and notes reference: Data on file. Pfizer Inc, New York, NY.
  • Poststudy treatments refer to any therapy that patients received after discontinuing the study; this includes 2nd- and later-line therapies, as well as SUTENT and IFN.
    Although it is possible that later lines of therapy may have had an impact on overall survival, no conclusions may be made regarding this impact.
    The only significant difference in treatment between the 2 arms poststudy was the percentage who received SUTENT (P<.0001).
    Slide and notes reference: Data on file. Pfizer Inc, New York, NY.
  • Response was defined by RECIST. RECIST defines partial response (PR) as a ≥30% decrease from baseline in the sum of the longest diameter of target lesions; stable disease (SD) as insufficient tumor shrinkage for PR but <20% increase for progressive disease (PD) in the smallest sum of the longest diameter of target lesions from baseline since the treatment started; PD as a ≥20% increase in the sum of the longest diameter of target lesions from the smallest sum of the longest diameter of target lesions recorded since the treatment started, or the appearance of one or more new lesions.1
    No patients achieved a complete response (CR) in either study arm.2
    Objective response rate (ORR) = CR + PR
    Ninety patients’ scans had not been read at the time of the first analysis.2
    Slide reference: Data on file. Pfizer Inc, New York, NY.
    Notes references: 1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205-216.2. Data on file. Pfizer Inc, New York, NY.
  • Data are based on the first analysis (November 2005).
    The most common grade 3/4 ARs (occurring in ≥5% of SUTENT patients vs IFN, respectively) were hypertension (10% vs <1%), fatigue (9% vs 14%), asthenia (7% vs 6%), diarrhea (6% vs 0%), and hand-foot syndrome (5% vs 0%).
    Patient management strategies included:
    Supportive therapy, temporary dose interruption, and dose adjustment
  • Data are based on the first analysis (November 2005).
    Few patients discontinued therapy due to treatment-emergent ARs
    The rates of treatment-emergent, nonfatal ARs resulting in permanent discontinuation for SUTENT vs IFN were 9% vs 12%, respectively
    The most common grade 3/4 ARs (occurring in ≥5% of SUTENT patients vs IFN, respectively) were hypertension (10% vs <1%), fatigue (9% vs 14%), asthenia (7% vs 6%), diarrhea (6% vs 0%), and hand-foot syndrome (5% vs 0%).
    Patient management strategies included:
    Supportive therapy, temporary dose interruption, and dose adjustment
    Rates of dose interruption for SUTENT vs IFN were 38% vs 32%, respectively
    Rates of dose reduction for SUTENT vs IFN were 32% vs 21%, respectively
  • The most common grade 3/4 lab abnormalities (occurring in ≥8% of SUTENT patients vs IFN respectively) were lipase (16% vs 6%), uric acid (12% vs 8%), neutrophils (12% vs 7%), lymphocytes (12% vs 22%), and platelets (8% vs 0%).
  • Slide references: 1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205-216. 2. Cancer Therapy Evaluation Program, NCI. Response Evaluation Criteria in Solid Tumors (RECIST) quick reference. Available at: http://ctep.cancer.gov/guidelines/recist.html. Accessed April 16, 2008. 3. Choi H, Charnsangavej C, Faria SC. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753-1759. 4. Demetri GD. Gastrointestinal stromal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins. 2004:1050-1060. 5. Blay J-Y, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors: report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol. 2005;16:566-578. 6. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™. Soft tissue sarcoma. V.2.2008. Available at: http://www.nccn.org. Accessed September 22, 2008. 7. Phongkitkarun S, Phaisanphrukkun C, Jatchavala J, Sirachainan E. Assessment of gastrointestinal stromal tumors with computed tomography following treatment with imatinib mesylate. World J Gastroenterol. 2008;14:892-898.8. Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST.J Clin Oncol. 2007;25:1760-1764. 9. Boyar MS, Taub RN. New strategies for treating GIST when imatinib fails. Cancer Invest. 2007;25:328-335.
  • The NCCN GIST guidelines (v.2.2008) include treatment with SUTENT after both limited and widespread disease progression in patients on imatinib.
    Slide references: 1. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™. Soft tissue sarcoma. V.2.2008. Available at: http://www.nccn.org. Accessed September 22, 2008.2. Boyar MS, Taub RN. New strategies for treating GIST when imatinib fails. Cancer Invest. 2007;25:328-335.3. Verweij J, Casali PG, Zalcberg J, et al, for the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group, and the Australasian Gastrointestinal Trials Group. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127-1134. 4. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480. 5. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182-4190.6. Siddiqui MAA, Scott LJ. Imatinib: a review of its use in the management of gastrointestinal stromal tumours. Drugs. 2007;67:805-820. 7. Sciot R, Debiec-Rychter M. GIST under imatinib therapy. Semin Diagn Pathol. 2006;23:84-90. 8. Sleijfer S, Wiemer E, Seynaeve C, Verweij J. Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment. Oncologist. 2007;12:719-726. 9. Van Glabbeke M, Verweij J, Casali PG, et al. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer—Italian Sarcoma Group—Australasian Gastrointestinal Trials Group study. J Clin Oncol. 2005;23:5795-5804. 10. Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumors.Br J Surg. 2003;90:1178-1186. 11. Blay J-Y, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors: report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol. 2005;16:566-578. 12. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764-4774.13. Badalamenti G, Rodolico V, Fulfaro F, et al. Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features. Ann Oncol. 2007;18(suppl 6):vi136-vi140. 14. Rubin BP, Duensing A. Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest. 2006;86:981-986. 15. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620-625. 16. Gleevec [package insert].East Hanover, NJ: Novartis Pharmaceuticals Corp; 2008.
    Notes reference: National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™. Soft tissue sarcoma. V.2.2008. Available at: http://www.nccn.org. Accessed September 22, 2008.
  • Slide references: 1. National Institutes of Health National Human Genome Research Institute glossary. Available at: http://www.genome.gov. Accessed March 21, 2008. 2. Demetri GD. Gastrointestinal stromal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins. 2004:1050-1060.3. National Library of Medicine. Your guide to understanding genetic conditions. Available at: http://ghr.nlm.nih.gov/glossary. Accessed March 21, 2008. 4. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182-4190. 5. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764-4774. 6. Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008;53:245-266.
  • Slide references: 1. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22:3813-3825. 2. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349. 3. Debiec-Rychter M, Sciot R, Le Cesne A, et al, on behalf of the EORTC Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group, and the Australasian Gastrointestinal Trials Group. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42:1093-1103. 4. Hopkins TG, Marples M, Stark D. Sunitinib in the management of gastrointestinal stromal tumours (GISTs). Eur J Surg Oncol. 2008;34:844-850.5. Braconi C, Bracci R, Bearzi I, et al. KIT and PDGFR mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study. Ann Oncol. 2008;19:706-710. 6. Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357-5364. 7. Steigen SE, Eide TJ, Wasag B, Lasota J, Miettinen M. Mutations in gastrointestinal stromal tumors—a population-based study from Northern Norway. APMIS. 2007;115:289-298. 8. De Giorgi U, Verweij J. Imatinib and gastrointestinal stromal tumors: where do we go from here? Mol Cancer Ther. 2005;4:495-501.9. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182-4190.
  • Slide references: 1. Sleijfer S, Wiemer E, Seynaeve C, Verweij J. Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment. Oncologist. 2007;12:719-726. 2. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764-4774. 3. Badalamenti G, Rodolico V, Fulfaro F, et al. Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features. Ann Oncol. 2007;18(suppl 6):vi136-vi140. 4. Rubin BP, Duensing A. Mechanisms of resistance to small molecule kinase inhibition in the treatment of solid tumors. Lab Invest. 2006;86:981-986. 5. De Giorgi U, Verweij J. Imatinib and gastrointestinal stromal tumors: where do we go from here? Mol Cancer Ther. 2005;4:495-501.6. Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006;12:1743-1749. 7. Fletcher JA, Rubin BP. KIT mutations in GIST. Curr Opin Genet Dev. 2007;17:3-7. 8. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182-4190. 9. Blay J-Y, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors: report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol. 2005;16:566-578. 10. Van Glabbeke M, Verweij J, Casali PG, et al. Initial and late resistance to imatinib in advanced gastrointestinal stromal tumors are predicted by different prognostic factors: a European Organisation for Research and Treatment of Cancer—Italian Sarcoma Group—Australasian Gastrointestinal Trials Group study. J Clin Oncol. 2005;23:5795-5804. 11. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620-625.
  • Slide references: 1. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182-4190. 2. Sleijfer S, Wiemer E, Seynaeve C, Verweij J. Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatment. Oncologist. 2007;12:719-726. 3. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764-4774. 4. Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008;53:245-266. 5. Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006;12:1743-1749. 6. Wardelmann E, Thomas N, Merkelbach-Bruse S, et al. Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol. 2005;6:249-251.
  • In a multicenter, double-blind, placebo-controlled study, 312 patients with imatinib-resistant or -intolerant GIST were randomized 2:1 to receive either SUTENT (50 mg once daily in cycles of 4 weeks on/2 weeks off) or placebo.
    Selected inclusion criteria1
    Histologically confirmed GIST
    Malignant and unresectable
    GIST following:
    Disease progression during treatment with imatinib (based on RECIST or World Health Organization criteria)
    Protocol did not require patients with disease progression to have a specific imatinib dose
    Intolerance to imatinib therapy
    ECOG performance status score 0 or 1
    Adequate organ function
    Slide and notes reference: 1. Data on file. Pfizer Inc, New York, NY.
  • Slide reference: 1. Data on file. Pfizer Inc, New York, NY.
  • OS data were not mature at the time of this analysis
    The Data Safety Monitoring Board unblinded the phase 3 trial early due to clear emerging benefit.
    Efficacy and safety endpoints were met at the first planned analysis (performed after 149 TTP events had occurred).
    All patients taking placebo were offered the option to immediately cross over to SUTENT
  • SUTENT demonstrated significant clinical efficacy regardless of prior imatinib dose, duration of prior imatinib treatment, age, or ECOG performance status score.
    7% of patients achieved partial response (95% CI: 3.7, 11.1).
    Median duration of response was 29.9 weeks (6.9 months)
    Slide and notes reference: Data on file. Pfizer Inc, New York, NY.
  • 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 laboratory abnormalities occurring in 5% of patients receiving SUTENT (vs placebo) included lipase (10% vs 7%), neutrophils (10% vs 0%), amylase (5% vs 3%), and platelets (5% vs 0%).
    Dose interruptions occurred in 59 patients (29%) on SUTENT and in 31 patients (30%) on placebo
    Dose reductions occurred in 23 patients (11%) on SUTENT and in none on placebo
  • Few patients in the mRCC and GIST trials discontinued therapy due to treatment-emergent ARs
    The rates of treatment-emergent, nonfatal ARs resulting in permanent discontinuation were:
    mRCC trial: 9% vs 12% for SUTENT vs IFN
    GIST trial: 7% vs 6% for SUTENT vs placebo
    Dose interruptions and dose reductions may have helped prevent treatment discontinuations
  • Hypertension is commonly associated with angiogenesis inhibitors.1
    Discontinuation of therapy due to hypertension in SUTENT clinical trials2:
    mRCC trial: SUTENT vs IFN (<1% vs 0%)
    Few patients had a dose interruption or reduction (4% vs 0%, respectively)
    GIST trial: SUTENT vs placebo (no patients discontinued therapy)
    Few patients had a dose interruption or reduction (1% vs 0%, respectively)
    Grade Descriptions*
    Grade 1. Asymptomatic OR transient (<24 hours) increase of >20 mm Hg (diastolic) OR >150/100 mm Hg if previously within normal limits (WNL)
    Grade 2. Recurrent or persistent (≥24 hours) OR symptomatic increase of >20 mm Hg (diastolic) OR >150/100 mm Hg if previously WNL
    Grade 3. Requiring more than 1 drug or more intensive therapy than previously
    Grade 4. Life-threatening (eg, hypertensive crisis)
    Additional Considerations
    Patients treated with SUTENT should be monitored for hypertension and treated as necessary with standard antihypertensive therapy.
    Consider current guidelines for hypertension treatment from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC)
    Slide and notes references: 1. Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006;24:1363-1369. 2. Data on file. Pfizer Inc, New York, NY.
  • No patients in SUTENT phase 3 clinical trials had a dose interruption or reduction due to hypothyroidism.1
    Grade Descriptions*
    Grade 1. Asymptomatic
    Grade 2. Symptomatic, not interfering with activities of daily living (ADL)
    Grade 3. Symptoms interfering with ADL
    Grade 4. Life-threatening myxedema coma
    Additional Considerations
    Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms of hypothyroidism or hyperthyroidism and treat per standard medical practice.
    Baseline laboratory measurement of thyroid function is recommended
    Routine monitoring was suggested in clinical trials of SUTENT (every 2 or 3 months, and at increased frequency of monitoring if sTSH is abnormal)2
    Hormone replacement may be initiated as per standard medical practice
    Slide and notes references: 1. Data on file. Pfizer Inc, New York, NY. 2. Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med. 2006;145:660-664.
  • Incidence of Hand-Foot Syndrome1
    mRCC trial: SUTENT vs IFN (all grades: 21% vs 1%; grade 3/4: 5% vs 0%)
    GIST* trial: SUTENT vs placebo (all grades: 14% vs 10%; grade 3/4: 4% vs 3%)
    mRCC trial: SUTENT vs IFN
    Few patients had a dose interruption or reduction (3.7% vs 0%, respectively)
    GIST* trial: SUTENT vs placebo
    Few patients had a dose interruption or reduction (3% vs 0%, respectively)
    Grade Descriptions†
    Grade 1. Minimal skin changes or dermatitis (eg, erythema) without pain
    Grade 2. Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function
    Grade 3. Ulcerative dermatitis or skin changes with pain interfering with function
    Additional Considerations
    ASCO® recommends treating hand-foot syndrome with2:
    Oral or topical corticosteroids
    Vitamin B6
    Over-the-counter pain relievers
    *Based on Common Terminology Criteria for Adverse Events v3.0 (CTCAE). August 9, 2006. Available at: http://ctep.cancer.gov/reporting/ctc_v30.html.
    Slide and notes references: 1. Data on file. Pfizer Inc, New York, NY. 2. American Society of Clinical Oncology (ASCO®). People Living With Cancer Web site. Managing side effects: hand-foot syndrome (palmar-plantar erythrodysesthesia). Available at: http://www.plwc.org/portal/site/PLWC/menuitem. Accessed May 24, 2007. 3. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). August 9, 2006. Available at: http://ctep.cancer.gov/reporting/ctc_v30.html.
  • Incidence of Fatigue1
    mRCC trial: SUTENT vs IFN (all grades: 58% vs 55%; grade 3/4: 9% vs 14%)
    GIST* trial: SUTENT vs placebo (all grades: 42% vs 47%; grade 3/4: 8% vs 8%)
    Discontinuation of therapy due to fatigue in SUTENT clinical trials1:
    mRCC trial: SUTENT vs IFN (<1% vs 4.7%)
    Few patients had a dose interruption or reduction (6.9% vs 10.8%, respectively)
    GIST* trial: SUTENT vs placebo (no patients discontinued therapy)
    Few patients had a dose interruption or reduction (3.5% vs 1%, respectively)
    Grade Descriptions†
    Grade 1. Mild fatigue over baseline
    Grade 2. Moderate or causing difficulty performing some ADL
    Grade 3. Severe fatigue interfering with ADL
    Grade 4. Disabling
    Additional Considerations
    NCCN® and current literature recommend treating fatigue by2,3:
    Improving dietary intake (consider consulting a dietician)
    Activity enhancement with physical exercise
    Medications to treat the underlying cause, contributing factor(s), and/or symptoms of fatigue
    Slide and notes references: 1. Data on file. Pfizer Inc, New York, NY. 2. National Comprehensive Cancer Network®. Clinical Practice Guidelines in Oncology™. Cancer-related fatigue. V.1.2008. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed September 10, 2008. 3. Wood LS. Managing the side effects of sorafenib and sunitinib. Community Oncol. 2006;3:558-562.
  • SUTENT® (sunitinib malate) Slide Kit

    1. 1. Please see full prescribing information. SUTENT® (sunitinib malate) Slide Kit .
    2. 2. Please see full prescribing information. 2 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
    3. 3. Please see full prescribing information. 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 3
    4. 4. Please see full prescribing information. SUTENT Dosing
    5. 5. Please see full prescribing information. 5 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
    6. 6. Please see full prescribing information. Mechanism of Action in RCC
    7. 7. Please see full prescribing information. 7 SUTENT Inhibits Multiple Signaling Pathways Resulting in a Dual-Action Antiproliferative and Antiangiogenic Effect1 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 al2 ; Sulzbacher et al3 ; Tsuchiya et al4 ) 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 progression2,5 A correlation between the mechanism of action and the clinical efficacy of SUTENT has not been established.
    8. 8. Please see full prescribing information. Mechanism of Action in GIST
    9. 9. Please see full prescribing information. 9 Sunitinib demonstrated direct antiproliferative activity by inhibiting PDGFα and KIT receptors Sunitinib demonstrated antiangiogenic activity by inhibiting PDGF receptors on pericytes and VEGF receptors on endothelial cells in preclinical studies2,4 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. SUTENT Inhibits Multiple Signaling Pathways SUTENT simultaneously inhibits PDGF, VEGF, and KIT receptors for an antiproliferative and antiangiogenic effect1 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 al2 ; Heinrich et al3 )
    10. 10. Please see full prescribing information. SUTENT in RCC
    11. 11. Please see full prescribing information. 11 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 group1 * “…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.
    12. 12. Please see full prescribing information. 12 Phase 3, Randomized, Multicenter Trial Compares SUTENT With IFNα 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.
    13. 13. Please see full prescribing information. Patient Baseline Characteristics Were Well Balanced Between the Arms1,2 13 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 IFNα group. 1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124. 2. Data on file. Pfizer Inc.
    14. 14. Please see full prescribing information. 14 Patient Baseline Characteristics Were Well Balanced Between the Arms1,2 (cont’d) Totals may not equal 100% because of rounding and/or missing data. *Data are missing for 17 patients in the IFNα 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. In both treatment arms (SUTENT and IFNα): — The majority of patients were white (94% and 91%) — Few patients had previous radiotherapy (14% and 14%)
    15. 15. Please see full prescribing information. 15 SUTENT More Than Doubled Single-Agent Median PFS vs IFNα Median PFS was 11 months vs 5 months (with IFNα) 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 IFNα1 1. Data on file. Pfizer Inc. Progression-Free Survival
    16. 16. Please see full prescribing information. 16 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)
    17. 17. Please see full prescribing information. SUTENT Achieved a Median OS of Single-Agent More Than 2 Years 17 *Stratification factors: ECOG performance status score, LDH, and prior nephrectomy. Data on file. Pfizer Inc. Overall Survival
    18. 18. Please see full prescribing information. Poststudy Treatments 18 *P<.0001. Data on file. Pfizer Inc. 6% of the patients in the IFNα arm crossed over to SUTENT during the study; poststudy, 33% of the patients in the IFNα arm received SUTENT
    19. 19. Please see full prescribing information. 19 5-Fold Higher Objective Response Rate With SUTENT vs IFNα 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
    20. 20. Please see full prescribing information. Treatment-Emergent ARs Reported in ≥10% of Treatment-Naïve mRCC Patients* 20 *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.
    21. 21. Please see full prescribing information. Treatment-Emergent ARs Reported in ≥10% of Treatment-Naïve mRCC Patients* (cont’d) 21 *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.
    22. 22. Please see full prescribing information. Laboratory Abnormalities Reported in ≥10% of Treatment-Naïve mRCC Patients* 22 *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 IFNα included uric acid (8%), lipase (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%).
    23. 23. Please see full prescribing information. Important Safety Information 23 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.
    24. 24. Please see full prescribing information. Important Safety Information (cont’d) 24 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.
    25. 25. Please see full prescribing information. SUTENT in Imatinib-Resistant or -Intolerant GIST
    26. 26. Please see full prescribing information. 26 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 GIST1-4 However, assessing response using current criteria and technology can still be challenging3-5 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.
    27. 27. Please see full prescribing information. 27 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 GIST2-10 — Primary resistance is defined as disease progression within 6 months of imatinib treatment8,9,11-14 Secondary resistance to imatinib occurs in more than 40% of patients with GIST3,5,6,8,9,12 — 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 therapy16 When disease progression or intolerance to imatinib occurs, imatinib therapy may no longer be appropriate1 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 resistance1
    28. 28. Please see full prescribing information. 28 Understanding Primary and Secondary Mutations in GIST Exons are genetic segments containing sequences that code for proteins, such as KIT and PDGFRα1 Exon mutations can result in structurally and functionally abnormal receptors that can lead to continual (“constitutive”) activation and tumor development2,3 A primary mutation refers to a mutation that occurs prior to GIST treatment4-6 A secondary mutation refers to a mutation that occurs in addition to the primary mutation and emerges during the course of treatment4-6 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.
    29. 29. Please see full prescribing information. Primary Mutations in KIT or PDGFRα Are Common in Patients With GIST 29 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.
    30. 30. Please see full prescribing information. 30 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 GIST1-5 * Secondary resistance is commonly associated with primary exon 11 mutations in patients with GIST2,3,5-8† Secondary resistance is associated with the emergence of secondary mutations — In one study (N=43), 67% of patients who developed secondary resistance had secondary mutations2 *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.
    31. 31. Please see full prescribing information. Primary and Secondary Mutations Are Associated With the Development of Resistance1-6 31 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.
    32. 32. Please see full prescribing information. 32 *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. 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
    33. 33. Please see full prescribing information. Patient Characteristics Were Well-Balanced Between the Arms 33 *Total does not equal 100% due to rounding. † n=205. 1. Data on file. Pfizer Inc.
    34. 34. Please see full prescribing information. 34 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
    35. 35. Please see full prescribing information. Consistent Efficacy Across Patient Subgroups 35 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.
    36. 36. Please see full prescribing information. Treatment-Emergent ARs (≥10%) With SUTENT and More Common Than With Placebo* 36 *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.
    37. 37. Please see full prescribing information. Treatment-Emergent Laboratory Abnormalities (≥10%) With SUTENT or Placebo* 37 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%).
    38. 38. Please see full prescribing information. 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. 38
    39. 39. Please see full prescribing information. Important Safety Information (cont’d) 39 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.
    40. 40. Please see full prescribing information. Some Strategies Used in Clinical Trials for Managing SUTENT Adverse Reactions
    41. 41. Please see full prescribing information. Few Patients Discontinued Therapy Due to ARs 41 *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.
    42. 42. Please see full prescribing information. 42 *Imatinib-resistant or -intolerant. Data on file. Pfizer Inc. Patient Management Strategies for Hypertension in the SUTENT Phase 3 Clinical Trial Hypertension may occur. Monitor blood pressure and treat as needed Patient management strategies for hypertension included: Incidence of severe (>200 mm Hg systolic or 110 mm Hg diastolic) hypertension — mRCC trial: SUTENT vs IFNα (5% vs 1%) — GIST* trial: SUTENT vs placebo (4% vs 1%) Incidence of hypertension — mRCC trial: SUTENT vs IFNα (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%)
    43. 43. Please see full prescribing information. 43 *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 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 Patient management strategies for hypothyroidism included: Incidence of hypothyroidism1 — mRCC trial: SUTENT vs IFNα (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 managed2† — 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
    44. 44. Please see full prescribing information. Some Patient Management Strategies for Hand-Foot Syndrome 44 *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 by2 : • 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 included1 :
    45. 45. Please see full prescribing information. Some Patient Management Strategies for Fatigue 45 *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, including2,3 : Patient management strategies for fatigue used in the SUTENT phase 3 clinical trial included1 : • Anemia • Nutrition (anorexia, gastrointestinal problems) • Pain • Depression/emotional distress • Sleep disturbances • Hypothyroidism • Patient activity level • Other medications (including over-the-counter and herbal products)
    46. 46. Please see full prescribing information. Important Safety Information 46 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.
    47. 47. Please see full prescribing information. 47 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 IFNα) 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 IFNα) 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.

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