Sunitinib (Sutent) is associated with an important identified risk of fistula formation. Fistulas are abnormal connections between organs that can develop spontaneously or after surgery and radiation. The mechanism may involve disturbed vascular integrity from VEGF inhibition. Incidence of fistula with sunitinib is highest in gastrointestinal stromal tumor and pancreatic neuroendocrine tumor patients. Fistulas can be life-threatening and require hospitalization but are sometimes preventable through monitoring of high-risk patients. More information is still needed on pediatric use and in patients with cardiac or severe liver impairment.

1. Sutent® (sunitinib malate) and its
Important Identified Risk
of Fistula Formation
Oscar Kwan, PharmD. 2018 Candidate
St. John’s University
College of Pharmacy and Health Sciences
oscar.kwan11@stjohns.edu

2. Objectives
• Provide an overview of Tyrosine Kinase Receptors (TKRs) role in Cancer and target anticancer therapy
• Describe sunitinib malate’s Therapeutic class, Mechanism of action, Approved indications, Dosage forms,
Posology, Safety profile, and Worldwide marketing approval status
• Present the serious, frequent adverse drug events and Important identified or potential risks of sunitinib
• Discuss the Incidence, Risk factors, Potential mechanisms of fistula formation in sunitinib patients
• Evaluate the Seriousness, Severity, and Outcomes of fistula adverse events in sunitinib
• Review the common and uncommon Pharmacologic class effects of other VEGF inhibitors
• Explain the Preventability and Impact on individual patients of fistula formation
• Provide New Information on fistula formation risk and Missing Information on sunitinib
• Summarize the Major aspects of fistula formation risk in sunitinib and how it affects its patients

3. Tyrosine Kinase Receptors (TKRs)
• Cell-surface receptors for many growth factors, cytokines, and hormones
• Key Regulators:
q Cell Growth
q Cell Differentiation
q Cell Proliferation
q Cell Migration
q Cell Metabolism
q Anti-Apoptosis
Figure 1. The functions of receptor tryosine kinases.
http://www.clontech.com/ID/Products/Cell_Biology_and_Epigenetics/Cancer_
and_Inflammation/Tyrosine_Kinases_Focus

4. Biological Mechanism of Action

5. Tyrosine Kinase Receptors and Cancer
• The role of Tyrosine Kinase Receptors in the control of cellular growth and
differentiation is CENTRAL to human cancers.2
• Oncogenic Activation of Tyrosine Kinase Receptors (TKRs):
Ø Mutations : Tyrosine Kinase Receptor dysregulation (receptor stimulation in the absence of a ligand)3
Ø Autocrine and Paracrine Loops : Constant signaling loop due to an abnormal overexpression of
either Tyrosine Kinase Receptors or its associated ligands
• Cancer Pathophysiology:
Dysregulation of Tyrosine Kinase Receptor activity
Abnormally increased signaling pathways and biological responses
Uncontrolled cell growth and proliferation (Angiogenesis)
CANCER

6. Target for Anticancer Agents
• Oncogenic activation in cells can be blocked by selective Tyrosine Kinase Receptor
inhibitors and thus considered a promising approach for cancer therapy. 2
• Different Approaches for Tyrosine Kinase Receptors Inhibition:
v Small molecule inhibitors
v Monoclonal antibodies
v Heat shock protein inhibitors
v Immunoconjugates
v Antisense drugs
v Peptide drugs

7. What is
Sutent®
(sunitinib malate)?

8. Sutent® (sunitinib malate)
• Oral, small molecule, multi-targeted Tyrosine Kinase Receptor inhibitor
• Tyrosine Kinase Receptors(RTKs):
Ø Vascular Endothelial Growth Factor Receptor (VEGFR)-1, VEGFR-2, VEGFR-3
Ø Platelet-Derived Growth Factor Receptor (PDGFR)-α, PDGFR-β
Ø Stem Cell Factor Receptor (KIT)
Ø Ret Proto-oncogene (RET)
Ø Fms-like Tyrosine Kinase-3 (FLT3)
Ø Colony Stimulating Factor Receptor Type 1 (CSF-1R)
Ø Glial Cell-line Derived Neurotrophic Factor Receptor (RET)

9. Approved Indications
Treatment for…
v Imatinib-resistant or intolerant Gastrointestinal Stromal Tumor (GIST) 4,5,6
v Treatment-naïve advanced and/or metastatic Renal Cell Carcinoma (mRCC) 4, 7, 8, 9, 10
v Advanced and/or mRCC after failure of Cytokine-based therapy 4, 7, 8
v Unresectable or metastatic, well-differentiated Pancreatic Neuroendocrine Tumors
(pNET) with disease progression 11, 12, 13, 14, 15
v Adjuvant therapy for adult patients at high risk for recurrent Renal Cell Carcinoma
(RCC) following nephrectomy 16

10. Sutent® Posology and Treatment Regimens
• For GIST and mRCC:
Ø 50 mg orally once daily x 4 weeks, followed by 2-week off period (Schedule 4/2) = 6-week cycle
• For pNET:
Ø 7.5 mg orally once daily without a scheduled rest period 16
• For Adjuvant treatment of RCC:
Ø 50 mg taken orally once daily on Schedule 4/2 for nine 6-week cycles (approximately 1 year) 11

11. Dosage Forms
• Pharmaceutical Form: Hard gelatin capsules 18
• Qualitative and Quantitative Composition:

12. Worldwide Marketing Approval Status
• January 26, 2006 : Sunitinib received its first regulatory approval in the United States
• Marketing authorization in 122 countries and is currently marketed in 115 countries.

13. Counseling Points
• Sunitinib may be taken with or without food.
• AVOID co-administration with CYP3A4 inducers and inhibitors, it may affect drug levels.
• AVOID eating grapefruit or drinking grapefruit juice.
• If you are a woman of childbearing age, AVOID becoming pregnant while taking sunitinib,
use adequate contraception you can trust to prevent pregnancy.
Ø Studies in animals have shown reproductive toxicity including fetal malformations 20, 21
• Bleeding occurs more easily, use caution and AVOID injury.
ü Use a soft toothbrush and an electric razor.
• Sunitinib impairs wound healing, AVOID scrapes and cuts to the skin.
• Sunitinib may cause high blood pressure, monitor your blood pressure often.
• Contact your doctor immediately if you experience any signs of bleeding (hematemesis,
hematuria, coughing up blood, or bleeding in the gums).

14. Cumulative Safety Profile

15. “Serious” Adverse Drug Events
q Has a fatal outcome;
q Is considered life threatening ;
q Requires hospitalization ;
q Results in prolongation of an existing hospitalization ;
q Results in persistent or significant disability or incapacity ;
q Is a congenital anomaly/birth defect ; or
q Is considered an important medical event that may jeopardize the patient or subject
and may require medical intervention to prevent one of the above outcomes.

16. Frequently Reported Adverse Events

17. Important Risk
Depends upon several factors…
1. Impact on the Individual patient:
q Effect on quality of life
q Serious consequences if left untreated
2. Seriousness of the risk:
q Severity
q Reversibility
q Outcomes
3. Impact on Public health:
q Incidence of the event
q Preventability
4. Impact on the risk-benefit balance of the product
q Contraindications
q Warnings and precautions

18. Identified Risk vs. Potential Risk
Potential Risk
An untoward occurrence with some basis for
suspicion of an association with the drug but this
association is not confirmed
Identified Risk
An untoward occurrence for which there is adequate
evidence of an association with the product of interest

19. Ongoing Safety Concerns

20. Missing Information of Sutent® (sunitinib malate)
Topic Description
Pediatric Patients Safety and efficacy have not been established.
Patients with
Severe Hepatic impairment
Sunitinib was not studied in subjects with severe
(Child-Pugh Class C) hepatic impairment.
Patients with
Cardiac impairment
Subjects with *cardiac events within 12 months
prior to sunitinib administration were excluded
from its clinical studies.
*Cardiac events: Myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass
graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism

21. Overview of Fistulas
• Fistula: an abnormal connection between two organs
• Blind or Incomplete: Open at one extremity only (i.e. End in a cul-de-sac)
• External vs. Internal:
Ø External: Pathological communications that connect an internal surface with the skin
Ø Internal: Connect internal organs or an organ with a surface such as the peritoneal or pleural space
Updated by: Subodh K. Lal, MD, gastroenterologist with Gastrointestinal
Specialists of Georgia, Austell, GA. Review provided by VeriMed
Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla
Ogilvie, PhD, and the A.D.A.M. Editorial team.
http://pedsurg.ucsf.edu/conditions--
procedures/esophageal-atresia.aspx

22. Potential Mechanisms of Fistula Formation
vThe pathophysiology of fistula formations is not well known but
may be related to the potent anti-angiogenic action of sunitinib
linked to VEGF inhibition on tumor vasculature.
vMost probably caused by disturbed homeostasis of the tight
endothelial cell-platelet interaction that maintains vascular integrity.

23. Potential Mechanisms of Fistula Formation
• The most common sites of fistula formation in the general population
involve the GI tract following surgery (75 – 85%)22
Ø Surgeries: Cancer, Inflammatory bowel disease, Lysis of adhesions, Pancreatitis
• 15 – 25% of fistulae form spontaneously, most commonly in patients with22:
o Colon Diverticular disease
o Inflammatory bowel disease
o Cancer or Radiation therapy
o Trauma
o Intestinal obstruction
o Mesenteric vascular disease
o Adjacent abscesses

24. Risk Factors for Fistula Formation1
q Cancer/Malignancies
q Local inflammation
q Abscess
q Infections
q Radiation
q Trauma
q Prior surgery
q Prior fistula
q Tumors

25. Incidence of Fistula Formation 22
• Gastrointestinal Stromal Tumour (GIST):
Ø Post-operative GI fistula: 0 – 12% (colorectal cancer surgical patients)
Ø Spontaneous fistula: 3.7% among 82 patients with metastatic colorectal cancer
• Metastatic Renal Cell Carcinoma (mRCC):
Ø There are no epidemiological data available to characterise the background
incidence/prevalence of fistula in RCC patients
• Pancreatic Neuroendocrine Tumours (pNET):
Ø Different types of pancreatic neoplasms: 23 – 63% *
• Adjuvant Renal Cell Carcinoma (RCC):
Ø Urocutaneous fistula: 0.3% among 329 post-nephrectomy patients in the U.S.

26. All-Causality Adverse Events of Fistula Formation in
12 Single-agent Studies of mRCC, GIST, pNET, and Adjuvant RCC 22

27. Post-authorization Adverse Events of Fistula Formation
Seriousness and Outcomes (Cumulative Through 31 August 2016) 22

28. Preventability of Fistula Formation
• Use caution in high risk patients (undergoing radiation therapy or surgery, prior
fistula history, infection, abscess, cancer, trauma, or local inflammation).
• Monitoring for infections and symptoms of fistula formations is suggested.
Ø Abnormal drainage
Ø Fever, chills, and a general feeling of fatigue
Ø Nausea & vomiting
Ø Bloody stools
Ø Abdominal discomfort, distension, or tenderness
Ø Fluid leakage from an opening in your abdomen or anus

29. Impact on Individual Patient of Fistula Formation
Site Complication(s)
Intestinal fistulae Sepsis
Fluid and electrolyte depletion
Necrosis of skin at a site of external drainage
Malnutrition
Infrequent bleeding due to erosion of blood vessel
Tracheoesophageal fistulae Respiratory infection
Colovesical fistulae Urinary tract infection
*Some types of fistulae close spontaneously after several weeks
Treatment of Fistulas:
v Supportive Care: Parenteral nutrition and volume repletion may be required.
v Surgery: If necessary, with resection of any diseased area and patching.
v If left untreated, fistulas may be fatal.1

30. New Information on Fistula Formation Risk
Periodic Safety Update Report (PSUR) 13: Reporting Period (01 May 2015 through 30 April 2016)
o No new information that would require mitigation of this risk
o No specific interventions to manage the severity of the risk
o No contraindications to special patient populations to reduce chance of risk
o No specific drug-drug combinations to prevent risk
Ø The risk is communicated through the Core Data Sheet (CDS) in
Section 4.8 Undesirable Effects and will continue to be monitored through
routine pharmacovigilance.

31. Pharmacologic Class Effects
q Fistula formation is described with other VEGF inhibitors and therefore maybe related to
VEGF inhibition.22
q The serious event most common among other pharmacological agents that inhibit some of
the same molecular interactions as sunitinib is haemorrhage.22
Risk Frequency Medicinal Product (s)
Fistula Common
(1/100 to <1/10)
bevacizumab (Avastin)
Uncommon
(1/1,000 to <1/100)
sunitinib (Sutent)
axitinib (Inlyta)
pazopanib (Votrient)
Risk Frequency Medicinal Product (s)
Haemorrhage Very common
(>1/10)
sunitinib (Sutent)
axitinib (Inlyta)
bevacizumab (Avastin)
sorafenib (Nexavar)
Common
(1/100 to <1/10)
pazopanib (Votrient)

32. Summary and Conclusions
Ø Fistula formation risk is uncommon in sunitinib malate (Sutent ®)
Ø Fistula formation is difficult to prevent in patients using sunitinib
Ø Symptoms and complications associated with fistulas depend on its site.
Ø Tracheoesophageal fistula: Coughing, choking, difficulty breathing
Ø Anal fistula: Pain, swelling, discharge of blood or pus from the anus, bloody stools
Ø There is Missing Information of sunitinib use in pediatric patients, patients
with severe hepatic impairment, and cardiac impairment.
Ø Patients should AVOID injury due to easy bleeding and impaired wound healing.
Ø Fistulas are fatal events if left untreated1
Ø Treatment of fistulas involve Supportive care and if needed, Surgery

34. References
1. Pfizer, Inc. Core Data Sheet, Sutent (Sunitinib Malate). 39. Mar 8, 2017.
2. Paul, M. K., & Mukhopadhyay, A. K. (2004). Tyrosine kinase – Role and significance in Cancer. International Journal of
Medical Sciences, 1(2), 101–115.
3. Koppal T Neglected kinase targets are now in vogue Drug Disc Develop 2003. Aug: 75-80
4. Module 2, Section 2.5. Clinical Overview of Treatment of gastrointestinal stromal tumor after failure of CTD for
imatinib mesylate therapy and of cytokine refractory renal cell carcinoma, dated July 2005.
5. Waters N. A Phase I/II Study of SU011248 in the Treatment of Patients with Malignant Gastrointestinal Stromal
Tumor (GIST) who Are Intolerant of, or with Disease Progressing on, Imatinib Mesylate (GleevacTM). Final Clinical
Study Report: SU011248. Protocol Number: RTKC-0511-013. Pfizer, Inc. 05-May-2005.
6. Waters N. A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of SU011248 in the Treatment of
Patients with Imatinib Mesylate (Gleevec®, Glivec®) - Resistant or Intolerant Malignant Gastrointestinal Stromal
Tumor. Interim Clinical Study Report: SU011248 (RTKC-0511, A618). Protocol Number: A6181004. Pfizer, Inc. 06-
July-2005.
7. Kinley A. Phase 2 Study of Single-Agent SU011248 in the Second-Line Treatment of Patients with Metastatic Renal
Cell Carcinoma. Final Clinical Study Report: SU011248. Protocol Number: RTKC-0511-014. Pfizer, Inc. 05-May-2005.
8. Waters N. A Pivotal Study of SU011248 in the Treatment of Patients with Cytokine-Refractory Metastatic Renal Cell
Carcinoma. Interim Clinical Study Report: SU011248 (RTKC-0511, A618). Protocol Number: A6181006. Pfizer, Inc.
22-June-2005.
9. Waters N. A Phase 3, Randomized Study of SU011248 versus Interferon- as First-Line Systemic Therapy for
Patients with Metastatic Renal Cell Carcinoma. Interim Clinical Study Report: Protocol Number A6181034. Pfizer, Inc.
22 February 2006.
10. Waters N. A Phase 3, Randomized Study of SU011248 versus Interferon- as First-Line Systemic Therapy for
Patients with Metastatic Renal Cell Carcinoma. Clinical Study Report (Interim Analysis 2). Data Cutoff Date: 15
November 2005. Protocol Number A6181034. Pfizer, Inc. 30 June 2006.

35. References
11. Module 2.7.4 Summary of Clinical Safety Pancreatic NET
12. A6181111 - Clinical Study Report. October 2009.
13. RTKC-0511-015 Clinical Study Report. October 2006.
14. A6181111- Supplemental Clinical Study Report. November 2010.
15. A6181111 Final BICR Report. December 2010.
16. Study A6181109 Clinical Study Report (February 2017).
17. Module 2, Section 2.7.2.3.4. Summary of Clinical Pharmacology Studies of CTD for gastrointestinal stromal tumor after
failure of imatinib mesylate therapy and of cytokine refractory renal cell carcinoma, dated July 2005.
18. Module 3, Section 3.2.P.1. Common Technical Document dated August 2006.
19. Raymond E, Dahan L, Raoul J-L, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J
Med. 2011;364(6):501-513.
20. Module 2, Table 2.6.7.13. Toxicology Written Summary Reproductive and Developmental Toxicity of CTD for
gastrointestinal stromal tumor after failure of imatinib mesylate therapy and of cytokine refractory renal cell carcinoma,
dated March 2005.
21. Morris D. SU010398 (PHA-290940AD): Oral Embryo-Fetal Development Study in the Female Rat. Study Report for Study
2003-0372. Pfizer, Inc. 19-November-2004.
22. Pfizer, Inc. Risk Management Plan, Sutent (Sunitinib Malate). February 2017.
23. Module 2, Section 2.7.4.2.1.3, Table 61. Summary of Clinical Safety of CTD for gastrointestinal stromal tumor after failure
of imatinib mesylate therapy and of cytokine refractory renal cell carinoma, dated July 2005.
24. Module 2.5 Clinical Overview; Sunitinib Malate: A Clinical Overview to support updates to Sections 4.4 and 4.8 of the
sunitinib PRODUCT LABEL: Review of ADRs. Pfizer Inc. January 2014.
25. Pfizer, Inc. Periodic Safety Update Report, Sutent (Sunitinib Malate). 13. 01 May 2015 through 30 April 2016.