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Please see Brief Summary and accompanying full Prescribing Information on slides 29-32. Indications may vary between countries. This piece is for promotional use with healthcare professionals upon local regulatory approval in your particular country. Each CPO is responsible for ensuring that this material is reviewed and approved in accordance with the local NP4 approval process.

UPDATE IN THE MANAGEMENT OF

NEUROENDOCRINE TUMOURS

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NEUROENDOCRINE TUMOUR

(NET) OVERVIEW

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NEUROENDOCRINE TUMOURS (NETs)

• Arise from cells of the neuroendocrine system1

• Most common type are gastroenteropancreaticNETs (GEP-NETs) of the gastrointestinal (GI) system2

• Generally small (< 1 cm in diameter) and slow-growing3

• Have metastatic potential3*Age-adjusted annual incidence per 100,000 in the 2000 US population; from the SEER 17 registry

GI SYSTEM (2.89)

Pancreas (0.32)

Liver (0.04)

Stomach (0.30)

Duodenum (0.19)

Jejunum/ileum

(0.67)

Cecum (0.16)

Appendix (0.15)

Colon (0.20)

Rectum (0.86)

LUNG (1.35)

THYMUS (0.02)

OTHER/UNKNOWN(0.74)

SITE OF PRIMARY TUMOUR2

(Incidence per 100,000)*

1. Ramage JK, Davies AH, Ardill J, et al. Gut. 2005;54:iv1-iv16. 2. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072. 3. Kufe DW, Pollock RE, Weichselbaum RR, et al. eds. Holland-Frei Cancer Medicine, 6th ed. Hamilton (ON): BC Decker; 2003.

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NETs ARE MORE PREVALENTTHAN MANY TUMOURS OF THE GI SYSTEM

1. National Cancer Institute. SEER Cancer Statistics Review 1975-2004. Complete and Limited-Duration Cancer Prevalence Estimates. http://seer.cancer.gov/csr/1975_2004/results_merged/topic_prevalence.pdf. Accessed 28 March 2011.

2. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.

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ASYMPTOMATICNETs

• Also called nonfunctioning NETs

• More common than symptomatic NETs1

• Do not cause clinical syndromes2

• Usually present due to mass effects and/or metastatic disease1,2

A LACK OF DISTINCT SYMPTOMS MAY DELAY NET DIAGNOSIS

1. Modlin IM, Öberg K, Chung DC, et al. Lancet Oncol. 2008;9:61–72. 2. Kaltsas G, Androulakis II, de Herder WW, Grossman AB. Endocr Relat Cancer. 2010;17:R173–R193.3. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Gastroenterology. 2005;128:1717–1751.

NETs ARE TYPICALLY PRESENT FOR 5–7 YEARS PRIOR TO DIAGNOSIS1

SYMPTOMATICNETs

• Also called functioning NETs

• Release bioactive substances to the bloodstream2

• May cause paraneoplastic disease2

• Symptoms may mimic other conditions1 (e.g. symptomatic GEP-NETs typically produce flushing and diarrhoea)3

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NEARLY HALF OF ALL NETs ARE ADVANCED AT DIAGNOSIS

Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.

*Includes the 78.4% of NET patients in the SEER 17 registry with staging information available at diagnosis.

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ADVANCED DISEASE IS ASSOCIATED WITH POORER 5-YEAR SURVIVAL

Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.

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WITHOUT TREATMENT, THE MAJORITY OF PATIENTS WITH ADVANCED MIDGUT NETs WILL PROGRESS

WITHIN 1 YEAR

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

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SOMATOSTATIN SIGNALLING

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• The majority of NETs express somatostatin receptors (SSTRs)2

• Approximately 80% of GEP-NETs express the SSTR2 subtype3

POTENTIAL THERAPEUTIC TARGET:SOMATOSTATIN SIGNALLING IN NETs

• Somatostatin signalling:1

―Decreases hormone secretion and controls symptoms

―Promotes cell death (apoptosis)

―Inhibits cell growth

1. Öberg KE, Reubi J-C, Kwekkeboom DJ, Krenning EP. Gastroenterology. 2010;139:742-753. 2. Hicks RJ. Cancer Imaging. 2010;10:S83-S91. 3. Kulaksiz H, Eissele R, Rössler D, et al. Gut. 2002;50:52-60.

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DIRECT AND INDIRECT ANTIPROLIFERATIVE EFFECTS OF SOMATOSTATIN SIGNALLING

SOMATOSTATIN RECEPTOR ACTIVATION

Indirect antiproliferative effect

Binding of somatostatin receptors on tumour cells

Inhibition of growth factor

effects

Inhibition of cell cycle

Pro-apoptotic effect

Systemic effect

Inhibition of growth factor and trophic hormones

Immune system

modulation

Inhibition of angiogenesis

Direct antiproliferative effect

Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742.

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DELAYING THE PROGRESSION

OF NEUROENDOCRINETUMOURS

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PROMID: PIVOTAL PHASE III TRIAL DEMONSTRATING TUMOUR CONTROL BY SANDOSTATIN LAR

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

• PROMID: Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine MIDgut Tumors

• Phase III, randomised, double-blind, placebo-controlled trial

• Designed to evaluate the antiproliferative effects of the somatostatin analogue Sandostatin® (octreotide) LAR® 30 mg

• Conducted at 18 centres in Germany (2001–2008)

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PROMID DESIGN AND ENDPOINTS

Primary Endpoint – TTP (defined as time to tumour progression or time to tumour-related

death)

Secondary Endpoints – Survival time– Quality of life– Clinical and biochemical response (in patients with symptomatic disease)– Safety

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

Randomised Patients (N = 85)• Treatment naïve• Karnofsky status > 60%• Tumour criteria

– Midgut origin– Well-differentiated histology– Locally inoperable or metastatic– Measurable (CT/MRI)

• Symptomatic or asymptomatic

Ran

dom

isati

on

(1:1

)

Sandostatin LAR 30 mg(N = 42) IM every 28 days

Placebo (N = 43)IM every 28 days

Treatment until tumour progression

or death

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PROMID PATIENT CHARACTERISTICS AT BASELINE

Sandostatin LAR 30 mg

(N = 42)

Placebo(N = 43)

Total(N = 85)

Median age, years (range) 63.5 (38–79) 61 (39–82) 62 (38–82)

Male (%) 20 (47.6) 23 (53.5) 43 (50.6)

Months since diagnosis (range) 7.5 (0.8–271.7) 3.3 (0.8–109.4) 4.3 (0.8–271.7)

Karnofsky performance status > 80% (%)

35 (83.3) 38 (88.4) 73 (85.9)

Symptomatic disease (%) 17 (40.5) 16 (37.2) 33 (38.8)

Resection of primary tumour (%) 29 (69.1) 27 (62.8) 56 (65.9)

Ki-67 up to 2% (%) 41 (97.6) 40 (93.0) 81 (95.3)

Octreoscan Positive (%)

Negative (%)

32 (76.2)4 (9.5)

31 (72.1)6 (14.0)

63 (74.1)10 (11.8)

Liver involvement ≤ 10% (%)

> 10% (%)

32 (76.2)10 (23.8)

32 (74.4)11 (25.6)

64 (75.3)21 (24.7)

Chromogranin A Elevated (%)

Not elevated (%)

26 (61.9)15 (35.7)

30 (69.8) 12 (27.9)

56 (65.9)27 (31.8)

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

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• More than double the median TTP (14.3 months with Sandostatin LAR 30 mg vs 6.0 months with placebo; P = 0.000072)

• 66% reduction in the risk of disease progression (HR = 0.34)

SANDOSTATIN LAR 30 MG SIGNIFICANTLYPROLONGS TTP* OVER PLACEBO

Results seen in the Sandostatin LAR 30 mg group, compared with placebo

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

*TTP: Time to tumour progression or tumour-related death

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• Symptomatic: HR = 0.23(95% CI: 0.09–0.57)

• Asymptomatic: HR = 0.25(95% CI: 0.10–0.59)

THE MAJORITY OF PATIENTS IN THE PROMID TRIAL WERE ASYMPTOMATIC

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

Sandostatin LAR 30 mg prolonged TTP over placebo, regardless of symptomatic or asymptomatic disease

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MAJORITY OF PATIENTS WHO RECEIVED SANDOSTATIN LAR 30 MG

ACHIEVED STABLE DISEASE AT 6 MONTHS*

Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

*As defined by WHO criteria

P = 0.0079

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SANDOSTATIN LAR IS GENERALLY WELL TOLERATED1

OBSERVED SAFETY FINDINGS IN THE PROMID TRIALWERE CONSISTENT WITH THOSE SEEN IN PREVIOUS

STUDIES OF SANDOSTATIN LAR IN PATIENTS WITH NETs1-3

Adverse events in PROMID3 Sandostatin LAR 30 mg(N = 42)

Placebo(N = 43)

Serious adverse event 11 10

Most frequent serious adverse events

Gastrointestinal tract 6 8

Haematopoietic system 5 1

General health status (fatigue, fever) 8 2

Adverse event causing discontinuation 5 0

1. Sandostatin LAR Basic Prescribing Information. Novartis Pharma AG. 20 May 2010.2. Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol. 1999;17:600-606.3. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663.

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GUIDELINES

CPO: Please provide your local guidelines here

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MANAGEMENT OFSYMPTOMATIC GEP-NETs

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GEP-NET SYMPTOMS CAN HAVE IMMEDIATE AND LONG-TERM CONSEQUENCES

1. Creutzfeldt W. World J Surg. 1996;20:126-131.2. McCormick D. Gastroenterol Nurs. 2002;25:105-113.3. Zuetenhorst JM, Taal BG. Oncologist. 2005;10:123-131.

• Diarrhoea and flushing are the two most common GEP-NET symptoms.1

– Patients may have up to 30 stools per day, accompanied by pain.2

– Flushing is an outwardly visible sign of the disease.2

• Potentially life-threatening dehydration, hypotension, arrhythmias, and unconsciousness can develop from early symptoms, like diarrhoea and flushing.3

COMMON GEP-NET SYMPTOMS1

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REDUCTION IN THE FREQUENCY OF DIARRHOEA WITH SANDOSTATIN LAR 20 MG

Data on file. Novartis Pharma AG.

IN FUNCTIONAL CARCINOID PATIENTS:

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REDUCTION IN THE FREQUENCY OF FLUSHING EPISODES WITH SANDOSTATIN LAR 20 MG

Data on file. Novartis Pharma AG.

IN FUNCTIONAL CARCINOID PATIENTS:

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SUPPRESSION OF 5-HIAA* LEVELS WITH SANDOSTATIN LAR 20 MG

Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol. 1999;17:600-606.

*5-hydroxyindoleacetic acid: serotonin metabolite used to assess tumour hormone secretion** 20 and/or 24 weeks

IN FUNCTIONAL CARCINOID PATIENTS:

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SANDOSTATIN LAR DOSING

Sandostatin LAR Basic Prescribing Information. Novartis Pharma AG. 20 May 2010.

IN PATIENTS WITH ADEQUATE SYMPTOM CONTROL WITH SANDOSTATIN SC

• Initiate Sandostatin LAR 20 mg every 4 weeks

• Continue Sandostatin SC for 2 weeks after initiating Sandostatin LAR

• After 3 months, assess need for dose adjustments based on symptomatic response

TUMOUR CONTROL

SYMPTOM CONTROL

• Sandostatin LAR 30 mg IM every 4 weeks

• Continue treatment in the absence of tumour progression

SANDOSTATIN IS AVAILABLE IN A SUBCUTANEOUS (SC) FORMULATION FOR BREAKTHROUGH

SYMPTOMS

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SUMMARY

1. National Cancer Institute. SEER Cancer Statistics Review 1975-2004. Complete and Limited-Duration Cancer Prevalence Estimates. http://seer.cancer.gov/csr/1975_2004/results_merged/topic_prevalence.pdf. Accessed 28 March 2011.

2. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072. 3. Kufe DW, Pollock RE, Weichselbaum RR, et al. eds. Holland-Frei Cancer Medicine, 6th ed. Hamilton (ON): BC Decker; 2003.4. Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656–4663. 5. Öberg KE. J Clin Oncol. 2009;27:4635-4636.6. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine Tumors. V.1.2011.

• The randomised, placebo-controlled phase III PROMID trial demonstrated that:

– Sandostatin LAR 30 mg is the only somatostatin analogue to significantly prolong TTP in patients with advanced midgut NETs.4,5

– Significantly more patients achieved stable disease with Sandostatin LAR than with placebo.4

• Sandostatin LAR is the first and only somatostatin analogue proven to have an antiproliferative effect on advanced midgut NETs.5

• Updated treatment guidelines now recommend Sandostatin LAR for early

tumour control in patients with advanced midgut NETs or unknown primary tumour location.6

• NETs are more prevalent than many other tumours of the GI system.1,2

• Although most NETs are small tumours, they can progress to metastatic disease, which has implications for survival.2,3

• Nearly half of all NET patients are diagnosed with advanced disease.2

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SUMMARY (CONTINUED)

• The most common symptoms are diarrhoea and flushing.1

• Potentially life-threatening dehydration, hypotension, arrhythmias, and unconsciousness can develop from early symptoms, like diarrhoea and flushing.2

• In functional carcinoid patients, Sandostatin LAR has been proven to reduce:

– The frequency of diarrhoea and flushing episodes.3,4

– 5-HIAA levels.4

• Sandostatin is available in a subcutaneous (SC) formulation for breakthrough symptoms.

1. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Gastroenterology. 2005;128:1717–1751.2. Zuetenhorst JM, Taal BG. Oncologist. 2005;10:123-131.3. Data on file. Novartis Pharma AG.4. Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol. 1999;17:600-606.

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FULL PRESCRIBING INFORMATION

CPO: Please provide your local full Prescribing Information

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BRIEF SUMMARY

Important note: Before prescribing, consult full prescribing information.

Presentation: Octreotide acetate. Vials containing 10 mg, 20 mg or 30 mg octreotide free peptide supplied as powder (microspheres) for suspension for injection together with a prefilled syringe (solvent for parenteral use), containing: sodium carboxymethylcellulose 12.5 mg, mannitol 15 mg; water for injection qs ad 2.5 mL; two needles [40 mm (1.5 inch), 19 gauge]. Sandostatin® LAR® suspension contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially ‘sodium-free’.

Indication: Acromegaly: in patients who are adequately controlled on SC treatment with Sandostatin; in patients in whom surgery or radiotherapy is inappropriate or ineffective; in the interim period until radiotherapy becomes fully effective. Relief of symptoms associated with functional gastro-entero-pancreatic endocrine tumours: carcinoid tumours with features of the carcinoid syndrome, VIPomas, glucagonomas, gastrinomas/Zollinger-Ellison syndrome, insulinomas, GRFomas. Treatment of patients with advanced neuroendocrine tumours of the midgut or unknown primary tumour location.

Dosage: 10 to 30 mg every 4 weeks, administered as a deep intragluteal injection.

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BRIEF SUMMARY (CONTINUED)

Contraindications: Known hypersensitivity to octreotide or to any of the excipients.

Warnings/Precautions: Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary; caution in patients with insulinomas; diabetes mellitus thyroid function should be monitored in patients receiving prolonged treatment with octreotide. Periodic examination of gallbladder; monitoring of vitamin B12 levels in patients who have a history of vitamin B12 deprivation; caution in patients with pregnancy, patients should be advised to use adequate contraception if necessary. Patients should not breast-feed during Sandostatin LAR treatment.

Interactions: Impaired intestinal absorption of ciclosporin, cimetidine; increased bioavailability of bromocriptine. Caution with concomitant use of drugs mainly metabolised by CYP3A4 and which have a low therapeutic index.

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BRIEF SUMMARY (CONTINUED)

Adverse reactions: Very common (≥1/10) adverse drug reactions are: diarrhoea, abdominal pain, nausea, constipation, flatulence, headache, cholelithiasis, hyperglycaemia, and injection-site localised pain. Common (≥1/100, <1/10) adverse drug reactions are: dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose stools, discolouration of faeces, dizziness, hypothyroidism, thyroid dysfunction (e.g. decreased thyroid stimulating hormone [TSH], decreased Total T4, and decreased Free T4), cholecystitis, biliary sludge, hyperbilirubinaemia, hypoglycaemia, impairment of glucose tolerance, anorexia, elevated transaminase levels, pruritus, rash, alopecia, dyspnoea, and bradycardia. Uncommon (≥1/1000, <1/100) adverse drug reactions are: dehydration, and tachycardia. Post-marketing the following adverse reactions have been reported: anaphylaxis, allergy/hypersensitivity reactions, urticaria, acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, arrhythmia, increased alkaline phosphatase levels, and increased gamma glutamyl transferase levels.

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