pancreatic neuroendocrine tumours
TRANSCRIPT
Pancreatic Neuroendocrine Pancreatic Neuroendocrine TumorTumor
Dr. Chirag DesaiDr. Chirag Desai, , MD, DM (Oncology)MD, DM (Oncology)
Hemato-oncology Clinic, Hemato-oncology Clinic, VEDANTAVEDANTA, , AhmedabadAhmedabad
NETs arise from cells which produce and secrete hormonesNETs arise from cells which produce and secrete hormones Most NETs are slow growing and malignant, with metastatic Most NETs are slow growing and malignant, with metastatic
potentialpotential Common sites of origin are:Common sites of origin are:
GI tractGI tract
LungsLungs
Pancreas Pancreas
22
Introduction to NETsIntroduction to NETs
Definitions: Classification, Grade, Definitions: Classification, Grade, and Stage and Stage
Classification = origin, tumor characteristics, behavior Classification = origin, tumor characteristics, behavior Different NET classification systems (WHO, ENET, AJCC) take Different NET classification systems (WHO, ENET, AJCC) take
into consideration different tumor characteristicsinto consideration different tumor characteristics
Grade = inherent biological aggressivenessGrade = inherent biological aggressiveness11
For example: low-grade malignant, intermediate-grade malignant,For example: low-grade malignant, intermediate-grade malignant,high-grade malignanthigh-grade malignant
Prognostic; may be independent from tumor stagePrognostic; may be independent from tumor stage
Stage = extent of diseaseStage = extent of disease22
For example, organ confined, locally invasive, metastatic, etc.For example, organ confined, locally invasive, metastatic, etc. Prognostic; may be independent from tumour gradePrognostic; may be independent from tumour grade
3
1. Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27 2. Rindi G, et al. Virchows Arch. 2007;451:757-762.
NETs have been traditionally NETs have been traditionally classified as foregut, midgut, classified as foregut, midgut, or hindgut, depending on site or hindgut, depending on site of originof origin
Replaced by new Replaced by new tumor-based classification tumor-based classification method developed by World method developed by World Health Organization (WHO)Health Organization (WHO)
44
ClassificationClassificationTraditional MethodTraditional Method
WHO classification defines NETs by degree of tumor differentiation, WHO classification defines NETs by degree of tumor differentiation, with specific clinicopathological featureswith specific clinicopathological features
The WHO classification system is based The WHO classification system is based on the following criteria:on the following criteria:
Biological behavior (malignancy)Biological behavior (malignancy) MetastasesMetastases Ki-67 indexKi-67 index AngioinvasionAngioinvasion Tumor sizeTumor size Histological differentiation Histological differentiation Hormonal syndromeHormonal syndrome
55
Classification Classification World Health Organization MethodWorld Health Organization Method
WHO Classification:WHO Classification:NET Grouped By Prognostic FactorsNET Grouped By Prognostic Factors
apancreatic NET
Prognosis of Patients With NET
Good Poor
6Strosberg JR, et al. GI Cancer Res. 2008;2:113-125.Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27.Strosberg JR, et al. GI Cancer Res. 2008;2:113-125.Klöppel G, et al. Ann Ny Acad Sci. 2004;1014:13-27.
77
WHO Classification for NETWHO Classification for NET
Ong SL, et al. Pancreatology. 2009;9:583-600.
NeuroendocrineTumours
Site of Origin•GI tract•Pancreas•Lungs•Thyroid•Pituitary•Others
Malignant Potential•Benign•Benign or low malignant potential (uncertain)•Low malignant potential•Highly malignant
Functional Activity•Functioning•Non-Functioning
The Pancreas Is the Most Common Primary Location The Pancreas Is the Most Common Primary Location of NET Breakdown in Middle East & Asia Pacific of NET Breakdown in Middle East & Asia Pacific
RegionRegion
Stomach 6%
Liver 4%
Bile duct and gallbladder 3%Omentum/abdominal lining 1%Rectum 1%Ovary 1%Lung 1%
Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.
Potential Reasons for Increased Potential Reasons for Increased Incidence and Prevalence in NETIncidence and Prevalence in NET
• Exact reasons are unknown but may include:Exact reasons are unknown but may include:
– Potential underdiagnoses and underreporting in the pastPotential underdiagnoses and underreporting in the past
– Improved diagnostic techniquesImproved diagnostic techniques
– Increased awareness of NET in the communityIncreased awareness of NET in the community
9
Clinical presentation of GI NETs varies widelyClinical presentation of GI NETs varies widely Often discovered incidentallyOften discovered incidentally
Symptoms due to:Symptoms due to: Mechanical bulkMechanical bulk FibrosisFibrosis Secretion of various hormonesSecretion of various hormones
Serotonin is most common Serotonin is most common substance secreted from GI NETsubstance secreted from GI NET
Serotonin release can cause Serotonin release can cause carcinoid syndromecarcinoid syndrome
1010
GI NETsGI NETsClinical PresentationClinical Presentation
Serotonin-producing GI NET (ileum)
Symptoms of carcinoid syndrome include:Symptoms of carcinoid syndrome include:
1111
GI NETsGI NETsCarcinoid SyndromeCarcinoid Syndrome
Rapid heart beat
Hypotension
Diarrhea
Flushing
Heart disease
Wheezing
Carcinoid syndrome is associated with metastatic disease
pNETs are rare, slow-growing pNETs are rare, slow-growing neoplasmsneoplasms
Symptoms from excess hormone Symptoms from excess hormone production or mechanical problemsproduction or mechanical problems
6.4% of all NETs are found in 6.4% of all NETs are found in pancreaspancreas
Incidence rate of 0.4 cases per Incidence rate of 0.4 cases per 100,000 persons100,000 persons
Incidence is increasingIncidence is increasing
pNETs may or may not have pNETs may or may not have secretory symptomssecretory symptoms
Secretory symptoms related to Secretory symptoms related to specific hormonesspecific hormones
Tumors (nonfunctional) may secrete Tumors (nonfunctional) may secrete peptides but cause no clinical peptides but cause no clinical symptoms symptoms
1212
Pancreatic NETs OverviewPancreatic NETs Overview
Pancreatic NETs TypesPancreatic NETs Types
TumorIslet cell
typePredominant hormone
producedMalignant potential
Gastrinoma Gamma Gastrin Very high
Insulinoma Beta Insulin Low
Glucagonoma Alpha Glucagon Very high
VIPoma Delta Vasoactive intestinal peptide High
Somatostatinoma Delta Somatostatin Very high
PPoma PP cells Pancreatic polypeptide Very high
1313
Relative frequency: Asymptomatic >Insulinoma > Gastrinoma > Glucagonoma > VIPomas > Somatostatinoma > Others
Tumors without secretory symptoms are not associated with a Tumors without secretory symptoms are not associated with a hormonal syndromehormonal syndrome
Often found incidentallyOften found incidentally Patients present late with large malignancies or advanced diseasePatients present late with large malignancies or advanced disease
Symptoms due to tumor growth or spreadSymptoms due to tumor growth or spread Abdominal painAbdominal pain JaundiceJaundice DiarrheaDiarrhea IndigestionIndigestion Weight lossWeight loss
1414
Pancreatic NETsPancreatic NETsClinical Presentation—Asymptomatic pNETsClinical Presentation—Asymptomatic pNETs
Natural History of Neuroendocrine Natural History of Neuroendocrine TumoursTumours
15Vinik A, et al. Pancreas. 2009 Nov;38(8):876-89
11 22 33 44 55 66 77 88 99
Time, yearsTime, years
Primary tumour growthPrimary tumour growthPrimary tumour growthPrimary tumour growth
MetastasesMetastasesMetastasesMetastases
FlushingFlushingFlushingFlushing
DiarrheaDiarrheaDiarrheaDiarrhea
DeathDeathDeathDeath
Vague abdominal symptomsVague abdominal symptomsVague abdominal symptomsVague abdominal symptoms
Estimated time to diagnosis: 5 to 7 yearsEstimated time to diagnosis: 5 to 7 yearsEstimated time to diagnosis: 5 to 7 yearsEstimated time to diagnosis: 5 to 7 years
**
**
**Symptoms of carcinoid syndrome
Nonspecific Symptoms Are CommonNonspecific Symptoms Are Commonto Multiple Diagnosesto Multiple Diagnoses
Menopause
Irritable Bowel Syndrome
Functional Bowel Disease
Anxiety
Neurosis
Food Allergy
Asthma
Alcoholism
Thyrotoxicosis
Peptic Ulcer
NET
SymptomsSymptoms
• • Sweating • FlushingSweating • Flushing• • DiarrheaDiarrhea
• • Intermittent abdominal painIntermittent abdominal pain•• Hypoglycemia Hypoglycemia •• Confusion Confusion
• • BronchoconstrictionBronchoconstriction• • Dyspepsia •Dyspepsia • GI bleedingGI bleeding
• • Cardiac diseaseCardiac disease
16Aggarwal G, et al. Cleve Clin J Med. 2008;75(12):849-855.
Incidence of NET is increasing Incidence of NET is increasing More prevalent than other cancers (ie, stomach, pancreas, More prevalent than other cancers (ie, stomach, pancreas,
esophagus)esophagus)
Associations between these symptoms suggest the Associations between these symptoms suggest the presence of NET over more common ailmentspresence of NET over more common ailments
Flushing with NET is unrelated to time or day, warmth, or Flushing with NET is unrelated to time or day, warmth, or perspirationperspiration
Hormone production differs from menopause, which is a typical Hormone production differs from menopause, which is a typical misdiagnosismisdiagnosis
Elevated chromogranin A (CgA) is the generally accepted Elevated chromogranin A (CgA) is the generally accepted marker for NETmarker for NET
80% to 100% of NET, regardless of symptoms, secrete CgA80% to 100% of NET, regardless of symptoms, secrete CgA
1717
Importance of Raising the Index of Importance of Raising the Index of SuspicionSuspicion
Peracchi M, et al. Eur J Endocrinol. 2003;148(1):39-43.
History and physical examHistory and physical exam
Biochemical markers (serum, tissue, urine)Biochemical markers (serum, tissue, urine)11
SerumSerum TissueTissue Urinary Urinary
ImagingImaging22
Computed tomography scan (CT)/ Magnetic Computed tomography scan (CT)/ Magnetic Resonance Imaging (MRI)Resonance Imaging (MRI)
Nuclear Imaging Nuclear Imaging Endoscopic ultrasound (pNET only)Endoscopic ultrasound (pNET only)
1818
Systematic Approach to Systematic Approach to Diagnosing NET Is NeededDiagnosing NET Is Needed
1. Ferolla P, et al. J Endocrinol Invest. 2008;31(3):277-286.2. Barakat MT, et al. Endocr Rel Cancer. 2004;11(1):1-18.
Treatment Treatment
2020
Depending on the results obtained from a workup, a patient’s Depending on the results obtained from a workup, a patient’s NET is classified as local, regional, or advanced.NET is classified as local, regional, or advanced.
Treatment goals should be curative where possible, with the use Treatment goals should be curative where possible, with the use of pharmacological management as necessary.of pharmacological management as necessary.
General Treatment Goals:General Treatment Goals:
Local Regional NETLocal Regional NETThe treatment goal for localized NETs is curative, which The treatment goal for localized NETs is curative, which
is most often accomplished with surgery.is most often accomplished with surgery.
Advanced NETAdvanced NETThe treatment goal for metastatic tumors is also curative The treatment goal for metastatic tumors is also curative
surgery if possible, followed by pharmacological treatment.surgery if possible, followed by pharmacological treatment.
General NET Treatment GoalsGeneral NET Treatment Goals
Therapeutic Options for Advanced Therapeutic Options for Advanced Neuroendocrine Tumours (NETs)Neuroendocrine Tumours (NETs)
SurgerySurgery Curative (rarely), ablative (very often)Curative (rarely), ablative (very often)
DebulkingDebulking Radiofrequency ablation Radiofrequency ablation Embolization / chemoembolization / radioembolization (SpherexEmbolization / chemoembolization / radioembolization (Spherex®®))
Medical therapyMedical therapy ChemotherapyChemotherapy Biological targeted agentBiological targeted agent
Somatostatin analogs IFN-Somatostatin analogs IFN-αα Targeted molecular therapy Targeted molecular therapy
VEGF-R inhibitorsVEGF-R inhibitors
mTOR inhibitorsmTOR inhibitors
Other TKIsOther TKIs
IrradiationIrradiation External (bone, brain metastases)External (bone, brain metastases) Tumour-targeted, radioactive therapy Tumour-targeted, radioactive therapy ((9090Y- DOTATOC, Y- DOTATOC, 177177Lu- DOTATATE)Lu- DOTATATE)
Somatostatin analoguesSomatostatin analogues
Interferon-alfaInterferon-alfa
Chemotherapy Chemotherapy
Peptide receptor–targeted therapyPeptide receptor–targeted therapy
Molecular-targeted therapiesMolecular-targeted therapies
2424
Current Systemic Treatment Options for Current Systemic Treatment Options for Patients With Advanced NETs Patients With Advanced NETs
Several types:Several types: Somatostatin analoguesSomatostatin analogues
Currently approved for the relief of certain symptoms associated with symptomatic Currently approved for the relief of certain symptoms associated with symptomatic (functional) (functional) GI NETs and pNETsGI NETs and pNETs
Cytotoxic therapyCytotoxic therapyGI and Lung NETs: An option when no other options are feasible because of the poor GI and Lung NETs: An option when no other options are feasible because of the poor efficacy and toxicity. Single-agent and combination therapies with doxorubicin, 5-FU, efficacy and toxicity. Single-agent and combination therapies with doxorubicin, 5-FU, dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and dacarbazine, actinomycin-D, cisplatin, alkylating agents, etoposide, streptozotocin, and carboplatin have resulted in response rates from 20-50%.carboplatin have resulted in response rates from 20-50%.pNETs: Systemic chemotherapy is recommended for patients with unresectable liver or pNETs: Systemic chemotherapy is recommended for patients with unresectable liver or lung metastases. Trials using doxorubicin, streptozocin, 5-FU, temozolomide, and lung metastases. Trials using doxorubicin, streptozocin, 5-FU, temozolomide, and dacarbazine have established cytotoxic effects in pNETs.dacarbazine have established cytotoxic effects in pNETs.
Biological TreatmentBiological TreatmentInterferonInterferonHormone-like proteins normally made by white blood cells to help the immune system Hormone-like proteins normally made by white blood cells to help the immune system fight infectionsfight infectionsSometimes helpful in shrinking or slowing growth of advanced NETs and improving Sometimes helpful in shrinking or slowing growth of advanced NETs and improving symptoms of symptoms of carcinoid syndromecarcinoid syndrome
Pharmacological Treatment of NETPharmacological Treatment of NET
Several types:Several types:
Targeted TherapiesTargeted TherapiesDesigned to attack some specific aspect of cancer cellsDesigned to attack some specific aspect of cancer cellsA number of investigational therapies have shown preliminary A number of investigational therapies have shown preliminary evidence of activity in patients with advanced NETsevidence of activity in patients with advanced NETsTargeted Therapies:Targeted Therapies:
mTOR InhibitorsmTOR Inhibitorseverolimus (AFINITOR)everolimus (AFINITOR)
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitorssunitinib, sorafenibsunitinib, sorafenib
VEGF InhibitorsVEGF Inhibitorsbevacizumabbevacizumab
Other AgentsOther AgentsPasireotide, a multiligand somatstatin analogue, is currently in phase Pasireotide, a multiligand somatstatin analogue, is currently in phase III development for NETIII development for NET
Pharmacological Treatment of NET (Continued)Pharmacological Treatment of NET (Continued)
Somatostatin (SST) Somatostatin (SST) receptors are highly receptors are highly expressed on the expressed on the surface of GI NETssurface of GI NETs
More than 80% of all More than 80% of all NETs express SST NETs express SST receptorsreceptors
Overexpression Overexpression provides provides basis for regulation by basis for regulation by SSTSST
SST receptor activation SST receptor activation inhibits secretory and inhibits secretory and proliferative activityproliferative activity
2727
PathophysiologyPathophysiologySignificance of Somatostatin SignalingSignificance of Somatostatin Signaling
Octreotide May Have a Direct Octreotide May Have a Direct Antitumour Effect via sstAntitumour Effect via sst22 and sst and sst5 5
sst5
↑ Apoptosis ↓ Cell growth
PI3K
PDK1
Akt
GSK3β
p53
↑Zac1
mTOR
p70S6K
sst2
JNK
G protein
SHP1
NF-KB
sst2
G protein
G protein
SHP1
SHP2
Src
PTPŋ
MAPK
p27
cGMP↓
PKG↓
• sst2 and sst5 both downregulate MAPK
• sst2 binding effects the P13K/Akt/mTOR pathway and SHP1 signalling
• Antiproliferative effect also mediated via protein tyrosine phosphatase (PTPase) modulation
Florio T et al. Front Biosci 2008;13:822–840Grozinsky-Glasberg S et al. Neuroendocrinology 2008;87:168–181Theodoropoulou M et al. Cancer Res 2006;66:1576–1582
Alterations in the mTOR pathway result in the development of some Alterations in the mTOR pathway result in the development of some NETsNETs
2929
PathophysiologyPathophysiologySignificance of the mTOR PathwaySignificance of the mTOR Pathway
mTOR is a central regulator of mTOR is a central regulator of growth, proliferation, metabolism, growth, proliferation, metabolism, and angiogenesisand angiogenesis1-31-3
NET have been linked to genetic NET have been linked to genetic alterations that activate the alterations that activate the mTOR pathwaymTOR pathway2,32,3
Everolimus inhibits mTOREverolimus inhibits mTOR33
Octreotide downregulates IGF-1, Octreotide downregulates IGF-1, an upstream activator of the an upstream activator of the PI3K/AKT/mTOR pathwayPI3K/AKT/mTOR pathway44
Everolimus + octreotide LAR has Everolimus + octreotide LAR has shown activity in a phase II trialshown activity in a phase II trial55
Rationale for Combining Everolimus and Rationale for Combining Everolimus and Octreotide LAROctreotide LAR
1. O’Reilly T, McSheehy PM. Transl Oncol. 2010;3(2):65-79. 2. Meric-Bernstam F, Gonzalez-Angulo AM. J Clin Oncol. 2009;27:2278-2287. 3. Faivre S, Kroemer G, Raymond E. Nat Rev Drug Disc. 2006;5:671-688. 4. Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742. 5. Yao JC, Phan AT, Chang DZ, et al. J Clin Oncol. 2008;26:4311-4318.
Growth andproliferation
PI3K
IGF-1RIGF-1RIGF-1RIGF-1R
IGF-1IGF-1IGF-1IGF-1
mTORinhibitor
IGF-1RIGF-1RIGF-1RIGF-1R
IGF-1IGF-1IGF-1IGF-1
VEGFVEGFVEGFVEGF
VEGFRVEGFRVEGFRVEGFR
mTOR
Angiogenesis
Survival
Metabolism
HIF1
a
VHL
TSC1/2
PTEN
NF1
AKT
XX XX XXXX
signaling
Caspase 8p53Bax
Caspase 8p53Bax
secretionligands
SHP1
MAPK
cGMP
sstr1-5sstr1-5sstr1-5sstr1-5
cAMP
sst analogsst analogsst analogsst analog
NFcbNFcb
CaCa2·2·
KK++KK++
Phase III randomized, double-blind, placebo-controlled studyPhase III randomized, double-blind, placebo-controlled study
Primary endpoint: Time to tumour progression (blinded central review)Primary endpoint: Time to tumour progression (blinded central review)
Secondary endpoints: objective response rate, survival, quality of life, safetySecondary endpoints: objective response rate, survival, quality of life, safety
PROMID: Evaluation of the PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR Antiproliferative Effect of Octreotide LAR
30 mg30 mg
Patients with midgut NETs
• Treatment naïve• Histologically confirmed • Locally inoperable
or metastatic• Well differentiated• Measurable (CT/MRI)• Functioning or non-
functioning
Octreotide LAR 30 mg im
every 28 days
Placebo im every 28 days
RA
ND
OM
IZA
TIO
N (
1:1)
Treatment until CT/MRI documented
tumour progression
or death
Month 3 6 9 12 15 18
Rinke A et al. J Clin Oncol 2009;27:4656–4663
Patient DemographicsPatient DemographicsOctreotide LAR
30 mg (n=42)Placebo(n=43)
Total(n=85)
Median age, years (range) 63.5 (38–79) 61.0 (39–82) 62.0 (38–82)
Sex male (%)
female (%)
47.6
52.4
53.5
46.5
50.6
49.4
Time since diagnosis, months (range) 7.5 (0.8–271.2) 3.3 (0.8–109.4) 4.3 (0.8–271.2)
Karnofsky score ≤80 (%) >80 (%)
16.7
83.3
11.6
88.4
14.1
85.9
Carcinoid syndrome* (%) 40.5 37.2 38.8
Resection of primary (%) 69.1 62.8 65.9
Hepatic tumour load0%0–10%10–25%25–50%50%
16.759.57.1
11.94.8
11.662.84.79.3
11.6
14.161.25.9
10.68.2
Octreoscan positive (%) 76.2 72.1 74.1
Ki-67 up to 2% (%) 97.6 93.0 95.3
CgA elevated (%) 61.9 69.8 65.9
* not requiring octreotide for symptom control
Rinke A, Müller HH, Schade-Brittinger C, et al. J Clin Oncol. 2009;27:4656-4663.
PROMID PROMID
Octreotide LAR 30 mg Extends TTP in Patients with Functioning and Non-functioning Tumours
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 900
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Based on the per protocol analysis
P=0.0008; HR=0.25 [95% CI: 0.10–0.59]
Pro
po
rtio
n w
ith
ou
t p
rog
res
sio
n
P=0.0007; HR=0.23 [95% CI: 0.09–0.57]
Pro
po
rtio
n w
ith
ou
t p
rog
res
sio
n
Patients with non-functioning tumours Patients with functioning tumours
Time (months)Time (months)
Octreotide LAR 30 mg: 17 pts / 11 events
Median TTP 14.26 months
Placebo: 16 patients / 14 events
Median TTP 5.45 months
Octreotide LAR 30 mg: 25 pts / 9 events
Median TTP 28.8 months
Placebo: 27 patients / 24 events
Median TTP 5.91 months
Arnold R. Abst #4508 presented at ASCO 2009, Orlando FLRinke A et al. J Clin Oncol 2009;27:4656–4663
Phase III Randomized Trial of Everolimus Phase III Randomized Trial of Everolimus (RAD001) vs Placebo in Advanced (RAD001) vs Placebo in Advanced
Pancreatic NETPancreatic NET (RADIANT-3) (RADIANT-3)
James YaoJames Yao11, Manisha Shah, Manisha Shah22, Tetsuhide Ito, Tetsuhide Ito33, , Catherine Lombard-Bohas Catherine Lombard-Bohas44, Edward , Edward
WolinWolin55, , Eric Van CutsemEric Van Cutsem66, David Lebwohl, David Lebwohl77, Sakina , Sakina HoosenHoosen77, Carolin Sachs, Carolin Sachs88, Jeremie Lincy, Jeremie Lincy88, ,
Timothy HobdayTimothy Hobday99 and Kjell Öberg and Kjell Öberg1010 for the RADIANT-3 study groupfor the RADIANT-3 study group
RADIANT-3 Study DesignRADIANT-3 Study Design
Everolimus 10 mg/d +best supportive care*
n = 207
Placebo +best supportive care*
n = 203
Multi-phasic CT or MRI performed every 12 weeks
Treatment until disease progression
Patients with advanced pNET, N = 410
Stratified by:•WHO PS•Prior Chemotherapy
Crossover
1:1
* Concurrent somatostatin analogs allowed
RANDOMIZE
Primary endpoint: • PFS (RECIST)
Secondary endpoints: • Response, OS, biomarkers, safety, and PK
Randomization August 2007 - May 2009
Phase III Double Blind Placebo Controlled Trial
Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
PFS by Central Review* PFS by Central Review*
* Independent adjudicated central review committee• P-value obtained from stratified one-sided log rank test• Hazard ratio is obtained from stratified unadjusted Cox model
Kaplan-Meier medians PFSEverolimus: 11.4 monthsPlacebo: 5.4 months
Hazard ratio = 0.34; 95% CI [0.26-0.44]P-value: <0.0001
No. of patients still at riskEverolimusPlacebo
Per
cent
age
even
t-fr
ee
Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
Overall SurvivalOverall SurvivalEverolimus 10mg
N = 207Placebo N = 203
No. of events – n (%) 51 (24.6%) 50 (24.6%)
HR = 1.05; 95% CI [0.71-1.55]; P = 0.594
No. censored – n (%) 156 (75.4%) 153 (75.4%)
Kaplan-Meier estimates [95% CI] at:
3 months 97.1 [93.6-98.7] 98.5 [95.5-99.5]
6 months 93.1 [88.7-95.9] 91.6 [86.8-94.7]
12 months 82.3 [76.0-87.0] 82.6 [76.5-87.3]
18 months 73.1 [65.1-79.6] 73.9 [66.1-80.2]
24 months 57.3 [43.0-69.2] 62.8 [51.1-72.4]
148 placebo patients crossed over to receive everolimus
Hazard ratio is obtained from the unadjusted stratified Cox modelP-value is obtained from the stratified one-sided log rank test
Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9
Everolimus provided a 65% reduction in risk for progression compared to placebo Everolimus provided a 65% reduction in risk for progression compared to placebo (HR = 0.35, (HR = 0.35, P P < 0.0001)< 0.0001)
• Everolimus therapy resulted in a significant 6.4 month increase in median Everolimus therapy resulted in a significant 6.4 month increase in median PFS PFS
– 4.6 months to 11.0 months4.6 months to 11.0 months
• 18 months PFS rate of 34% vs 9% placebo demonstrates that everolimus 18 months PFS rate of 34% vs 9% placebo demonstrates that everolimus provides a durable benefitprovides a durable benefit
Disease control rate (CR+PR+SD) was 77.7% with a significant response Disease control rate (CR+PR+SD) was 77.7% with a significant response difference, difference, PP < 0.0001 < 0.0001
Everolimus showed a consistent benefit in all subgroupsEverolimus showed a consistent benefit in all subgroups
Everolimus has an acceptable safety profileEverolimus has an acceptable safety profile
SummarySummary
Investigator, algorithmic, and central analysis of PFS showed a median Investigator, algorithmic, and central analysis of PFS showed a median difference in PFS of 5.9 to 7.2 months (HR, 0.32-0.42) favoring sunitinibdifference in PFS of 5.9 to 7.2 months (HR, 0.32-0.42) favoring sunitinib
The increase in PFS was not statistically significantThe increase in PFS was not statistically significant Though there is evidence of a clinically meaningful benefit, the magnitude of this Though there is evidence of a clinically meaningful benefit, the magnitude of this
benefit remains unclear due to the study being terminated earlybenefit remains unclear due to the study being terminated early These PFS results may be an overestimate because of early looks at the data and These PFS results may be an overestimate because of early looks at the data and
premature study terminationpremature study termination
The FDA did an additional analysis, and found a median PFS of 10.2 months The FDA did an additional analysis, and found a median PFS of 10.2 months for sunitinib and 5.4 months for placebo; these data were used in the Sutent for sunitinib and 5.4 months for placebo; these data were used in the Sutent prescribing informationprescribing information
There was no statistically significant improvement in OS There was no statistically significant improvement in OS (43% event rate; 69% crossover)(43% event rate; 69% crossover)
There was an increased risk for serious AEs associated with sunitinib, There was an increased risk for serious AEs associated with sunitinib, including 2 deaths from cardiac failureincluding 2 deaths from cardiac failure
Median exposure to treatment and follow up were 4.6 months and 10.2 Median exposure to treatment and follow up were 4.6 months and 10.2 months in the sunitinib arm and 3.7 months and 5.4 months in the placebo months in the sunitinib arm and 3.7 months and 5.4 months in the placebo armarm
4040
Sunitinib Phase III Trial: Sunitinib Phase III Trial: SummarySummary
The sunitinib trial and RADIANT-3 are both phase III, The sunitinib trial and RADIANT-3 are both phase III, randomized, double-blind studies that assessed the randomized, double-blind studies that assessed the effects of treatment on PFS in patients with advanced effects of treatment on PFS in patients with advanced pNETpNET
However, the trials differ substantially in design, patient However, the trials differ substantially in design, patient population, and study conduct and, therefore, can not be population, and study conduct and, therefore, can not be directly compareddirectly compared
4242
SummarySummary
THANK YOUTHANK YOU