selection of appropriate treatment · the increasing incidence of nets yao jc, et al. j clin oncol....
TRANSCRIPT
Expert Review in Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs):
Selection of Appropriate Treatment
Reference Slide Deck
Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies
• Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body1
• NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms2,3
– Gastroenteropancreatic neuroendocrine tumors (GEP-NETs)3
– Islet cell tumors2
– Typical/atypical/poorly differentiated lung carcinoid2
– Small cell carcinoma of the lung2,3
– Pheochromocytoma/paraganglioma2,3
– Medullary thyroid carcinoma
– Merkel cell carcinoma2,3
– Kidney, bladder, breast, prostate, thymus…
1. Caplin ME, et al. Lancet. 1998;352(9130):799-805. 2. NCCN Clinical Practice Guidelines in Oncology™: Neuroendocrine Tumors V2.2016.
Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed November 11, 2016. 3. Modlin IM, et al.
Gastroenterology. 2005;128(6):1717-1751.
The Increasing Incidence of NETs
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
Lung and bronchus
Small intestine
Rectum
Stomach
Pancreas
Appendix
Colon
Cecum
Year
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003
Inc
ide
nc
e p
er
10
0 0
00
• Annual age-adjusted incidence of NETs in the US population by anatomic location
The Gastrointestinal Tract (GI) Is the Most Common Primary Location of NET (US SEER Data)
58%15%
27%Digestivesystem
Lung
Other/unknown
Percent distribution (%)
17.2 Rectum
13.4 Jejunum/ileum
6.4 Pancreas
6.0 Stomach
4.0 Colon
3.8 Duodenum
3.2 Cecum
3.0 Appendix
0.8 Liver
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
NETs Are the Second Most Prevalent Type of GI Malignancy
1. National Cancer Institute: SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/archive/csr/1975_2004/.
Accessed: September 8, 2016. 2. Modlin IM, et al. Cancer. 2003;97(4):934-959.
Colorectal1 Stomach1 Pancreas1 Esophagus1 Hepatobiliary1GEP-NET2
100,000
Prevalence in SEER Database
1,100,000
1,200,000
0
2 times more prevalent than pancreatic cancer
Neuroendocrine Tumors (NETs) Are Heterogeneous With a Wide Spectrum of Characteristics
Öberg KE, et al. Cancer Metastasis Rev. 2011;30 Suppl 1:3-7.
Localized
Metastatic
Symptomatic
Asymptomatic
Indolent Aggressive
Functioning
Nonfunctioning
Well-differentiated
Poorly differentiated
NET
NETs Are Often Advanced at the Time of Diagnosis
0,4
2,75
9,25
18,5
0 5 10 15 20
Local
Regional
Metastatic
Poorly differentiatedmetastatic
Median Survival, Years
Well and moderately
differentiated
18.5
9.25
2.75
0.4
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. Soga J. Cancer. 2005;104(6):1180-1187. Alexiev BA, et al. Diagn
Pathol. 2007;2:28. Modlin IM, et al. Lancet. 2008;9(1):61-72.
Carcinoids M1 at Dx SV 5 and M1
Small intestine 70% 55%
Colon 71% 20%
Appendix 10% 34%
Rectum 15% 30%
Pancreatic NETs 50%-60% 30%-50%
Correlation of Primary Tumor Site With Survival
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
Known prognostic factors include:
• Location of primary tumor
• Extent of disease
• Tumor stage
• Degree of differentiation/
proliferative index
• Tumor grade
• Patient age
• Performance status
65% of patients with advanced NETs will not be alive in 5 years
Distant metastases
1.0
0.8
0.6
0.4
0.2
Su
rviv
al P
rob
ab
ility
012 24 36 48 60 72 84 96 108 120
Time, months
ColonLungPancreasRectumSmall bowel
Prognostic Value of Ki67<2% 15% 75%
Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097.
Scarpa A, et al. Mod Pathol. 2010;23(6):824-833.Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798-7803.
Grade Mitotic Count (10 HPF)
Ki-67 Index (%)
G1 2 ≤2
G2 2-20 3-20
G3 20 20
Prognostic Value of Differentiation
Poorly differentiated histology
Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.
HistologyWell- and moderately-differentiated histology
High Complexity for NETs ClassificationDifferentiation Grade Mitotic Count Ki67 Index Traditional ENETS; WHO
Well differentiated
Low grade
(G1)
<2 per 10 high
power fields
(HPFs)
≤2% Carcinoid, islet
cell, pancreatic
(neuro)endocrine
tumor
Neuroendocrine
tumor; grade 1
Intermediate
grade (G2)
2-20 per 10
HPFs
3%-20% Carcinoid, islet
cell, pancreatic
(neuro)endocrine
tumor
Neuroendocrine
tumor; grade 2
Poorly
differentiated
High grade
(G3)>20 per 10 HPFs >20%
Small cell
carcinoma
Neuroendocrine
tumor; grade 3,
small cell
Large cell
neuroendocrine
carcinoma
Neuroendocrine
tumor; grade 3,
large cell
Well-Differentiated Poorly-Differentiated
Grade (ENETS) Low (G1) Intermediate (G2) High (G3)
Ki67 index (%) ≤2 3-20 >20
Anatomic imaging More rapid growth on serial imaging
Functional imaging Octreoscan SPECT
or SSTR PET-positive
FDG PET-positive
Prognosis Indolent (slowly growing) Aggressive
Bosman FT, eds. WHO Classification of Tumours of the Digestive System. 4th Ed. Lyon, France: The International Agency for
Research on Cancer; 2010. Rindi G, et al. Virchows Arch. 2006;449(4):395-401. Rindi G, et al. Virchows Arch. 2007;451(4)757-762.
Jensen RT, et al. Neuroendocrinology. 2006;84(3):173-182.
Integrating Grade and Tumor Burden
Treatment goals: Tumor control and QoL
Tumor Aggressiveness (eg, Ki67)
Tumor
Burden
High
Low
Moderate(up to Ki67 = 20%)
Low
Advanced, unresectable, well to moderately differentiated NETs:
Primary treatment goals
Tumor response/control &
QoLTumor response/control
Rapid Tumor
Response
QoL & tumor controlTumor control &
QoLTumor control/response
QoL & tumor
controlTumor control & QoL
Tumor control
& QoL
Syndromes With Nonspecific Symptoms Caused by Hormones and Peptides Secreted by
Functional NETs*
*There are many other hormones, syndromes, and symptoms that can be caused by NETs. These are some of the most common.
Modlin IM, et al. Lancet Oncol. 2008;9(1):61-72. Kaltsas GA, et al. Endocr Rev. 2004;25(3):458-511. Barakat MT, et al.
Endocr Relat Cancer. 2004;11(1):1-18.
NET Location
Hormone
/peptide
Associated
syndrome
GastrinSerotonin InsulinVasoactive
intestinal peptideGlucagon
Carcinoid
syndrome
Zollinger-Ellison
syndrome
Hypoglycemia
syndrome
Verner-Morrison
syndrome
Diarrhea
Flushing
Cramping Rash
Glucose intolerance /
diabetes
Weight
lossWheezing
Ulcers
Weight
gain
Insulin
resistance
Hypo-
glycemia
Small bowel Pancreas
Carcinoid Syndrome
CNS, central nervous system; PCPA, parachlorophenylalanine
1. Kulke MH, et al. N Engl J Med. 1999;340(11):858-868. 2. Rubin J, et al. J Clin Oncol. 1999;17(2):600-606. 3. Strosberg,
et al. Gastrointest Cancer Res. 2013;6(3):81-85. 4. Engelman K, et al. N Engl J Med. 1967;277(21):1103-1108.
• Tumoral release of serotonin and other vasoactive substances into the systemic circulation causes carcinoid syndrome1
• Treatment with somatostatin analogs (SSAs) is associated with improved symptom control, but patients may not maintain adequate control of symptoms2,3
• Inhibition of serotonin synthesis with PCPA was previously shown to provide symptom control, but its utility was limited by CNS side effects4
Urinary 5-Hydroxyindoleacetic Acid (5-HIAA)
• Measured in a 24-hour urine
specimen
• Arises in the setting of hepatic
metastases or due to direct drainage
into systemic circulation
• Severity of carcinoid syndrome may
correlate with urinary 5-HIAA levels
• High levels have prognostic value
and are associated with:
- Reduced survival
- Progressive carcinoid heart
disease
Kocha W, et al. Curr Oncol. 2010;17(3):49-64. Feldman JM, et al. Clin Chem. 1986;32(5):840-844. Formica V, et al. Br J
Cancer. 2007;96(8):1178-1182. de Herder WW. Best Pract Res Clin Endocrinol Metab. 2007;212(1):33-41. Strosberg JR,
et al. Clincal features of the carcinoid syndrome. Available at: www.uptodate.com. Last update: July 2015.
When to Treat?Factors to Consider in Nonfunctioning GI NETs
Tumor factors to consider
• Signs and symptoms
– Pain, weight loss, etc
• Tumor volume
– What is the risk if tumor
grows?
• Tumor aggressiveness
– Growth rate, Ki 67, marker
levels
Treatment factors
• Short-term risks, long-term risks
• Reversibility of AEs
• Patient
– Functional status, organ
function
– Preferences
Risk from treatment
Risk from tumor
progression
MIBG, meta-iodobenzylguanidine; mTOR, mammalian target of rapamycin; PRRT, peptide-receptor radiotherapy; TKI,
tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor
Salazar R, et al. Neuroendocrinology. 2012;95(2):71-73. National Comprehensive Cancer Network. NCCN Clinical Practice
Guidelines in Oncology (NCCN® Guidelines): Neuroendocrine tumors. v2.2016. Available at:
https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed October 7, 2016.
Surgery Debulking / Locoregional Therapy
• Resection of primary tumor
• Cytoreductive surgery of unresectable
tumor
• Curative (rarely), ablative (very often)
• Radiofrequency ablation (RFA)
• Embolization / chemoembolization /
radioembolization
Medical Therapy Nuclear Medicine and Irradiation
• Somatostatin analogs (SSAs)
• Interferon-α
• Targeted therapies
– mTOR inhibitors
– VEGFR inhibitors
– Other TKIs
• Chemotherapy
• Tumor-targeted, radioactive therapy:
PRRT using, eg
– MIBG
– 90Y-DOTATOC
– 177Lu –DOTATATE
• External irradiation (for bone, brain-
metastases)
• Brachytherapy (for liver metastases)
Treatment Options for NETs
Factors Influencing the Therapeutic Decision in NETs
Type of NET
(pancreatic vs GI)
TNM stage and grade
(G1/G2 vs G3)
ResectabilityFunctioning vs non-
functioning tumor
Patient performance status
and comorbidities
Availability of different
therapeutic modalities
Patient preference and
convenience
Uptake on somatostatin
receptor scintigraphy
ENETS Guidelines for 1st-Line Treatment
Drug Functionality Grading Primary Site SSTR
status
Special Considerations
Octreotide +/- G1 Midgut + Low tumor burden
Lanreotide +/- G1/G2 (~10%) Midgut, pancreas + Low and high (>25%) liver tumor
burden
IFN-alpha 2b +/- G1/G2 Midgut If SSTR negative
STZ/5-FU +/- G1/G2 Pancreas Progressive in short-term* or high tumor
burden or symptomatic; if STZ is
contraindicated or not available
TEM/CAP +/- G2 Pancreas Atypical carcinoid and/or SSTR
negative
Everolimus +/- G1/G2 Lung Insulinoma or contraindication for CTX
Pancreas Insulinoma or contraindication for CTX
Midgut If SSTR negative
Sunitinib +/- G1/G2 Pancreas Contraindication for CTX
PRRT +/- G1/G2 Midgut +
(required)
Extended disease; extrahepatic
disease, eg, bone metastasis
Cisplatin†/
etoposide
+/- G3 Any All poorly differentiated NEC
Pavel M, et al. Neuroendocrinology. 2016;103(2):172-185.
* ≤6-12 months; †Cisplatin can be replaced by carboplatin
AC, atypical carcinoid; AJCC; American Joint Committee on Cancer; CS, carcinoid syndrome; ENETS, European Neuroendocrine Tumor Society; ESMO; European
Society for Medical Oncology; EVE, everolimus; GEP, gastroenteropancreatic; GI NETs, gastrointestinal neuroendocrine tumors; LAN, lanreotide; LAR, long-acting
repeatable; m, metastatic; NANETS, North American Neuroendocrine Tumor Society; NEC, neuroendocrine carcinomas; NET, neuroendocrine tumors; NF,
nonfunctional; OCT, octreotide; pNET, pancreatic NET; SC, subcutaneous; STZ, streptozotocin; TC, typical carcinoid; UICC, Union for International Cancer Control;
WHO, World Health Organization
CLARINETLAN GEP
NET16,17,29
2014/15
1980 2000 2005
STZ combination:
Survival benefit pNET2
1992
1900
RADIANT-4EVE NF GI and
lung NET15,19
2015/16
TELESTARtelotristat etiprate
CS20
NDA filed 3/30/16
NETTER-1177Lu-Dotatate
midgut NET18RADIANT-2
EVE + OCT, LAR in mNET w/CS14
2010/11
Sunitinib phase IIIpNET13,31,34
2015
PROMIDOCT LAR:
Antitumor
activity9,31
2009
LANsymptom
control24
1998
OCT LARcarcinoid
tumors23,26,28
US
approva
l
US/EU
approva
l
EU
approva
l
Tre
atm
en
ts
ELECTLAN:
Symptom
control27
2010
OCT
SCCS 25,30
1988/89
RADIANT-3EVE in pNET 11,12,32,33
2015
STZ pNET36
1982
New Options in NETs Treatment
Somatostatin Analogs
1. Susini C, et al. Ann Oncol. 2006;17(12):1733-1742. 2. Öberg KE, et al. Gastroenterology. 2010;139(3):742-753.
Overview
• Synthetic derivatives of somatostatin1
• Bind to somatostatin receptors
(SSTRs)1
• Similar to endogenous somatostatins
but with1:
– Increased affinity for specific SSTRs
– Longer half-life and greater stability
– Longer duration of action in the
body
• Have different SSTR affinity profiles2
– Octreotide and lanreotide have high
affinity for SSTR2 and lower
affinities for SSTR3 and SSTR5
– Pasireotide has high affinity for
SSTR1-3, and SSTR5
SSTR1
SSTR2
SSTR3
SSTR4
SSTR5
Octreotide
and
Lanreotide2 Pasireotide2
PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR 30 mg
• Primary endpoint: Time to tumor progression (blinded central review)
• Secondary endpoints: Objective response rate, survival, quality of life, safety
Patients with midgut NETs
• Treatment naïve
• Histologically confirmed
• Locally inoperable or
metastatic
• Well differentiated
• Measurable (CT/MRI)
• Functioning or
nonfunctioning
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
tumor
progression or
death
Month 3 6 9 12 15 18
CT, computed tomography; IM, intramuscular; MRI, magnetic resonance imaging
Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.
Phase III randomized, double-blind, placebo-controlled study
Tumor Control in NET: Octreotide LAR Significantly Prolongs TTP
Octreotide LAR 30 mg: 42 patients/26 events
Median TTP = 14.3 months (95% CI 11.0-28.8)
Placebo: 43 patients/40 events
Median TTP = 6.0 months (95% CI 3.7-9.4)
Time, Months
Pro
po
rtio
n o
f P
ati
en
ts
Wit
ho
ut
Pro
gre
ss
ion
0
0.25
0.50
0.75
1.00
0 6 12 18 24 30 36 42 48 54 60 66 72 78
66% reduction in the risk of tumor progression
HR = 0.34; 95% CI: 0.20-0.59; P = .000072
PROMID: Well-differentiated midgut NET
HR, hazard ratio; TTP, time to progression
Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.
Octreotide LAR 30 mg Achieved Superior Tumor Response at 6 Months (WHO)
Octreotide
LAR 30 mg (n = 42)
Placebo
(n = 43)
Complete response, n 0 0
Partial response, n 1 1
Stable disease, n 28 16
Progressive disease, n 10 23
Unknown, n 3 3
Wilcoxon-Mann-Whitney test: P = .0079
WHO, World Health Organization
Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.
Octeotride LAR: Safety Profile• No treatment-related deaths
• Serious AEs (SAEs) were observed in 11 octreotide LAR–treated and 10 placebo-treated patients
• Most common SAEs affected
- GI tract (octreotide LAR, n = 6; placebo, n = 8)
- Hematopoietic system (octreotide LAR, n = 5; placebo, n = 1)
- General health status (fatigue and fever; octreotide LAR, n = 8; placebo, n = 2)
• Treatment discontinuation due to AEs occurred 5 octreotide LAR recipients and no placebo recipients
• WHO grade 2-4 adverse events were observed more often in the octreotide LAR arm and included diarrhea and flatulence
• Bile stones were recorded six times (octreotide LAR recipients n = 5)
Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.
CLARINET: Study Design
PFS, progression-free survival
Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.
Study design:
• Phase III, 96-week, randomized, double-blind, placebo-controlled, multicenter study (14 countries: United States, India, and 12 European countries)
• Primary endpoint: Progression-free survival, defined as time to disease progression or death
Population:
• N = 204 adults with well or moderately differentiated, progressing, metastatic, and/or locally advanced unresectable GEP NETs, and Ki67 <10%
Treatments:
• Lanreotide autogel 120 mg (fixed dose) vs placebo every 28 days
1:1
12-24 weeks
1 12 24 36 48 72 96
(baseline)Study Visits, Weeks
Scan 1 Scan 2
Lanreotide autogel SC 120 mg q28 days
Placebo SC q28 days
Primary Endpoint = PFS
Tumor Control in NETs: Lanreotide Autogel Significantly Prolongs PFS
Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.
Lanreotide Autogel 120 mg
32 events/101 patients
Median, not reached
Placebo
60 events/103 patients
Median, 18.0 months (95% CI 12.1-24.0)
53% reduction in the risk of tumor progression
HR = 0.47; 95% CI 0.30-0.73; P = .0002
0 3 6 9 12 18 24 27
0
10
20
30
40
50
60
70
80
90
100
Pa
tie
nts
Ali
ve
an
d W
ith
No
Pro
gre
ss
ion
, %
Time, Months
62%
22%
CLARINET: Well/moderately differentiated nonfunctioning GEP NET
PFS According to Subgroups
Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.
Event Lanreotide (n = 101) Placebo (n = 103)
Diarrhea 26 (26) 9 (9)
Abdominal pain 14 (14) 2 (2)
Cholelithiasis 10 (10) 3 (3)
Flatulence 8 (8) 5 (5)
Injection-site pain 7 (7) 3 (3)
Nausea 7 (7) 2 (2)
Vomiting 7 (7) 0
Headache 5 (5) 2 (2)
Lethargy 5 (5) 1 (1)
Hyperglycemia 5 (5) 0
Decreased level of pancreatic enzymes 5 (5) 0
Lanreotide Autogel: Safety ProfileStudy Treatment-Related Adverse Events in ≥5% of Patients
Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.
Trial (Prospective/
Retrospective)
Primary/
Number
Prior
SSA
? Intervention Symptoms DCR ORR
Biochemical
Response Toxicity
Anthony 1993 (P) NET (14) N Octreotide 500-2000 mcg tid
lanreotide 750-3000 mcg tid
N 46% 31% NA No major AE
di Bartolomeo
1996 (P)
SBNET/PN
ET (58)
N Octreotide 500 mcg tid (n =
23)
or 1000 mcg tid (n = 35)
Diarrhea improved
in 40%,
flushing in 50%
50% 3% 77% (u5HIAA) Gallstones (4%),
Steatorrhea (4%)
Filosso 2002 (P) Bronchial
NET (7)
N Octreotide 1500 mcg/d All improved 100% 42% 100% Nil
Eriksson 1997 (P) SBNET/PN
ET(19)
N Lanreotide 750 mcg qid to
3 mg qid
Flushing better
(P = .06)
NA NA 58% 4 ceased due to AE
(gallstone, diarrhea)
Faiss 1999 (P) Foregut
NET (30)
Y Lanreotide 5 mg tds Improved on the
whole
36% 6% Decreased
(CgA/u5HIAA)
Fatigue (30%), steatorrhea
(6%), cholelithiasis (3%)
Strosberg 2014 (R) Metastatic
NET (239)
Y Octreotide 40-133 mg/month 70% to 80%
reported
improvement in
flushing/diarrhea
NA NA NA NA
Welin 2004(P) Midgut
NET (12)
N Octreotide 160 mg/m2 weeks NA 75% 0% CgA 33%,
u5HIAA 16%
Gallstone (8%), fever (50%)
Al-Efraij 2014 (R) Metastatic
NET (27)
Y Octreotide 40-60 mg Diarrhea 62%,
flushing 76%,
palpitation 100%
29% 0% CgA 31%,
u5HIAA 23%
NA
Weber 2012 (R) Metastatic
NET (337)
Y Octreotide 40-60 mg Diarrhea 62%,
56% flushing
NA NA NA NA
Modica 2015 (R) Metastatic
NET (21)
Y Octreotide LAR (15),
lanreotide (6)
63% improved 53% 5% NA Abdominal discomfort (5%),
gallstones (5%), T2DM (5%)
Albertelli 2016 (P) Metastatic
NET (35)
Y Lanreotide ATG 180 mg NA NA NA NA 21% SAE
(cholelithiasis/cholecystitis)
Trials Investigating Somatostatin Analogs
Somatostatin Dose Escalation
• No official dose-finding studies have been
performed
• There may be a value in dose escalation in
indolent tumors
• Those with carcinoid syndrome may also
benefit from dose escalation
• The NETTER-1 trial included a double dose
octreotide (60 mg)
CLARINET FORTE Trial Design
Primary Endpoint: Median PFS
Secondary Endpoints: TTP, OS, ORR, DCR, best overall response, median duration
of SD, total number of stools and flushing episodes, change in QOL from baseline,
change in tumor biomarker concentrations from baseline
120 mg lanreotide
every 14 days
NETs grade 1 or 2,
metastatic or locally
advanced
unresectable
pancreatic or
intestinal
neuroendocrine tumor
progressing on
standard dose of
lanreotide
US National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02651987. Accessed November 1, 2016.
RADIANT-2 Study Design
Multiphasic CT or MRI performed every 12 weeks
Everolimus 10 mg/d +
Octreotide LAR 30 mg/28
days
n = 216
Placebo +
Octreotide LAR 30 mg/28
days
n = 213
Treatment
until
disease
progression
R
A
N
D
O
M
I
Z
E
Patients with
advanced NET
and a history of
symptoms
attributed to
carcinoid
syndrome,
N = 429
1:1
Crossover
Primary endpoint:• PFS (RECIST)
Secondary endpoints:• Tumor response, OS, biomarkers, safety, PK
Enrollment January 2007 - March 2008
Phase III, Double-Blind, Placebo-Controlled Trial
OS, overall survival; PK, pharmacokinetics
Pavel ME, et al. Lancet. 2011;378(9808):2005-2012.
RADIANT-2: PFS by Central Review*
Time, MonthsNo. of patients still at riskE + OP + O
216
213
202
202
167
155
129
117120
106
102
84
81
72
69
65
63
57
56
50
50
42
42
35
33
24
22
18
17
11
11
9
4
3
1
1
1
0
0
0
* Independent adjudicated central review committee
• P-value is obtained from the one-sided log rank test
• Hazard ratio is obtained from unadjusted Cox model
E + O = Everolimus + Octreotide LAR
P + O = Placebo + Octreotide LAR
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Perc
en
tag
e E
ven
t-F
ree
Kaplan-Meier median PFS
Everolimus + Octreotide LAR: 16.4 months
Placebo + Octreotide LAR: 11.3 months
Hazard ratio = 0.77; 95% CI [0.59 -1.00]
P value = .026
Total events = 223
Censoring times
E + O (n/N = 103/216)
P + O (n/N = 120/213)
Pavel ME, et al. Lancet. 2011;378(9808):2005-2012.
RADIANT-4: Study Design
*Two strata: Stratum A appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary
Stratum B lung, stomach, rectum, and colon except cecum
Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary
analysis.
Endpoints:
• Primary: PFS (central)
• Key Secondary: OS
• Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK
Everolimus 10 mg/day
N = 205Treated until
centrally
confirmed
PD or
intolerable
toxicity
Patients with advanced,
progressive, nonfunctional
NET of lung or GI origin
(N = 302)
• Absence of active
symptoms or any history of
carcinoid syndrome
• Pathologically confirmed
advanced disease
• Radiologic disease
progression in ≤6 months
2:1
R
A
N
D
O
M
I
Z
E
Placebo
N = 97
Stratified by:
• Prior SSA treatment (yes vs no)
• Tumor origin (stratum A vs B)*
• WHO PS (0 vs 1)
Yao JC, et al. Lancet. 2016;387(10022):968-977.
0 2 4 6 8 10 12 15 18 21 24 27 30
Months
0
10
20
30
40
50
60
70
80
90
100
Pro
ba
bil
ity o
f P
rog
res
sio
n-F
ree
Su
rviv
al
(%) Kaplan-Meier median PFS
Everolimus: 11.0 months (95% CI, 9.2-13.3)
Placebo: 3.9 months (95% CI, 3.6-7.4)
HR = 0.48 (95% CI, 0.35-0.67); P<.00001
Censoring times
Everolimus (n/N = 113/205)
Placebo (n/N = 65/97)
Yao JC, et al. Lancet. 2016;387(10022):968-977.
RADIANT-4: Everolimus for Advanced Neuroendocrine Tumors of the Lung or GI Tract:
Centrally Confirmed PFS
RADIANT-4: Everolimus for Advanced Neuroendocrine Tumors of the Lung or GI-Tract:
Investigator-Assessed PFS
P value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.
205 171 148 132 108 93 75 59 33 15 5 0
97 70 47 35 27 25 21 19 10 6 4 0Placebo
Everolimus
Months
0
10
20
30
40
50
60
70
80
90
100
Pro
ba
bil
ity o
f P
rog
res
sio
n-F
ree
Su
rviv
al,
%
No. of patients still at risk
Kaplan-Meier median PFS
Everolimus: 14.0 months (95% CI, 11.24-17.71)
Placebo: 5.5 months (95% CI, 3.71-7.39)
HR = 0.39 (95% CI, 0.28-0.54); P<.00001
Censoring times
Everolimus (n/N = 98/205)
Placebo (n/N = 70/97)
2 4 6 8 10 12 15 18 21 24 270 30
0
0
Yao JC, et al. Lancet. 2016;387(10022):968-977.
RADIANT-4: PFS HR by Stratification FactorsCentral Review
Hazard ratio obtained from unstratified Cox model.
SSA, somatostatin analogs; WHO PS, World Health Organization performance status
Prior SSA treatment
Yes
No
Tumor origin*
Midgut
Non midgut
WHO PS
0
1
157
145
153
149
216
86
Hazard Ratio (95% CI)No.Subgroups
0.52 (0.34-0.81)
0.60 (0.30-0.94)
0.63 (0.40-1.02)
0.43 (0.28-0.66)
0.58 (0.41-0.84)
0.50 (0.28-0.91)
0.1 0.4 1 10
Everolimus Better Placebo Better
*Based on prognostic level, grouped as:
Stratum A (better prognosis) - appendix,
cecum, jejunum, ileum, duodenum, and NET of
unknown primary)
Stratum B (worse prognosis) - lung, stomach,
rectum, and colon except cecum)
Yao JC, et al. Lancet. 2016;387(10022):968-977.
RADIANT-4: Activity in Less Favorable Subgroups
None
≤10%
>10%-25%
>25%
Hazard Ratio (95% CI)
Liver Tumor Burden
48
180
37
35
No.
0.49 (0.20-1.20)
0.67 (0.45-1.00)
0.62 (0.20-1.93)
0.18 (0.06-0.50)
0.1 0.4 1 10
Everolimus Better Placebo Better
Grade 1
Grade 2
194
107
0.57 (0.39-0.84)
0.49 (0.29-0.83)
Treatment naïve*
Yes
No
117
185
0.65 (0.39-1.08)
0.51 (0.35-0.76)
Prior chemotherapy
Yes
No
Baseline CgA
>2xULN
≤2xULN
77
225
139
138
0.35 (0.19-0.64)
0.60 (0.42-0.86)
0.40 (0.25-0.62)
0.70 (0.45-1.11)
Tumor grading
Yao JC, et al. Lancet. 2016;387(10022):968-977.
RADIANT-4: Adverse Events
Presented are drug-related adverse events in ≥15% of patients (safety set)
*Includes stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration†Includes all infections‡Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis
Everolimus
N = 202
Placebo
N = 98
Drug-related adverse events All grades Grade 3/4 All grades Grade 3/4
Stomatitis* 63% 9% 19% 0
Diarrhea 31% 7% 16% 2%
Fatigue 31% 3% 24% 1%
Infections† 29% 7% 4% 0
Rash 27% 1% 8% 0
Peripheral edema 26% 2% 4% 1%
Nausea 17% 1% 10% 0
Anemia 16% 4% 2% 1%
Decreased appetite 16% 1% 6% 0
Asthenia 16% 1% 5% 0
Noninfectious pneumonitis‡ 16% 1% 1% 0
Dysgeusia 15% 1% 4% 0
Yao JC, et al. Lancet. 2016;387(10022):968-977.
RADIANT-4 QoL: Time to Definitive Deterioration ≥7 Points on the FACT-G Total Score
Pavel M, et al. J Clin Oncol. 2016;34(suppl): Abstract e15657
Midgut NET: NETTER-1Phase III Study of 177Lu-Dotatate + Octreotide vs High-Dose
Octreotide
Strosberg J et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6.
Midgut NET
Octreoscan
positive
Progression
within 3
years
n = 115
Dose 1
n = 115
Treatment and assessments
Tumor burden assessment (RECIST criteria) every 12 weeks
5 years
of
follow-
up
Dose 2 Dose 3 Dose 4
4 administrations of 7.4 GBq of 177Lu-Dotatate
every 8 weeks + octreotide 30 mg
Octreotide LAR 60 mg every 4 weeks
N = 229 (ITT)
Number of events: 90 177Lu-Dotatate: 23
Octreotide 60 mg LAR: 67
NETTER-1: PFS
HR 0.209; 95% CI: 0.129-0.338
P<.0001
Octreotide LAR 60 mg
Median PFS: 8.4 months
177Lu-Dotatate
Median PFS: Not reached
0 5 10 15 20 25 30
1.0
0.8
0.6
0.4
0.2
0
Strosberg J et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6.
NETTER-1: Objective Response Rate
177-Lu-Dotatate
(n = 101)
Sandostatin LAR
60 mg (n = 100)
Complete response (n) 1 0
Partial response (n) 17 3
Objective response rate 18% 3%
Confidence interval (95%) 10%-25% 0%-6%
Statistical significance P = .0008
All patients (n = 116) (n = 113)
Progressive disease 5 (4%) 27 (24%)
Stable disease 77 (66%) 70 (62%)
Strosberg J et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6.
NETTER-1: Most Common Adverse Events177Lu-Dotatate + 30 mg OCT
LAR
(n = 111)
60 mg OCT LAR
(n = 110)
All Grades Grade 3-4 All Grades Grade 3-4
Nausea 59% 4% 12% 2%
Vomiting 47% 7% 10% 0%
Fatigue/asthenia 40% 2% 25% 2%
Diarrhea 29% 3% 19% 2%
Musculoskeletal pain 29% 2% 20% 1%
Abdominal pain 26% 3% 26% 5%
Thrombocytopenia 25% 2% 1% 0%
Lymphopenia 18% 9% 2% 0%
Decreased appetite 18% 0% 8% 3%
Strosberg JR, et al. J Clin Oncol. 2016;34(suppl 3): Abstract 194.
Sunitinib Phase III: PFS by Investigator Review
Median PFS
Sunitinib 11.4 months (95% CI 7.4, 19.8)
Placebo 5.5 months (95% CI 3.6, 7.4)
HR = 0.42 (95% CI 0.26, 0.66)
P<.001
86 39 19 4 0 0
85 28 7 2 1 0
Number at risk
Sunitinib
Placebo
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n o
f P
ati
en
ts
0 5 10 15 20 25Time, Months
Events
Sunitinib 30/86
Placebo 51/85
Raymond E, et al. N Engl J Med. 2011;364(6):501-513. Blumenthal GM, et al. Oncologist. 2012;17(8):1108-1113.
Phase III Trial: Sunitinib vs Placebo in pNET
Raymond E, et al. N Engl J Med. 2011;364:501-513.
Event Sunitinib (n = 83) Placebo (n = 82)
All grades Grade 1 or 2 Grade 3 or 4 All grades Grade 1 or 2 Grade 3 or 4
Number of patients (%)
Diarrhea 49 (59) 45 (54) 4 (5) 32 (39) 30 (37) 2 (2)
Nausea 37 (45) 36 (43) 1 (1) 24 (29) 23 (28) 1 (1)
Asthenia 28 (34) 24 (29) 4 (5) 22 (27) 19 (23) 3 (4)
Vomiting 28 (34) 28 (34) 0 25 (30) 23 (28) 2 (2)
Fatigue 27 (32) 23 (28) 4 (5) 22 (27) 15 (18) 7 (8)
Hair-color changes 24 (29) 23 (28) 1 (1) 1 (1) 1 (1) 0
Neutropenia 24 (29) 14 (17) 10 (12) 3 (4) 3 (4) 0
Abdominal pain 23 (28) 19 (23) 4 (5) 26 (32) 18 (22) 8 (10)
Hypertension 22 (26) 14 (17) 8 (10) 4 (5) 3 (4) 1 (1)
Palmar-plantar
erythrodysesthesia19 (23) 14 (17) 5 (6) 2 (2) 2 (2) 0
Anorexia 18 (22) 16 (19) 2 (2) 17 (21) 16 (20) 1 (1)
Stomatitis 18 (22) 15 (18) 3 (4) 2 (2) 2 (2) 0
TELESTAR: Phase III Study Design
*Including a blinded titration step of one week of 250 mg TID
BM, bowel movement; TID, three times daily
Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.
TELESTAR: Inclusion/Exclusion Criteria
Key Inclusion Criteria
• Well-differentiated metastatic NET
• Documented carcinoid syndrome with ≥4 BMs/day
• Currently receiving stable-dose (≥3 months) SSA therapy
• Minimum SSA dose:
Octreotide LAR 30 mg or lanreotide depot 120 mg, every 4 weeks
• Higher dose/frequency allowed
Key Exclusion Criteria
• >12 BMs/day
• Evidence of Clostridium difficile or other enteric infection
• Previous tumor-directed therapy (≤4 weeks prior to screening)
• History of short bowel syndrome
Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.
TELESTAR: Reduction in Daily BM Frequency Averaged Over Double-Blind Treatment Phase
Hodges-Lehman estimator of treatment differences estimated a reduction
versus placebo of
• -0.81 BMs daily for telotristat etiprate 250 mg dose (P<.001)
• -0.69 for telotristat etiprate 500 mg dose (P<.001)Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.
TELESTAR: Reduction in Mean Daily BM Frequency at Baseline and Week 12
All patients continue SSA therapy throughout study period. Data included only
patients for whom both baseline and week 12 assessments were available.
Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.
TELESTAR: Mean Absolute Change in Urinary 5-HIAA (mg/24 h) From Baseline to Week 12
All patients continue SSA therapy throughout study period. Data included only patients for whom both baseline and week 12 assessments were available.
• Wilcoxon rank-sum test showed significant differences for each telotristat etiprate dose vs placebo (P<.001)
Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.
TELESTAR: Adverse Events (AEs) of Interest
• Events of depression and nausea were mild or moderate and did not lead
to treatment discontinuation
Category, n (%)
Placeboa
(n = 45)
Telotristat
Etipratea
250 mg (n = 45)
Telotristat
Etipratea
50 mg (n = 45) Total
Nausea 5 (11.1) 6 (13.3) 13 (28.9) 24 (17.8)
Severe nausea 1 (2.2) 1 (2.2) 0 2 (1.5)
Discontinuation due to nausea 1 (2.2) 0 0 1 (0.7)
Depression 3 (6.7) 1 (2.2) 6 (17.7)) 10 (7.4)
Depressed mood 0 1 (2.2) 2 (4.4) 3 (2.2)
Severe depression or
depressed mood0 0 0 0
Discontinuation due to
depression or depressed mood0 0 0 0
aAll patients continue SSA therapy throughout study period
Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.
TELECAST: A Phase III Companion Trial to TELESTAR
250 mg telotristat
etiprate TID (n = 25)
500 mg telotristat
etiprate TID (n = 25)
Placebo TID (n = 26)
R
A
N
D
O
M
I
Z
E
N = 76
Treated
with SSA
with <4
BM/day or
not treated
with SSA
Primary endpoint: Safety and percentage change from baseline in urinary 5-HIAA
Secondary endpoint: change from baseline in number of bowel movements, stool consistency, number of cutaneous flushing episodes, abdominal pain, and change in the frequency of rescue short-acting, somatostatin analog used to treat carcinoid syndrome symptoms
Pavel M, et al. Presented at: North American Neuroendocrine Tumor Society (NANETS); October 1, 2016;
Jackson, Wyoming. Abstract C8.
TELECAST ResultsPlacebo Treatment
Treatment description Placebo Telotristat
etiprate 250 mg
P value vs
Placebo
Telotristat
etiprate 500 mg
P value vs
Placebo
Number of patients 26 25 25
Number of evaluable patients N/A N/A N/A
Placebo-adjusted change in urinary 5-HIAA
from baseline to week 12
(Endpoint = primary)
N/A -54.0%
(P<.001)
-89.7%
(P<.001)
Placebo-adjusted change in daily BM
frequency from baseline to week 12
(Endpoint = secondary)
N/A -0.45 events/day
(P = .004)
-0.54 events/day
(P<.001)
≥30% reduction in BM frequency
for at least 50% of the days
(Endpoint = secondary)
0% 40%
(P = .001)
40%
(P = .001)
Pavel M, et al. Presented at: North American Neuroendocrine Tumor Society (NANETS); October 1, 2016;
Jackson, Wyoming. Abstract C8.
Treatment Landscape for Advanced NETs 2016
*RADIANT-3 requires documentation of progressive disease (PD) in the prior 12 months. RADIANT-4 requires documentation of PD
during prior 6 months.
Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663. Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. Strosberg
J, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6. Raymond E, et al. N Engl J Med. 2011;364(6):501-513. Yao
JC, et al. J Clin Oncol. 2008;26(26):4311-4318. Yao JC, et al. N Engl J Med. 364(6):514-523. Yao JC, et al. Lancet.
2016;387(10022):968-977.
Site Octreotide Lanreotide177Lu-
DOTATATEStreptozocin Sunitinib Everolimus
Disease statusTreatment
naïveStable
Progressive
over 3 yearsHistorical
Progressive
over 12
months
Progressive
over 6
months*
Lung RADIANT-4
Stomach CLARINET RADIANT-4
Duodenum CLARINET RADIANT-4
Pancreas CLARINET Historical Phase III RADIANT-3*
Small bowel
AppendixPROMID CLARINET NETTER-1 RADIANT-4
Colon CLARINET RADIANT-4
Rectum CLARINET RADIANT-4
Unknown 1° RADIANT-4
GEP NETs represent a heterogeneous disease with multiple facets and increasing incidence; typical features include high somatostatin receptor expression and relatively slow growth
Careful consideration of primary site, disease extent, histology (grade/Ki67), symptoms, performance status, and functional imaging findings needed to optimize treatment decisions at each point in the disease
Somatostatin analogs are the backbone of systemictreatments
Effective second-line and further line antiproliferative treatments include everolimus, sunitinib, PRRT andtelotistat etiprate (if approved) for symptom control of carcinoid syndrome