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Philippe RUSZNIEWSKIPôle des Maladies de l’Appareil Digestif
Hôpital Beaujon, Clichy, et Université Paris VII, France
Athens, July 5th 2014
ANTIPROLIFERATIVE EFFECTS OF SOMATOSTATIN ANALOGUES
IN GI-NETs
NET Masterclass
SSAs use in NET
Background
Physiological actionsInhibitory Peptides
Inhibit Neurotransmission Endocrine and exocrine secretions Pituitary (GH, prolactin, TSH, ACTH)
Thyroid (T3, T4)
Pancreas (endocrine and exocrine)
Stomach (gastrin, acid)
Bowel (CCK, VIP)
Liver (bile)
Kidney (renin, reabsorption H2O)
Digestive motricity (intestine, biliary, stomach, gallbladder)
Cell proliferation / tumor growth Review issue, Mol Cell Endocrinol. 2008.
Inhibitory Effects of SST Receptors
Inhibitory effects sst1 sst2 sst3 sst4 sst5
Hormone secretion
GH + + +
ACTH + +
TSH + +
Insulin + +
Glucagon +
Exocrine secretion
Gastric acid +
Amylase +
Bowel secretion + +
Cell proliferation
Induction of cell cycle in G1
+ + + +
Induction of apoptosis
+ +
Oberg et al. Annals of Oncology. 2004.
Detection of mRNA sst receptors in NETs
Small bowel sst2 ( 85 % ) > sst5 > sst1 > sst3 ≥ sst4(n=87)
Gastrinomas sst2 ( 95% ) > sst5 ≥ sst1 > > sst3 > sst4(n=23)
Insulinomas sst5 ( 77% ) = sst3 > sst2 > sst4 > sst1(n=15)
Glucagonomas, PHEOC, MTC sst2 ( 87% ) > sst1 > sst5 = sst4 > sst3(n=16)
Pituitary tumors sst2 (86 %) > sst5 > sst1 > sst3(n = 63)
sst1 sst2
sst3 sst4 sst5
Nasir A et al. Cancer Control 2006;13: 52 -60
Öberg K et al. Annals Oncol 2004;15:966-973Kulakasiz H et al. Gut 2002;50:52-60
NETs Pancre
asSmall bowel
sst1 68 80
sst2 86 95
sst3 46 65
sst4 93 35
sst5 57 75
SST 1-5 Expression in NETs
Schmid H, Mol Cell Endocrinol 2008;286(1-2):69-74
Binding affinity of SSAs for SSTs
IC50 (nM)sst
1sst2 sst3 sst4
sst5
Somatostatin-140,93 0,15
0,56
1,50,29
Octreotide 280 0,387,10
>1000
6,30
Lanreotide 180 0,50 14 230 17
Pasireotide (SOM230)
9,3 1 1,5>100
0,16
x40 x30 x5
INDIRECT EFFECT
Inhibition of secretion of
trophic factors
Inhibition of angiogenesis
(VEGF)
Modulation of immune system(Natural killers)
DIRECT EFFECT
Arrest of cell cycle
Inhibition of growth factors
Cell death by apoptosis
Buscail et al 1994, Sharma et al. 1998, Danesi et al. 1997, Albini et al. 1998, Pages et al. 1999, Florio et al 2003
Octreotide sst2
Antitumoral effectsSomatostatin
Somatostatin analogs and GEP-ET Recommendations
(Oberg K et al. Ann Oncol 2004)
Before and after aggressive treatments Control of symptoms in functioning tumors Tumor progression in F or NF tumors
Indications of SSAs (French AMM) :
-Somatuline LP : treatment of symptoms in carcinoid tumors
-Sandostatine LP : treatment of symptoms in digestive tumors after stabilization with Sandostatin (Carcinoids, Vipomas, Glucagonomas)
Antitumor effects of SMS analogues on progressive NETs (non comparative studies)
SSA OR/S Duration
(months)
Panzuto2006 31/Dig-Pa divers 0%/45 % 26(6-60)
Arnold2005 51/Dig-Pa Oc 600 µg/j 2%/25% at 6 mosFaiss2003 23/GEP-Pa Lan 3000 µg/j 4%/28% - Aparicio200135/GEP-Pa divers 3%/57% 11(6-48)Ducreux1999 14/GEP-Pa Lan30 /14j 7%/43% 8Shojamanesh99 15/Gas divers 6%/47% at 3
mosWymenga1999 31/Dig-Pa Lan30 /7-14j 6%/81% at 6
mosSaltz1993 34/Dig-Pa Oc <750 µg/j 0%/50% 5 (0-27)
Antitumoral effect of SMS analogues
Randomized studies in patients with progressive tumors
n duration PR + SD
FAISS S et al (1) LAN 1 mg x 3/d SC 25 1+7
IFN 5 millionUx3/ 27 1 year 1+7
week SC
LAN+IFN 28 2+5
ARNOLD R et al (2) OCT 200µgx3/d SC 51 1 year 30 % (6 mo)
OCT+IFN 4.5 millionUx3/ 54 (until 21 % (1 year)
week SC progression
30 %
J Clin Oncol 2003 (1) ; Clin Gastroenterol Hepato 2005 (2)
Predicting tumor stabilization with SSAs….A difficult challenge
Studies Significant Non significant
Arnold, 1996/52 KI age,sex,F/NF,site,treatments, resp S/H,SRS
Ducreux, 2000/14 - ECOG, F/NF
Aparicio, 2001/32 Slope, WHO SRS
Shomanesh, 2002/15 Slope age, sex,MEN1, dur., non liver mets
Ruszniewski, 2004/71 - traitements(chir, ana SMS), SRS
Panzuto, 2006/31 Non liver mets age, sex, size, Ki67, F/NF, CgA
Butturini, 2006/21 KI,Ki67, F/NF age, sex, CgA, number and size T
The slope of tumor growth predicts tumor response…
Stabilisation 6 mos according to the slope at 3 mois
Aparicio Am J Cancer 2001; p<0.02 : n=29
33%
76%
Stabilisation 3 mos according to prett slope
Shojamanesh H Cancer 2002; p<0.001 : n=15 gastrinomas
0
10
20
30
40
50
60
70
80
>50% <50%0
10
20
30
40
50
60
70
80
> 50% < 50%
86%
In summary….
Modlin IM, et al. Aliment Pharmacol Ther. 2009
A compilation of the efficacy of different somatostatin analogues and different formulation.Mean (top) and median in parentheses.
PROMID study To evaluate the antitumor effect of octreotide LAR Randomized, double-blind, placebo-controlled,
Phase IIIb 18 centers in Germany from 2001 to 2008 85 patients treated from a planned 162 Planned interim analysis
Based on 67 tumor progressions and 16 observed deaths Log-rank test Two-sided P-value of 0.0122 as defined by Lan-DeMets
a-spending function indicates statistical significance Other statistical methods used include univariate
and multivariate Cox regression, Fisher’s exact test and Wilcoxon-Mann-Whitney tests
The PROMID Study
Month -1 0 3 6 9 12 15 18Screening
Informedconsent
Randomization1:1
Continuation of treatment if no progression
Octreotide LAR 30 mg i.m. every 4 weeks
Placebo i.m. every 4 weeks
Primary endpoint: time to tumor progression
• Treatment was continued until CT or MRI documented tumor progression (WHO)
• Follow-up until death• CT and/or MRI was evaluated by a blinded central reader• No observation period prior to treatment to judge spontaneous tumor growth
Patient population Newly diagnosed and treatment naive Histologically confirmed, locally
inoperable or metastatic well-differentiated midgut NETs
Functionally active or inactive midgut NETs
Primary tumor located in the midgut or unknown primary if no evidence of a
primary tumor outside the midgut No curative therapeutic option available Measurable tumor by CT or MRI
Octreotide LAR significantly prolongs PFS
Octreotide LAR vs placebo P=0.000072HR= 0.34 [95% CI: 0.20–0.59]
Octreotide LAR: 42 patients / 26 events
Median 14.3 months [95% CI: 11.0–28.8]
Placebo: 43 patients / 40 events
Median 6.0 months [95% CI: 3.7–9.4]
Time (months)
Pro
po
rtio
n w
ith
ou
t p
rog
res
sio
n
0
0.25
0.5
0.75
1
0 6 12 18 30 36 42 48 54 60 66 72 78
Based on the conservative ITT analysis
Octreotide LAR: 10 patients / 8 events
Median TTP 10.35 months
Placebo: 11 patients / 10 events
Median TTP 5.45 months
Stratified log-rank testP<0.0001; HR=0.26 [95% CI: 0.14–0.50]
Octreotide LAR: 32 patients / 18 events
Median TTP 27.14 months
Placebo: 32 patients / 31 events
Median TTP 7.21 months
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Pro
po
rtio
n w
ith
ou
t p
rog
res
sio
n
Time (months)
Stratified log-rank testP=0.345; HR=0.64 [95% CI: 0.25–1.63]
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60
Pro
po
rtio
n w
ith
ou
t p
rog
res
sio
n
Time (months)
Patients with tumor load ≤10% Patients with tumor load >10%
Based on the ITT analysis
…mostly in patients with limited hepatic involvement
Overall survivalOctreotide LAR median survival duration not yet reached (>77.4 months)
Placebo: 73.7 months
Octreotide LAR: 42 patients / 7 events
Median >77.4 months (not reached)
Placebo: 43 patients / 9 events
Median 73.7 months
0
0.25
0.5
0.75
1
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84
Pro
po
rtio
n w
ith
ou
t p
rog
res
sio
n
Time (months)
• PFS médiane : 29 mois• Ki 67 < 5 %, envahissement hépatique < 25 %, stabilité préthérapeutique
significativement associés à la non-progression sous traitement (analyse multivariée)
Palazzo et al Eur J Gastroenterol 2013
Tumor Control with Lanreotide in 68 Patients with Digestive NETs
Retrospective Study
12–24 weeks Lanreotide Autogel 120 mg every 28 days (s.c.)
Study aim and design
ClinicalTrials.gov NCT00353496; EudraCT 2005-004904-35.
Aim
• To compare effect of lanreotide Autogel 120 mg vs. placebo on PFS in well-/moderately differentiated non-functioning GEP-NETs
• International multicentre randomized placebo-controlled phase III3 studyD
esig
n
CLARINET(Controlled study of Lanreotide Antiproliferative Response In NET)
Study visits (weeks)
24 48 72 961 (Baseline)
36 12
Placebo every 28 days (s.c.)CT scan 1
CT scan 2
1:1 randomization
Sporadic non-functioning GEP-NET* Well-/moderately-differentiated tumour
with low proliferation index (Ki-67 <10%) Metastatic and/or locally advanced
inoperable tumour Tumour measurable according to RECIST
criteria v1.0 (central assessment)
Grade ≥2 on somatostatin receptor scintigraphy (Krenning scale)
No use of interferon, chemoembolization or chemotherapy in previous 6 months, and SSA naive
Patient population
* Including gastrinomas with adequate symptom control with PPIs and NETs of unknown primary origin.
Study endpoints Primary endpoint PFS (time to disease progression
or death) within 96 weeks of first injection
Disease progression confirmed centrally with RECIST criteria v1.0
Secondary endpoints Percentage of patients alive and without disease
progression at weeks 48 and 96 Time to progression Overall survival Tumour markers Safety (Quality of life)
Lanreotide Autogel(n=101)
Placebo(n=103)
Men, n (%) 53 (52) 54 (52)
Age in years, mean (SD) 63 (10) 62 (11)
Time since diagnosis in months, mean (SD) 33 (46) 34 (41)
Primary tumour resected, n (%) 40 (40) 39 (38)
NET origin, n (%) Pancreas Midgut Hindgut Unknown/Other
42 (42)33 (33)11 (11)15 (15)
49 (48)40 (39)3 (3)
11 (11)
Chromogranin A, n (%) ≤1 × ULN 1–2 × ULN >2 × ULN Unknown
33 (33)25 (25)41 (41)
2 (2)
34 (33)18 (17)48 (47)
3 (3)
Baseline characteristics (ITT population, N=204)
Primary endpoint: PFS (ITT population, N=204)
P-value derived from stratified log-rank test; HR derived from Cox proportional hazard model. HR, hazard ratio; ITT, intention-to-treat.
Lanreotide Autogel 120 mg32 events / 101 patientsmedian, not reached
Placebo60 events / 103 patientsmedian, 18.0 months [95% CI: 12.1, 24.0]
Lanreotide Autogel vs. placebop=0.0002 HR=0.47 [95% CI: 0.30, 0.73]
0 3 6 9 12 18 24 270
10
20
30
40
50
60
70
80
90
10 0
Pat
ient
s al
ive
and
with
no
prog
ress
ion
(%)
Time (months)
62%
22%
Subgroup analyses (ITT)
Midgut vs. pancreatic NETs
P-value derived from log-rank test; HR derived from Cox proportional hazards model. NC, not calculable.
0 3 6 9 12 18 24 270
10
20
30
40
50
60
70
80
90
100
Pat
ient
s al
ive
and
with
no
prog
ress
ion
(%)
Time (months)
Lanreotide Autogel 120 mg8 events / 33 patientsmedian, not reached
Placebo21 events / 40 patientsmedian, 21.1 months [95% CI: 17.0, NC]
Midgut NETs (n=73)Lanreotide Autogel vs. placebop=0.0091 HR=0.35 [95% CI: 0.16, 0.80]
0
10
20
30
40
50
60
70
80
90
100
Time (months)
Lanreotide Autogel 120 mg18 events / 42 patientsmedian, not reached
Placebo31 events / 49 patientsmedian, 12.1 months [95% CI: 9.4, 18.3]
pNETs (n=91)Lanreotide Autogel vs. placebop=0.0637 HR=0.58 [95% CI: 0.32, 1.04]
0 3 6 9 12 18 24 27
Subgroup analyses (ITT)Effect of tumour grade
0
10
20
30
40
50
60
70
80
90
100
Pat
ient
s al
ive
and
with
no
prog
ress
ion
(%)
Time (months)
Lanreotide Autogel 120 mg19 events / 69 patientsmedian, not reached
Placebo40 events / 72 patientsmedian, 18.3 months [95% CI: 12.7, 24.0]
G1 tumours (n=141)Lanreotide Autogel vs. placebop=0.0016 HR=0.43 [95% CI: 0.25, 0.74]
0
10
20
30
40
50
60
70
80
90
100
Time (months)
Lanreotide Autogel 120 mg13 events / 32 patientsmedian, not reached
Placebo19 events / 29 patientsmedian, 12.1 months [95% CI: 9.0, 18.0]
G2 tumours (n=61)Lanreotide Autogel vs. placebop=0.0235 HR=0.45 [95% CI: 0.22, 0.91]
P-value derived from log-rank test; HR derived from Cox proportional hazards model.
3 6 9 12 18 24 270 0 3 6 9 12 18 24 27
P-value derived from log-rank test; HR derived from Cox proportional hazards model. NC, not calculable.
Tumour load ≤25% (n=137)Lanreotide Autogel vs. placebop=0.0002 HR=0.34 [95% CI: 0.18, 0.62]
Tumour load >25% (n=67)Lanreotide Autogel vs. placebop=0.0170 HR=0.45 [95% CI: 0.23, 0.88]
Subgroup analyses (ITT)Effect of hepatic tumour
load
0
10
20
30
40
50
60
70
80
90
100
Pat
ient
s al
ive
and
with
no
prog
ress
ion
(%)
Time (months)
Lanreotide Autogel 120 mg14 events / 62 patientsmedian, not reached
Placebo41 events / 75 patientsmedian, 21.1 months [95% CI: 17.6, 24.4]
0 3 6 9 12 18 24 270
10
20
30
40
50
60
70
80
90
100
Time (months)
Lanreotide Autogel 120 mg18 events / 39 patientsmedian, 24.1 months [95% CI: 9.3, NC]
Placebo19 events / 28 patientsmedian, 9.4 months [95% CI: 6.3, 12.0]
0 3 6 9 12 18 24 27
Overall survival (ITT)
P-value derived from log-rank test.* Survival was followed throughout the randomized study for patients on study medication for up to 96 weeks or until early withdrawal / PD , and then continued to be followed during the post-study survival phase (when the patient may or may not have continued or switched to lanreotide).
Lanreotide Autogel 120 mg vs. placebop=0.8791
Pat
ient
s al
ive
(%)
Lanreotide19 deaths / 101 patients
Placebo17 deaths / 103 patients
Time (months)
0 12 24 36 60 72 840
20
40
60
80
100
48
Randomized double-blind study for ≤96 weeks*
Post study survival phase*
101 89 78 59 14 5 037
103 88 73 51 16 6 035
Lanreotide, n
Placebo, n
Chromogranin A: Proportion of patients with ≥50% reduction from baseline of value
>ULN (ITT)
0
10
20
30
40
50
3 6 12 18 24 Last value
Time (months)
Pa
tie
nts
(%
)
≥50% reduction at last valuep<0.0001, OR 15.2 [95% CI: 4.3, 53.9]
Lanreotide Autogel 120 mg
Placebo
57 50 38 35 35Lanreotide, n
59 49 32 20 15Placebo, n
64
64
Data are percentage of patients in this subgroup (excluding those with missing data).
Safety and tolerability No treatment-related deaths and few
withdrawals due to AEs AEs consistent with known profile of lanreotide
Autogel
Data are number (%) of patients.* Serious AEs are defined as AEs that result in disability/incapacity, hospitalization, death, or are life-threatening (this differs from severe AEs which are defined on their intensity based on investigator judgement).
Lanreotide Autogel (n=101)
Placebo (n=103)
Any treatment emergent AEs
89 (88) 93 (90)
Related to treatment 50 (50) 29 (28)
Severe / moderate / mild
26 (26) / 46 (46) / 17 (17)
32 (31) / 44 (43) / 17 (17)
Any serious AEs* 25 (25) 32 (31)
Related to treatment 3 (3) 1 (1)
Withdrawals due to treatment emergent AEs
3 (3) 3 (3)
Related to treatment 1 (1) 0
Treatment-related AEs occurring in ≥10% of patients
Diarrhoea 26 (26) 9 (9)
Abdominal pain 14 (14) 2 (2)
Cholelithiasis 10 (10) 3 (3)
SOME QUESTIONS FOR THE FUTURE
1. The more, the merrier ?High dose…
High-Dose Octreotide: Advanced Midgut Carcinoid
TumorsDESIGN
Open-label, non-controlled N=12, extensive prior Tx Octreotide pamoate 160 mg IM
2 wk x 2 mo Q mo x 12 If stable, continue x 12 mo
OBJECTIVE Assess Sx response
OUTCOMES Median survival: Pts continued Tx (n=6) or d/c (n=3, non-
disease related)=37 mo Median survival: Pts with PD=12 mo after Tx
Welin S, et al. Eur J Endocrinol. 2004;151(1):107-112.
High-Dose Octreotide: Advanced Midgut Carcinoid
Tumors (cont.)
Welin S, et al. Eur J Endocrinol. 2004;151(1):107-112.
2. SSAs, and what else ?
Are SSAs synergistic with :- Everolimus (radiant 1 and 2)- Sunitinib (Sunland) ?
Schmid H, Mol Cell Endocrinol 2008;286(1-2):69-74
3. Which potential for pasireotide ?
IC50 (nM)sst
1sst2 sst3 sst4
sst5
Somatostatine-140,93 0,15
0,56
1,50,29
Octreotide 280 0,387,10
>1000
6,30
Lanreotide 180 0,50 14 230 17
Pasireotide (SOM230)
9,3 1 1,5>100
0,16
x40 x30 x5
4. After Promid and Clarinet…
- SSAs in MEN ?- SSAs in benign non resected
PNETs ?- Maintenance after chemo / PRRT ?- Lung tumors ?
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