Philippe RUSZNIEWSKI Pôle des Maladies de l’Appareil Digestif Hôpital Beaujon, Clichy, et...

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


Median TTP 10.35 months



Stratified log-rank testP<0.0001; HR=0.26 [95% CI: 0.14–0.50]





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


Median >77.4 months (not reached)


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)


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)



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)



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)



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)



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]


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 ?

Philippe RUSZNIEWSKI Pôle des Maladies de l’Appareil Digestif Hôpital Beaujon, Clichy, et...

Documents

Transcript of Philippe RUSZNIEWSKI Pôle des Maladies de l’Appareil Digestif Hôpital Beaujon, Clichy, et...