Coordinación científica: Dr. Fernando Rivera Hospital Universitario Marqués de Valdecilla,

Santander

Organizado por: Fundación para el progreso

de la oncología en Cantabria

Nuevas alternativas en el manejo de TNE avanzados

Jaume Capdevila

Hospital Universitari Vall d’Hebron

Barcelona

CLARINET LAN GEP

NET16,17,29

2014/15

1980 2000 2005

STZ combination: survival benefit pNET2

1992

1900

RADIANT-4 EVE NF GI and

lung NET15,19

2015/16

TELESTAR telotristat etiprate

CS20

NDA filed 3/30/16

NETTER-1 177Lu-Dotatate

midgut NET18 RADIANT-2

EVE + OCT, LAR in mNET w/CS14

2010/11

Sunitinib phase 3 pNET13,31,34

2015/2017

PROMID OCT LAR:

antitumor

activity9,31

2009

LAN symptom

control24

1998

OCT LAR carcinoid

tumors23,26,28

ESMO

guidelines22,

27

2012

NANETS

guidelines8

2010

ENETS

guidelines

including TC/AC21

2015/16

ENETS

guidelines4;

TNM

staging5,7

2006/08

WHO

classification NET

and NEC6

2000

WHO

classification

Carcinoids3

1980

“Karzinoide”

coined by

Oberndofer1

1907

US

Approv

al

US/EU

Approv

al

EU

Approv

al

Cla

ss

ific

ati

on

/Gu

ide

lin

es

T

reatm

en

ts

ELECT LAN: symptom

control27

2010

OCT

SC CS 25,30

1988/89

RADIANT-3 EVE in pNET 11,12,32,33

2015

STZ pNET36

1982

WHO

classification Lung

NET/carcinoids35

2015

AJCC/UICC TNM

classification GI/pNET10

2009

PROGRESS IN THE LAND OF NENS

WHO

classification GEP-

NENs

2017

Frilling A, et al Lancet Oncol 2014

Unresectable NENs

Si-NET panNET LUNG NET NEN G3

G1 G2 G1 G2 G1 G2 NETG3 NECG3

Octreotide (PROMID) Everolimus RADIANT-4 Chemotherapy

Lanreotide (CLARINET) Somatostatin Analogues Somatostatin Analogues?

Everolimus RADIANT-3 & RADIANT-4 Chemotherapy Targeted agents?

PRRT

NETTER-1 Sunitinib

Interferon Chemotherapy

ADVANCED NENS

THERAPEUTIC ALGORITHM

PROMID AND CLARINET STUDIES

Screening period Treatment period

Study visits (weeks)

Lanreotide Autogel 120 mg s.c. every 28 days

Placebo s.c. every 28 days

Randomization 1:1

12–24 weeks*

CT scan 1 CT scan 2

24 48 72 9636 12 1(baseline)

Phase II Pancreatic

NETs

Everolimus

w/wo

Octreotide LAR

E ORR 9.6%

PFS 9.7m

E+O ORR 4.4%

PFS 16.7m

Phase III

Non-

Pancreatic

NETs

Octreotide LAR +

Everolimus

vs

Octreotide LAR +

placebo

16.4 vs 11.3m

HR 0.77 P=0.026 (one sided)

Phase III Pancreatic

NETs

Everolimus

vs

Placebo

11 vs 4.6m

HR 0.35 P<0.001

Phase III GI & Lung

NETs

Everolimus

vs

Placebo

11 vs 3.9m

HR 0.48 P<0.00001

RADIANT-1

RADIANT-2

RADIANT-3

RADIANT-4

RADIANT PROGRAM

RAD001 IN NEUROENDOCRINE TUMORS

RADIANT-4 STUDY DESIGN

*Based on prognostic level, grouped as: Stratum A (better prognosis) appendix, caecum, jejunum, ileum, duodenum, and

NET of unknown primary. Stratum B (worst prognosis) lung, stomach, rectum, and colon except caecum.

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=205 Treated until PD,

intolerable AE, or

consent withdrawal

Patients with well-

differentiated (G1/G2),

advanced, progressive,

nonfunctional NET of lung

or GI origin (N=302)

• Absence of active 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

PRIMARY ENDPOINT:

PFS BY CENTRAL REVIEW

52% reduction in the relative risk of progression or death with

everolimus vs placebo

HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001

P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.

CI, confidence interval; HR, hazard ratio.

205 168 145 124 101 81 65 52 26 1 0 3 0 0

97 65 39 30 24 21 17 15 11 6 5 1 0 Placebo

Everolimus

No.of patients still at risk

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

bilit

y o

f P

rog

res

sio

n-f

ree

Su

rviv

al

(%)

Kaplan–Meier medians

Everolimus: 11.0 months (95% CI, 9.23-13.31)

Placebo: 3.9 months (95% CI, 3.58-7.43)

Censoring Times

Everolimus (n/N = 113/205)

Placebo (n/N = 65/97)

Yao JC, et al. Lancet 2016

INTERIM OVERALL SURVIVAL ANALYSIS

*P-value boundary for significance = 0.0002. P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. NS, not significant.

205 195 184 179 172 170 158 143 100 59 31 5 0

97 94 86 80 75 70 67 61 42 21 13 5 0 Placebo

Everolimus

No. of patients still at risk

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

bab

ility

of

Ove

rall

Surv

ival

(%

)

Censoring Times

Everolimus (n/N = 42/205)

Placebo (n/N = 28/97)

Everolimus vs Placebo HR = 0.64 (95% CI, 0.40-1.05); P = 0.037 (NS)*

First interim OS analysis performed with 37% of information fraction favored the everolimus arm

Next interim analysis is expected in 2016

Yao JC, et al. Lancet 2016

PFS HR BY PRIMARY TUMOR ORIGIN – RETROSPECTIVE

ANALYSIS, CENTRAL REVIEW

Lung

GI†

NET of unknown primary

Hazard Ratio (95% CI) Subgroups*

90

175

36

No.

0.1 0.4 1 10

0.50 (0.28-0.88)

0.56 (0.37-0.84)

0.60 (0.24-1.51)

Everolimus Better Placebo Better

*One patient with thymus as primary tumor origin was not included. †Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI.

Hazard ratio obtained from unstratified Cox model. GI, gastrointestinal; NET, neuroendocrine tumors.

Yao JC, et al. Lancet 2016

Pavel M, et al. Lancet, 2011

Aim

Design International, multicenter, randomized, comparator-controlled, parallel-

group

Evaluate the efficacy and safety of 177Lu-Dotatate (Lutathera®) plus

Octreotide30 mg compared to Novartis Octreotide LAR 60mg (off-label

use)1 in patients with inoperable, somatostatin receptor positive, midgut

NET, progressive under Octreotide LAR 30mg (label use)

Baseline

and

Randomization

n = 115

Dose 1

n = 115

Treatment and Assessments Progression free survival (Recist criteria) every 12 weeks

5

Years

follow

up

Dose 2 Dose 3 Dose 4

NETTER -1 STUDY DESIGN

4 administrations of 7.4 GBq of LUTATHERA

every 8 weeks + Octreotide30 mg

Octreotide LAR 60mg every 4 weeks

Strosberg J, et al. N Engl J Med 2017

POPULATION CHARACTERISTICS

AT ENROLLMENT (N=229)

177Lu-Dotatate

(n=116) Octreotide LAR 60mg

(n=113)

Age (years), mean (SD) 63 (±9) 64 (±10)

Gender, n (%) Male Female

53 (46%) 63 (54%)

60 (53%) 53 (47%)

Primary tumor site, n (%) Jejunum Ileum Appendix Right colon Other

6 (5%)

86 (74%) 1 (1%) 3 (3%)

20 (17%)

9 (8%)

82 (73%) 2 (2%) 1 (1%)

19 (17%)

Site of metastasis, n (%) Liver Lymph nodes Bone Lungs Other

97 (84%) 77 (66%) 13 (11%) 11 (10%) 40 (35%)

94 (83%) 65 (58%) 12 (11%)

5 (4%) 37 (33%)

Strosberg J, et al. N Engl J Med 2017

PRIMARY ENDPOINT:

PROGRESSION-FREE SURVIVAL

Strosberg J, et al. ENETS 2018

SECONDARY ENDPOINT:

OVERALL SURVIVAL

Strosberg J, et al. ENETS 2018

SWOG S0518

STUDY DESIGN

Bevacizumab 15 mg/kg q21 d

octreotide LAR 20 mg q21 d

Interferon α-2b 5 mu 3 d/wk

octreotide LAR 20 mg q21 d

Treatment until disease progression

R

A

N

D

O

M

I

Z

E

Study population

Advanced G1/2 NET with

poor prognosis

• Progressive disease

• Refractory syndrome

• G2 with 6+ lesion

• Colorectal or gastric

primary

1:1

Multiphasic CT or MRI performed every 9 wk

Primary endpoint:

• PFS (Central radiology review)

Stratification factors:

• Primary site: Midgut vs others

• PD since diagnosis

• Histologic grade: G1 vs G2

• Octreotide 2 months prior to registration

Yao JC, et al. ASCO 2015

TELOTRISTAT ETIPRATE

THE PHASE III TELESTAR CLINICAL TRIAL

Serotonin

Tryptophan

5-Hydroxytryptophan (5-

HTP)

Serotonin (5-HT)

Urine

Serotonin

Hormonal syndrome Diarrhoea.....

NET-cell 5-HIAA

5-HIAA: 5-hydroxyindole acetic acid

SSA somatostatin analogue

SSTR somatostatin receptor SSA

Telotristat

etiprate Tryptophan-

hydroxylase

SSTR

TELESTAR

PHASE 3 STUDY DESIGN

Telotristat etiprate 500 mg TID* (n=45)

Telotristat etiprate 250 mg TID (n=45)

Placebo TID (n=45)

All patients required to be on SSA at enrollment and continue SSA therapy throughout study period

1:1:1

3- to 4-week

run-in (n=135) R

Telotristat

etiprate

500 mg TID

Evaluation of primary endpoint:

Reduction in number of daily BMs from baseline (averaged over 12-

week double-blind treatment phase)

Run in: Evaluation of

bowel movement

(BM) frequency

Kulke M, et al. J Clin Oncol 2017

• Hodges–Lehmann estimator of treatment differences showed a median reduction versus placebo of

– –0.81 BMs daily for telotristat etiprate 250 mg dose (P<0.001)

– –0.69 for telotristat etiprate 500 mg dose (P<0.001)

TELESTAR: REDUCTION IN DAILY BOWEL

MOVEMENT FREQUENCY AVERAGED OVER DOUBLE-BLIND

TREATMENT PHASE

BM, bowel movement. Kulke M, et al. J Clin Oncol 2017

TREATMENT ALGORITHM IN siNETS

• SOMATOSTATIN ANALOGUES:

• Functioning & non-functioning

• Octreoscan +ive & -ive

• Ki67 up to 10%

1st Treatment option

• EVEROLIMUS (EVEROLIMUS + SSAs)

• Non-functioning (functioning)

• Octreoscan +ive & -ive

• High & low tumor burden 2nd Treatment option

• 177Lu-DOTATATE

• Functioning & non-functioning

• Octreoscan +ive 3rd Treatment option

4th Treatment option

• INTERFERON

• Indication based on a negative

trial & old trials

ADVANCED NENS

THERAPEUTIC ALGORITHM

Unresectable NENs

Si-NET panNET LUNG NET NEN G3

G1 G2 G1 G2 G1 G2 NETG3 NECG3

Octreotide (PROMID) Everolimus RADIANT-4 Chemotherapy

Lanreotide (CLARINET) Somatostatin Analogues Somatostatin Analogues?

Everolimus RADIANT-3 & RADIANT-4 Chemotherapy Targeted agents?

PRRT

NETTER-1 Sunitinib

Interferon Chemotherapy

PFS in midgut vs pancreatic NET

0 3 6 9 12 18 24 27

0

10

20

30

40

50

60

70

80

90

100

Ti m e, m o nt hs

Lan r eot i de A u t ogel 120 m g 8 e v e n t s / 3 3 p a t i e n t s m e d i a n , n o t r e a ch e d

P l a ce b o 2 1 e v e n t s / 4 0 p a t i e n t s m e d i a n , 2 1 . 1 m o n t h s [ 9 5 % C I : 1 7 . 0 , N C ]

Mi d g u t NE T s ( n = 7 3 ) La nr e ot i de Au t o g e l vs p l aceb o P = . 0 0 9 1 HR = 0 . 3 5 [ 9 5 % C I : 0 . 1 6 , 0 . 8 0 ]

0

10

20

30

40

50

60

70

80

90

100

Ti m e, m o nt hs

Lan r eot i de A u t ogel 120 m g 1 8 e v e n t s / 4 2 p a t i e n t s m e d i a n , n o t r e a ch e d

P l a ce b o 3 1 e v e n t s / 4 9 p a t i e n t s m e d i a n , 1 2 . 1 m o n t h s [ 9 5 % C I : 9 . 4 , 1 8 . 3 ]

pN E T s (n = 9 1 ) La nr e ot i de Au t o g e l vs p l aceb o P = . 0 6 3 7 HR = 0 . 5 8 [ 9 5 % C I : 0 . 3 2 , 1 . 0 4 ]

0 3 6 9 12 18 24 27

Pat

ien

ts A

live

and

Wit

h N

o P

rog

ress

ion

, %

Caplin ME, et al. N Engl J Med. 2014

CLARINET PFS IN ENTEROPANCREATIC NET

RADIANT-3: STUDY DESIGN

Everolimus 10 mg/d +

best supportive care1

n = 207

Placebo +

best supportive care1

n = 203

Multiphasic CT or MRI performed every 12 weeks

Treatment until

disease

progression

Patients with advanced pNET (N = 410)

• Advanced well or moderately differentiated

• Radiologic progression ≤12 months

• Prior antitumour therapy allowed

• WHO PS ≤2

Stratified by:

• WHO PS

• Prior chemotherapy

Crossover at disease

progression

1Concurrent somatostatin analogues allowed

R

A

N

D

O

M

I

S

E

Phase III, Double-Blind, Placebo-Controlled Trial

Primary Endpoint: Progression-free survival By investigator review

Secondary Endpoints: OS, ORR, biomarkers, safety, pharmacokinetics (PK)

1:1

Yao JC, et al. N Engl J Med. 2011

RADIANT-3

PFS BY CENTRAL REVIEW COMMITTEE

Yao JC, et al. N Engl J Med. 2011

P value obtained from stratified 1-sided log-rank test

Hazard ratio is obtained from stratified unadjusted Cox model

Kaplan-Meier median PFS

Everolimus: 11.0 months

Placebo: 4.6 months

Hazard ratio = 0.35; 95% CI 0.27-0.45

P value: <.0001

Time (months)

100

80

% E

ven

t-fr

ee

Censoring times

Everolimus (n/N = 109/207)

Placebo (n/N = 165/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

EVEROLIMUS IS CLINICALLY BENEFICIAL REGARDLESS OF PRIOR

CHEMOTHERAPY USE

Lombard-Bohas C, et al. J Clin Oncol. 2012; 30 suppl. 34; abstract # 224.

p value is obtained from the unstratified one-sided log-rank test. Hazard ratio is obtained from unstratified unadjusted Cox model.

In the everolimus arm, median PFS did not significantly differ in patients who did and did not receive prior chemotherapy In the placebo arm, a trend toward shorter median PFS was observed in patients who had received prior chemotherapy compared

with chemo-naive patients

SUNITINIB VS PLACEBO

IN ADVANCED PNET

Raymond E, et al. N Engl J Med. 2011

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

• Trial terminated after unplanned early analysis

Primary Endpoint:

• PFS

Sunitinib 37.5 mg/day orally

Continuous daily dosing*

n = 86

Placebo*

n = 85

* With best supportive care

Somatostatin analogues were permitted

Secondary Endpoints:

• OS

• ORR

• TTR

• Duration of response

• Safety

• Patient-reported outcomes

R A N D O M I S E

1:1

Well differentiated advanced

pNET patients

(N = 171 enrolled / 340

planned)

• Disease progression in past 12

mos

• Not amenable to curative

treatment

SUNITINIB VS PLACEBO

IN ADVANCED PNET

Per

cent

age

of e

vent

-fre

e

Time (months)

Censoring times

Sunitinib (n/N = 30/86)

Placebo (n/N = 51/85)

Kaplan-Meier median PFS

Sunitinib: 11.4 months

Placebo: 5.5 months

HR = 0.42 ; 95% CI [0.26-0.66]

P value <.001; nominal critical z value = 3.8506

0 5 10 15 20 25

86

85

39

28

19

7

4

2

0

1

0

0

Number at risk:

Sunitinib

Placebo

0

20

40

60

80

100

* Local review

Raymond E, et al. N Engl J Med. 2011

Maximum change from baseline of target lesions in patients from

the sunitinib phase III study*

The RECIST-defined ORR in patients receiving sunitinib was 9.3%;

however, the majority of patients had some degree of tumour shrinkage

(Clinical Benefit Rate 72%)†

SD

PR: ≥30% decrease

PD: ≥20% increase

Sunitinib Placebo

Confirmed partial or complete response

−100

−80

−60

−40

−20

0

20

40

60

Ch

an

ge

fro

m b

as

eli

ne

(%

)

Raymond E, et al. N Engl J Med. 2011

DEGREE OF TUMOUR SHRINKAGE IN THE

SUNITINIB PHASE III STUDY

ESTIMATES OF OVERALL SURVIVAL

Faivre S, et al. Ann Oncol 2016

STZ-BASED CHEMOTHERAPY

IN PNETS

Moertel C, et al. N Engl J Med, 1992

TEMOZOLOMIDE + CAPECITABINE

Crespo G, et al. Future Oncol 2016

TEMOZOLOMIDE + CAPECITABINE

TEMOZOLOMIDE + CAPECITABINE

RR: 28% vs 33% (p=0.47)

G3-4 AEs: 22% vs 44% (p=0.007)

THERAPEUTIC ALGORITHM FOR panNETS

• SOMATOSTATIN ANALOGUES:

• Functioning & non-functioning

• Octreoscan +ive

• Ki up to 10%

• Not too much liver involvement

1st Treatment option

• EVEROLIMUS / SUNITINIB / CHT

• Progressive disease

• Higher tumor burden

• Symptoms related with tumor

burden

2nd Treatment option

1st Treatment option

• EVEROLIMUS / SUNITINIB / CHT

• Sequential therapies

Unresectable NENs

Si-NET panNET LUNG NET NEN G3

G1 G2 G1 G2 G1 G2 NETG3 NECG3

Octreotide (PROMID) Everolimus RADIANT-4 Chemotherapy

Lanreotide (CLARINET) Somatostatin Analogues Somatostatin Analogues?

Everolimus RADIANT-3 & RADIANT-4 Chemotherapy Targeted agents?

PRRT

NETTER-1 Sunitinib

Interferon Chemotherapy

ADVANCED NENS

THERAPEUTIC ALGORITHM

Lung

GI*

NET of unknown

primary (n=36) or

Others (n=8)

Hazard Ratio (95% CI) Subgroups

90

168

44

No.

0.1 0.4 1 10

0.50 (0.28-0.88)

0.60 (0.39-0.91)

0.50 (0.22-1.16)

Everolimus Better Placebo Better

PFS HR BY PRIMARY TUMOR ORIGIN –

RETROSPECTIVE ANALYSIS, CENTRAL REVIEW

*Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI

tract.

Yao JC, et al. Lancet 2016

Granberg D, et al. Ann Oncol 2011

LOW EFFICACY EVIDENCE

OF CHEMOTHERAPY IN G1/G2 LUNG NETS

RETROSPECTIVE EFFICACY

EVIDENCE OF SSAs IN LUNG NETS

Sullivan I, et al. Eur J Cancer 2017

THERAPEUTIC ALGORITHM FOR LUNG NETS

• SOMATOSTATIN ANALOGUES…

• Functioning & non-functioning

• Octreoscan +ive (mainly)

• Typical (atypical)

1st Treatment option

2nd Treatment option • EVEROLIMUS

3rd Treatment option • CHT / PRRT

Unresectable NENs

Si-NET panNET LUNG NET NEN G3

G1 G2 G1 G2 G1 G2 NETG3 NECG3

Octreotide (PROMID) Everolimus RADIANT-4 Chemotherapy

Lanreotide (CLARINET) Somatostatin Analogues Somatostatin Analogues?

Everolimus RADIANT-3 & RADIANT-4 Chemotherapy Targeted agents?

PRRT

NETTER-1 Sunitinib

Interferon Chemotherapy

ADVANCED NENS

THERAPEUTIC ALGORITHM

NET G3 (40%) Small cellNEC G3 (95%)

Ki-67

Nuñez-Valdovinos B, et al. The Oncologist 2018

Fazio N & Milione M. Cancer Treatment Reviews 2016

SUGGESTED CHEMOTHERAPY

IN FIRST-LINE REGARDING NEW CLASSIFICATION

SUNITINIB IN NET G3

Pellat A, et al. Neuroendocrinology 2017

• G1 & G2 tumors show comparable response to PRRT

• Up to Ki67 of 20%, no impaired response

• Potential cut-off for treatment failure >30-40%1 (up to 55% last ENETS 2018 meeting2)

• No differences of PRRT benefit comparing Ki67 index of 10, 15 and 20%1

1.Ezziddin S, et al. Eur J Nucl Med 2011

2. Skovgaard D, et al. ENETS 2018

PRRT IN NET G3

jacapdevila@vhebron.net

jcapdevila@vhio.net