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
Top Related