Tumores neuroendocrinos pancreáticos: Nuevo abordaje del
tratamiento con laintegración de Everolimus
Enrique GrandeHospital Ramón y Cajal
Biología Molecular que Justifica el empleo de Afinitor en TNEs
de Wilde RF, et al. Nat Rev Gastroenterol Hepatol 2012;9:199-208
Biología Molecular que Justifica el empleo de Afinitor en TNEs
Chiu and Hanahan. J Clin Oncol 2010;28(29):4425-33
Biología Molecular que Justifica el empleo de Afinitor en TNEs
Yao JC, et al. Cancer Res 2013;73:1449-1453
Mecanismo de Acción de Everolimus (Afinitor®)
Protein production
Reduced genetranscription
Reduced VEGFproduction
Reducedcell growth
Reducedproliferation
NutrientsAmino acids
Integrins
ILK
4E-BP1
eIF-4E P 70 S6k
Energy
PTEN
TSC1/2
mTOR
PI3K
AKT
FKBP12
Everolimus
Growth factors
mTORFKBP12
VEGF
VEGFR
Reduced cell growthand proliferation
PI3K
AKT
Everolimus(RAD001)
Everolimus
Tumor Growth InhibitionCancer Cell
Angiogenesis InhibitionEndothelial cells / pericytes
Evidencia Preclínica de Everolimus (Afinitor®) en TNEs
Chiu and Hanahan. J Clin Oncol 2010;28(29):4425-33
Everolimus (Afinitor®) como Antiangiogénico en TNEs
VEGFPDGF
VEGFPDGF
blood vessels
Tumor
Manegold C, et al. Clin Cancer Res 2008;14:892-900
Biología Molecular que Justifica el empleo de Afinitor en TNEs
Missiaglia E, et al. J Clin Oncol. 2010;28(2):245-55
Akt/PKB
PI3-K
PTENOxygen, nutrients and energy
TSC2 TSC1
Growth FactorsIGF-1, VEGF, ErbB, etc
Protein synthesis4E-BP1
S6
S6K1
elF-4E
mTORRas/Raf Kinase pathway
Ras/Raf,
Abl, ER
AngiogenesisCellular Division
Estudio Fase II SMSUS52 (MDACC)
No. of Patients (%)
Overalln = 30
Carcinoidn = 17
Islet Celln = 13
Partial responses (PR) 4 (13) 2 (12) 2 (15)
Stable disease (SD) 22 (73) 14 (82) 8 (62)
Progressive disease (PD) 4 (13) 1 (6) 3 (23)
PFS (24 wk) 64%
Yao JC, et al. J Clin Oncol 2008;26(26):4311-8
Estudio de fase 2 abierto de RAD001 +/- octreótida LAR en NET pancreáticos avanzados tras fallo a QT (2239)
Objetivo Primario: Tasa de RespuestasReclutamiento completado: 160 pacientes
Estudio de fase 3 controlado con placebo de RAD001 en tumores carcinoides avanzados en tratamiento con octreótida LAR (2325)
Objetivo Primario: SLPReclutamiento completado: 415 pacientes
Estudio de fase 3 controlado con placebo de RAD001 +/- BSC en NET pancreáticos avanzados (2324)
Objetivo Primario: SLPReclutamiento activo: 313/392 pacientes
RADIANT 1: Phase 2 study of RAD001 in advanced pancreatic islet cell tumors after chemotherapy failure
Yao JC, et al. J Clin Oncol 2010;28(1):69-76
RADIANT 1: Phase 2 study of RAD001 in advanced pancreatic islet cell tumors after chemotherapy failure
Yao JC, et al. J Clin Oncol 2010;28(1):69-76
Time Since Study Start (Months)
PFS
(%)
HR = 0.2595% CI: 0.13-0.51P = 0.00004
Median PFS (months)Early response (n/N = 16/33) = 13.3No early response (n/N = 26/38) = 7.5
240 63 129 1815 21 240 63 129 1815 21
HR = 0.2595% CI: 0.10-0.58P = 0.00062
CgA NSE
Time Since Study Start (Months)
Median PFS (months)Early response (n/N = 17/28) = 8.6 No early response (n/N = 10/11) = 2.9
PFS
(%)
0
20
40
60
80
100
0
20
40
60
80
100
RADIANT 3: A randomized placebo-controlled study of SandostatinLAR ± RAD001 in advanced pancreatic islet cell tumors after
chemotherapy failure
Yao JC, et al. N Engl J Med 2011;364(6):514-23
Patients with advanced pNET
• Measurable disease by radiologic assessment
• Performance Status 0‐2
N = 410
Everolimus 10 mg/d +best supportive care1
n = 207
Placebo +best supportive care1
n = 203
Treatment until disease progression
RANDOMISE
1:1
Multiphasic CT or MRI performed every 12 weeks
Crossoverat time of disease progression (73 %)
Primary endpoint:• PFS (RECIST 1.0)
Secondary endpoints:• Response, OS, biomarkers, safety, and PK
Everolimus10mg (N = 207)
%
Placebo (N = 203)
%
Somatostatin analogs 49 50
Systemic anti-tumour therapy 58 58
Chemotherapy 50 50
Targeted therapy 5 7
Immunotherapy 3 4
Hormonal therapy 1 1
Other 10 13
RADIANT 3: A randomized placebo-controlled study of SandostatinLAR ± RAD001 in advanced pancreatic islet cell tumors after
chemotherapy failure
Yao JC, et al. N Engl J Med 2011;364(6):514-23
RADIANT 3: A randomized placebo-controlled study of SandostatinLAR ± RAD001 in advanced pancreatic islet cell tumors after
chemotherapy failure
Yao JC, et al. N Engl J Med 2011;364(6):514-23
PFS rate (18 months) Everolimus: 34.2% Placebo: 8.9%
RADIANT 3: A randomized placebo-controlled study of SandostatinLAR ± RAD001 in advanced pancreatic islet cell tumors after
chemotherapy failure
RADIANT 3: A randomized placebo-controlled study of SandostatinLAR ± RAD001 in advanced pancreatic islet cell tumors after
chemotherapy failure
Yao JC, et al. N Engl J Med 2011;364(6):514-23
RADIANT 3: A randomized placebo-controlled study of SandostatinLAR ± RAD001 in advanced pancreatic islet cell tumors after
chemotherapy failure
Lombard-Bohas C, et al. ASCO GI 2013. Poster Presentation
RADIANT 3: A randomized placebo-controlled study of SandostatinLAR ± RAD001 in advanced pancreatic islet cell tumors after
chemotherapy failure
Yao JC, et al. N Engl J Med 2011;364(6):514-23
AE, %
Primary Analysis Latest Safety UpdateEverolimus (n = 204)
Placebo (n = 203)
Everolimus (n = 204)
Placebo(n = 203)
Stomatitisa 52.9 11.3 52.9 12.3Infectionsa 22.5 5.9 24.0 5.9Pulmonary events 16.7 0 16.7 0Hyperglycemia 13.2 4.4 13.7 4.9
AE (Gr 3/4), %
Primary Analysis Latest Safety UpdateEverolimus (n = 204)
Placebo (n = 203)
Everolimus (n = 204)
Placebo(n = 203)
Hyperglycemia 5.4/0 1.5/0.5 5.9/0 1.5/0.5Stomatitisa 4.9/0 0/0 4.9/0 0/0Anemia 4.9/1.0 0/0 4.9/1.0 0/0
Drug‐related AEs occurring in ≥ 5% of patients, any grade
Grade 3/4 AEs occurring in ≥ 5% of patients
Median time on treatment = 8.8 months for everolimus pts, 3.7 months for placebo pts
Pulmonary AEs including pneumonitis were mainly Gr 1/2 and were manageable; pneumonitis discontinuation rate was 3%
13% of pts withdrew from study due to treatment‐related AEs
TNEs No Pancreáticos
Foregut• Thymus• Esophagus• Lung• Stomach• Pancreas• Duodenum
Midgut• Appendix• Ileum• Cecum• Ascending colon
Hindgut• Distal large bowel• Rectum
Deleción
Adición
Small Intestine Carcinoid
pNET
Nagano Y, et al. Endocr Relat Cancer. 2007;14(2):483-492.Kim do H, et al. Genes Chromosomes Cancer. 2008;47(1):84-92.
RADIANT 2: A randomized placebo-controlled study of RAD001 in patients receiving sandostatin LAR for advanced carcinoid tumors
Pavel ME, et al. Lancet 2011;378(9808):2005-12
Progression Free Survival according to Independent Review Committee (IRC)
RADIANT 2: A randomized placebo-controlled study of RAD001 in patients receiving sandostatin LAR for advanced carcinoid tumors
Pavel ME, et al. Lancet 2011;378(9808):2005-12
Progression Free Survival according to Investigator
RADIANT 2: A randomized placebo-controlled study of RAD001 in patients receiving sandostatin LAR for advanced carcinoid tumors
1.0
0.8
0.6
0.4
0.2
Sur
viva
l pro
babi
lity
0 12 24 36 48 60 72 84 96 108120Time (months)
ColonLungPancreasRectumSmall bowel
Wolin EM, et al. J Clin Oncol 2011(suppl; abstract 4075#)
RADIANT 2: A randomized placebo-controlled study of RAD001 in patients receiving sandostatin LAR for advanced carcinoid tumors
CgA*
0.0Fold
cha
nge
from
bas
elin
e
0.4
0.8
1.2
1.6
2.0
2.4
0 2 3 4 5 6 7 8 9 10 11 12Cycle:
Everolimus 10 mgPlacebo
0.2
0.6
1.0
1.4
1.8
2.2
2.6
P <0.0001First-cycle fold change: 0.57 (95% CI, 0.45-0.73).Range fold change from baseline: 0.39-0.57.
NSE*
0.0
Fold
cha
nge
from
bas
elin
e
0.5
1.51.22.5
3.0
0 2 3 4 5 6 7 8 9 10 11 12Cycle:
Everolimus 10 mgPlacebo
1.0
3.54.0
P <0.0001First-cycle fold change: 0.50 (95% CI, 0.32-0.80).Range fold change from baseline: 0.23-0.51.
Gastrin*
0.0Fold
cha
nge
from
bas
elin
e
0.4
0.8
1.2
1.6
2.0
0 2 3 4 5 6 7 8 9 10 11 12Cycle:
Everolimus 10 mgPlacebo
0.2
0.6
1.0
1.4
1.8
P <0.0001First-cycle fold change: 0.70 (95% CI, 0.52-0.94).Range fold change from baseline: 0.45-0.70.
Glucagon*
0.0Fold
cha
nge
from
bas
elin
e0.4
0.8
1.2
1.6
2.0
0 2 3 4 5 6 7 8 9 10 11 12Cycle:
Everolimus 10 mgPlacebo
0.2
0.6
1.0
1.4
1.8
P <0.0001First-cycle fold change: 0.66 (95% CI, 0.49-0.89).Range fold change from baseline: 0.45-0.66.
RADIANT 2: A randomized placebo-controlled study of RAD001 in patients receiving sandostatin LAR for advanced carcinoid tumors
Castellano D, et al. Oncologist 2013;18(1):46-53
El Futuro de Afinitor en los TNEs
RAMSETE
EVEROLIMUS + BEVA
RAMSETE: A Single‐Arm, Multicenter, Single‐Stage Phase II Trial of RAD001 (Everolimus) in Advanced and Metastatic Silent NETs in Europe
Pavel ME, et al. ASCO 2012. Presented as a Poster. Abstract 4122#
EVEROLIMUS + BEVACIZUMAB
Yao JC, Phan AT, Fogelman D, et al. J Clin Oncol. 2010;28(15s suppl):abstract 4002
Everolimus
Bevacizumab
BevacizumabEverolimus
fCTs*
BevacizumabEverolimus
Ran
dom
A
ssig
nmen
t
PR (confirmed) 8 (21%)
PR (any) 10 (26%)
SD 27 (69%)
PD 1 (3%)
Unknown 1 (3%) -60%
-40%
-20%
0%
20%
40%
Patients
El Futuro de Afinitor en los TNEs
RAMSETE
EVEROLIMUS + BEVA
COOPERATE‐2: Phase II Trial of Everolimus+/‐ Pasireotide in Advanced PNET
Patients:• Well‐differentiated PNET• No prior treatment with mTOR inhibitors or pasireotide
• Progressive disease within the last 12 monthsN = 150
Everolimus 10 mg/day
Everolimus 10 mg/day + pasireotide LAR 60 mg/28 days
Primary endpoint:• Progression‐free survival
1:1
RANDOMIZE
Secondary endpoints:• Objective response rate• Disease control rate• Overall survival
Treatment until tumor progression,intolerable toxicity,
or death
Open‐label, Randomized Study
COOPERATE‐2: Phase II Trial of Everolimus+/‐ Pasireotide in Advanced PNET
Chan JA, et al. Endocr Rel Cancer 2012;19:615–623
RADIANT‐4: Everolimus in Advanced Gastrointestinal NET and Lung NET
Everolimus 10 mg/day +best supportive care
n = 186
Placebo +best supportive care
n = 93
2:1
RANDOMIZE
Interim analysis at 60% of PFS events
PFS assessment until PD as determined by central radiology review
Crossover to open‐label only after IA and DMC recommendation
Primary endpoint: • PFS
(RECIST by central review)
• Patients with advanced well‐differentiated, nonfunctional GI or lung NETs
• Stratified by tumor site, WHO, and prior SSA
• N = 279
Secondary endpoints:• Overall survival• Objective response rate• Biomarkers• Quality of life (FACT‐G)• Time to WHO PS deterioration• Safety and tolerability
LUNA: Phase 2, 3‐arms trial to Evaluate Pasireotide LAR/EverolimusAlone/in combination in Patients with Lung/Thymus NET
Everolimus 10 mg/day
Pasireotide LAR + Everolimus
1:1:1
RANDOMIZE
Primary endpoint: • PFS at 12 months
• Patients with advanced well‐differentiated, NET of the Lung and Thymus
• Radiological documentation of disease progression within 12 months prior to randomization
• N = 112
Secondary endpoints:• Overall survival• PFS• Objective response rate• Time to response• DORSafety
Pasireotide LAR 60 mg im
SEQTOR: Randomized phase III open label cross‐over study to compare the efficacy and safety of everolimus followed by chemotherapy with STZ‐5FU upon progression or the reverse sequence,
chemotherapy with STZ‐5FU followed by everolimus upon progression, in advanced progressive pNETs
Arm A: Everolimus Everolimus(10 mg, daily) (10 mg, daily)
Arm B: STZ-5FU STZ-5FU(Moertel or Uppsala) (Moertel or Uppsala)
Progression
Primary Endpoint: Rate of second progression free survival at 84 weeks of treatment
N = 180 pts
E2212: randomized, double blinded, placebo controlled, phase II study of adjuvant everolimusfollowing the resection of metastatic pancreatic NETs of the liver
Everolimus 10 mg/day + for 12 months (n=75)
Placebo daily for 12 months(n=75)
Primary endpoint:• Progression‐free survival
1:1
RANDOMIZE
Study is pending activationPI: Steve Libutti, approved by GISC
Advanced pancreatic NET following R0 or R1 resection +/‐ RF ablation of hepatic metastases
CBEZ235Z2401: Phase II trial of BEZ235 vs Everolimus in mTORi naive pNET
BEZ235 400 mg bidn = 70
Everolimus 10 mg/d n = 70
Multi-phasic CT or MRI performed every 12 weeks
Eligibility:• Advanced
pancreatic NET• PD within past
12 months• No prior
everolimus
Stratified by:• Prior therapy• CgA
May have failed prior somatostatin analogues; concurrent SSA is allowed
N ~ 1401:1
Treatment until disease progression
EndpointsPrimary:•PFS
Secondary:•ORR, safety,
Exploratory:•Biomarkers, CgA
FPFV November 2012
REG
ISTR
ATIO
N
Algoritmo de Tratamiento de los TNEs
Dis
ease
Bur
den
Agressiveness
SSA
Algoritmo de Tratamiento de los TNEs
Dis
ease
Bur
den
Agressiveness
Novel TargetedAgents
Novel TargetedAgents
Novel TargetedAgentsSSA
Algoritmo de Tratamiento de los TNEs
Dis
ease
Bur
den
Agressiveness
Novel TargetedAgents
Novel TargetedAgents
Novel TargetedAgentsSSA
Chemotherapy
Nuevos Retos en el Tratamiento con mTOR
Pool SE, et al. Cancer Res 2013;73(1):12-8Yao JC, et al. Cancer Res 2013;73:1449-1453
Muchas Gracias!!!!
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