Tumores neuroendocrinos pancreáticos: Nuevo abordaje del ... · Tumores neuroendocrinos...

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!!!!

egrande@oncologiahrc.com