tumores neuroendocrinos: personalización terapéutica · personalización terapéutica enrique...

Tumores Neuroendocrinos:

Personalización Terapéutica

Enrique Grande Hospital Ramón y Cajal de Madrid

No One Single Patient with pNET is the Same than Other

Puzzle Pieces in NETs

Sunitinib Everolimus Interferon

SSA Capecitabine

Temozolomide Carboplatin/

Etoposide Streptozocin


SSA

Efficacy of Octreotide LAR in Midgut

Carcinoids: the PROMID Trial

Rinke A et al. J Clin Oncol 2009;27:4656–4663

Octreotide LAR 30 mg: 42 patients / 26 events

Median TTP = 14.3 months [95% CI: 11.0–28.8]

Placebo: 43 patients / 40 events

Median TTP = 6.0 months [95% CI: 3.7–9.4]

Time (months)

Pro

port

ion

wit

hou

t p

rogre

ssio

n

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78

66% reduction in the risk of tumour progression HR=0.34; 95% CI: 0.20–0.59; P=0.000072

Efficacy of Lanreotide autogel in

enteropancreatic NET: the CLARINET study

Caplin M, et al. N Engl J Med 2014;371:224-33

pNET subgroup

HR 0.58 (95% CI 0.32–1.04)

p=0.0637 (NS)*

Lanreotide

n=42

Median,

not reached

Placebo

n=49

Median, 12.1 months

Time (months) 0 3 6 9 12 18 24 27

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

aliv

e a

nd

with

no

pro

gre

ssio

n (

%)

For pNET, there was no significant difference in PFS for lanreotide autogel

120 mg compared with placebo in the CLARINET core study

ITT population

HR 0.47 (95% CI 0.30–0.73)

p<0.001*

Pa

tie

nts

aliv

e a

nd

with

no

pro

gre

ssio

n (

%)

Lanreotide

n=101

Median,

not reached

Placebo

n=103

Median, 18.0 months

0 3 6 9 12 18 24 27

0

10

20

30

40

50

60

70

80

90

100

Time (months)


Capecitabine

Temozolomide Carboplatin/

Etoposide Streptozocin

Chemotherapy for Growing Control of pNETs

Moertel CG, et al. N Engl J Med. 1980; 2. Moertel C, et al. N Engl J Med. 1992; 3. Ramanathan RK, et al. Ann Oncol. 2001; 4. Kulke MH, et al. J Clin Oncol. 2006; 5. Chan JA, et al. J Clin Oncol. 2012; 6. Kulke MH, et al. ASCO Gastrointestinal Cancers Symposium 2010; 7.

Kouvaraki MA, et al. J Clin Oncol. 2004; 8. Turner NC, et al. Br J Cancer. 2010; 9. Kulke MH, et al. Clin Cancer Res. 2009; 10. Ekeblad S, et al. Clin Cancer Res. 2007; 11.Strosberg JR, et al. Cancer. 2011;

Retrospective Studies

STZ + DOX + 5-FU — 84 39 37 18 20047

STZ + 5-FU + Cisplatin 47 38 31.5 9.1 20108

Temozolomide (diverse regimens) — 53 34 35.3 13.6 20099

Temozolomide (single agent) — 12 14 — — 200710

Temozolomide + capecitabine — 30 70 — 18 201011

Regimen Phase No. of

Pts

Tumour RR

(%)

Median OS

(mos) PFS (mos) Year

Prospective Studies

STZ + 5-FU III 42 63 26 — 19801

STZ III 42 36 16.4

STZ + DOX III 36 69 26.4

— 19922 STZ + 5-FU III 33 45 16.8

CLZ III 33 30 18

DTIC II 50 34 19.3 — 20013

Temozolomide + thalidomide II 11 45 NR NR 20064

Temozolomide + bevacizumab II 15 33 41.7 14.3 20125

Temozolomide + everolimus I/II 24 35 — — 20106

Chemotherapy toxicity profile in advanced pNET

Chemotherapy is associated with a high

incidence of severe toxicities

Severe† Severe Severe Severe§ All‡ All All All Severe All Severe

Nausea Vomiting Diarrhoea Stomatitis Neutropenia

All*

Thrombocytopenia

Chlorozotocin

Streptozocin + fluorouracil

NR NR NR

Streptozocin + doxorubicin

Moertel CG et al. N Engl J Med 1992;326:519–523

Temozolomide in pNETs: Have we got a Biomarker?

Kulke M, et al. Clin Cancer Res 2009;15(1):338-4

Pro

po

rtio

n a

live

1.00

0.75

0.50

0.25

0

0 10 20 30 40 50 60 70

Months

MGMT-intact MGMT-deficient Censored patients

N Response

(RECIST)

Response

(CgA)

Median

PFS (m)

Median

OS (m)

MGMT

positive

16 0/16 0/10 9.3 19.1

MGMT

negative

5 4/5 4/5 19.2 NR

MGMT positive MGMT negative


Sunitinib Everolimus

Novel Targeted Agents in pNETs

Genes pNET

MEN-1 44%

DAXX, ATRX 43%

Genes in mTOR pathway 15%

Antiangiogenic treatment

Central necrosis

Jiao Y, et al. Science. 2011;331:1199-203. Capurso G, et al. J Mol Endocrinol. 2012;49:R37-50. Faivre S, et al. Nat Rev Drug Discov. 2007;6:734-45.

Receptor Growth factor

PI3K

Akt

mTORC1 Rheb

TSC1

TSC2

PTEN

Pathway blocked

VEGF VEGFR

Carcinoid (N=67) 70% 70%

Pancreatic

endocrine tumor

(N=16)

100%

85%

Improvement in PFS with targeted agents

in advanced pNET

Raymond E, et al. N Engl J Med 2011;364(6):501-13. Yao J, et al N Engl J Med 2011;364:514−523

SUNITINIB EVEROLIMUS

Multikinase inhibitor

100

80

60

40

20

0

0 5 10 15 20 25

Sunitinib (n = 86) mPFS: 11.4 mo

Placebo (n = 85) mPFS: 5.5 mo

HR 0.42, 95% CI 0.26–0.66 p 0.001

Pro

bab

ility

of

PFS

(%

)

Months

Pro

bab

ility

of

PFS

(%

)

mTOR inhibitor

100

80

60

40

20

0

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

Placebo (n = 203) mPFS: 4.6 mo

Everolimus (n = 207) mPFS: 11.0 mo

HR 0.35, 95% CI 0.27–0.45 p 0.001

Censoring times

Months

Everolimus prolongs OS in patients with

advanced pNET: Final analysis

Yao JC et al. ESMO 2014 (abstract 11320)

• Everolimus demonstrated a survival advantage compared with placebo for patients with advanced progressive

pNET, although the difference was not statistically significant (HR 0.94, p=0.300)

• Median OS was not reached in the placebo RPSFT analysis due to the high number of censored patients

Ove

rall

su

rviv

al (%

)

Time (months)

Kaplan–Meier medians (95% CI), months

Everolimus: 44.02 (35.61–51.57)

Placebo: 37.68 (29.14–45.77)

Placebo RPSFT*: NA (20.61–NA)

Censoring times

Everolimus (n/N = 126/207)

Placebo (n/N = 130/203)

Placebo RPSFT (n/N = 76/203)

+++

Sunitinib provides an OS benefit in patients with

advanced pNET: 2-year interim analysis

Faivre S et al. ESMO 2012 (abstract 11550)

• Adjusting for crossover suggests that the effect of sunitinib on OS might have been more pronounced had no crossover occurred

• RPSFT analyses demonstrate a survival advantage and interim analysis further support the clinical benefit of sunitinib for patients with advanced progressive pNET

Time (months)

100

Placebo (n=85)

RPSFT model

Median: 16.4 months

80

60

40

20

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 0

Pro

ba

bil

ity o

f s

urv

iva

l (%

)

Sunitinib (n=86)

ITT analysis

Median: 33.0 months

Placebo (n=85)

ITT analysis

Median: 26.7 months

Toxicity profile of Everolimus

Yao JC et al. N Engl J Med 2011;364:514–523

The toxicity profile for everolimus is favourable, with a low incidence of severe events

Severe Severe Severe Severe All All All All Severe All Severe All

Everolimus

Placebo

2

Diarrhoea Fatigue Infections Nausea Stomatitis

Rash

Toxicity profile of Sunitinib

Raymond E et al. N Engl J Med 2011;364:501–513

The toxicity profile for sunitinib is favourable, with a low incidence of severe events

Severe Severe Severe Severe All All All All Severe All Severe

Asthenia Vomiting Fatigue Hair-colour changes Diarrhoea

All

Nausea

Sunitinib

Placebo

2 1

Own Experience with Sunitinib

Castellano D, Grande E, and Barriuso J. N Engl J Med 2011;364:1872-3

Guidelines for pNETs

Falconi M, et al. Neuroendocrinology. 2012;95:120-34.

Jensen RT, et al. Neuroendocrinology. 2012;95:98-119.

Öberg K, et al. Ann Oncol. 2012;23:124-30.

Pavel M, et al. Neuroendocrinology. 2012;95:157-76.

Singh S, et al. Ann Surg Oncol. 2014 Nov 4 [Epub ahead of print]

Grade Ki-67 Recommended treatment

G1 / G2 2–20% Everolimus or sunitinib

G2 5–20% STZ + 5-FU / doxorubicin

G2 / G3 > 10% TMZ

G3 > 20% Carboplatin + etoposide

NS NS PRRT

Everolimus

Sunitinib

CIS /

etoposide

chemotherapy

PRRT

G3 G2 G1

Wait and

watch

Stable / slowly

progressive

STZ-based

chemotherapy

STZ-based

chemotherapy

ESMO

ENETS

Tumor Recommended treatment

Indolent–moderately

progressive

Everolimus or sunitinib

G1 / G2, rapidly progressive Chemotherapy

G3 Chemotherapy

SSTR-positive PRRT

Canadian National Expert Group

Everolimus

Sunitinib

SSA

How I Treat my Daily Clinical Practice Patients

Favour

chemotherapy

Dis

ea

se v

olu

me

Favour

targeted

therapy/SSA Ki-67

Figure adapted from Lamarca A et al. TJOP 2014;2:15–25 Diez M et al. Ann Gastroenterol 2013;26(1):29-36

The Importance of Multidisciplinary Tumor

Board in Neuroendocrine Tumors

Díez JJ, et al. Med Clin (Bar) 2015

Endocrinology General Surgery

Medical Oncology

H&N Surgery

Radiology

Clinic Biochemistry

Radiation Oncology

Neurosurgery

Nuclear Medicine

Pathology

What’s the future for pNETs?

Relationship between date of publication and number of patients enrolled in clinical studies

Large studies, previously

thought impossible

Record numbers of

patients entering clinical

trials

Moving towards small

studies in selected patient

subgroups

900

800

700

600

500

400

300

200

100

0 1980–84 1985–89 1990–94 1995–99 2000–04 2005–09 2010–12

Year of publication

Nu

mb

er

of

pati

en

ts e

nro

lle

d

Targeted

Endostatin

IFN

Liver-directed

SSA

Mixed

Chemotherapy

Valle JW et al. Cancer Treatment Reviews 2014;40:376–389

The Future in pNETs: Sequencing Strategy

T size

1st Line 2nd Line

3rd Line

time

Previous multitarget

12.4 months (95% CI 11.3–13.5)

No previous biological treatment

9.5 months (95% CI 8.8–10.1)

Previous mTOR inhibitor

6.8 months (95% CI 0.0–15.3)

Previous multitarget and mTOR

4.0 months (95% CI 1.3–6.8) Pro

ba

bilit

y

Time (months)

p = 0.040

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27

Grande E, et al. In press.


Grande E, Oral Presentation at ESMO 2012, Viena. Austria. Abstract 11507

7-2010 12-2011

Ascites

02-2008

Sunitinib 37.5 mg/d 29 mo Everolimus 10 mg/d 15 mo

10-2010 10-2007

Symptoms control Tumor shrinking

Gastrin production Ectopic-ACTH production (transforming)

Tumor shrinking

01-2008

Octreotide LAR

30mg/m 4 mo

Courtesy by Dr. Daniel Castellano



Courtesy by Dr. Daniel Castellano

12-2011 Ectopic-ACTH production

Pazopanib (PAZONET trial)



9-2012

9 + mo

12-2011 Ectopic-ACTH production

Pazopanib (PAZONET trial)

Muchas gracias

[email protected]

tumores neuroendocrinos: personalización terapéutica · personalización terapéutica enrique...

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