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Lorenzo Antonuzzo SC Oncologia Medica

Azienda Ospedaliero Universitaria Careggi

Firenze

Neuroendocrine tumors

Presented By Arturo Loaiza-Bonilla at 2017 Gastrointestinal Cancers Symposium

PANCREAS

Dasari et al. JAMA ONCOL 2017

2010 to 2017 WHO classif icat ion

•NETumor, G1

•NETumor, G2

•NECarcinoma, G3• Small cell type• Large cell type

Well differentiated NET

PoorlyDifferentiated = NEC

G3-NET not included in the last (2010) WHO

First report of G3-NET: 2013 Velyoudom-Cephise, ERC

2010 t o 2017 WHO classif icat ion

•NETumor, G1

•NETumor, G2

•NETumor, G3

•NECarcinoma, G3• Small cell type• Large cell type

Well differentiated NET

PoorlyDifferentiated=NEC

Well-diff NET of grade 3 are included in the 2017 WHO for Pan-NENEvaluation of the grade does not change in the new WHO

≤ 2%

2 – 20%

> 20%

≤ 2%

2 – 20%

> 20%

> 20%

Ki 67

Ki 67

Treatment choice

• QoL

• Late toxiciy

Treatment (diagnostic) availability

Regulatory Authorities

Patient

AGE

Co

mo

rbid

ity

Clinical Trials

o Syndrome control o Tumour growth control -> Disease Cronicization

AIM of Treatment

Logistic

Primary-Stage Grade – Ki67 SSr expression Functionality Liver dominant

Disease

TACE TAE RF

• Somatostatin Analogs • Interferon • Others (PPI, diazoxide) • Teloristat

• Somatostatin Analogs • PRRT • Targhet agents • Chemotherapy

Syndrome

control

Tumor

control

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news Paziente

Endocrinologia

Oncologia

Chirurgia

Gastroenterologia Medi

cina Nucle

are

Radiologia

Genetica

Anatomia

Patologica

Primary resection Metastasectomy Debulking OLT

Interventional Radiology

Surgery



Syndrome

control

Tumor

control

news

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Kulke et al. JCO 2017

10

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




Syndrome

control

Tumor

control

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204 entero-pancreatic NETs

Lanreotide vs placebo

86 intestinal NETs

Octreotide vs placebo

Somatostatin analogs improves PFS in «low grade» digestive NETs

Rinke et al, J Clin Oncol 2009 – Caplin et al NEJM 2014

CLARINET OLE: data from open label extension study

Caplin et al Endocr Related Cancer 2016

Mean LAN treatment exposure: 43.5 m in LAN-LAN and 18.8 m in PBO-LAN

Additional SSA questions being addressed by ongoing studies

Maintenance?

Dose-intensification?

Combination?

CLARINET-Forte | Efficacy and Safety of Lanreotide 120 mg administered every 14 days in Pancreatic or

Midgut NETs Having Progressed Radiologically While Previously Treated With Lanreotide 120 mg

[NCT02651987]

REMINET | A Study Evaluating Lanreotide as Maintenance Therapy in Patients With Non-Resectable Duodeno-

Pancreatic Neuroendocrine Tumors [NCT02288377]

SONNET | Combination of Lanreotide Autogel 120mg and Temozolomide in Progressive GEP-NET

[NCT02231762]

SSAs | SELECTED ONGOING GEP NET STUDIES



Syndrome

control

Tumor

control

news

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90Y

177Lu +

DTPA

DOTA + ocreotate

Peptide Receptors Radiolabelled Therapy (PRRT)

Adapted from Kaltsas et al. Endocr Related Cancer 2005

Van der Zwan et al Eur J Endocrinol 2014

Strosberg et al. NEJM Jan 2017

Population Characteristics at Enrolment<br />

Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium

Progression-Free Survival


Objective Responses<br />


Overall Survival (interim analysis)


Key Adverse Events: all grades and grades 3-4


MDS in 2.3% of pts Acute leukemia in 1.1%

Nephrotoxicity

Hematological toxicity

N =1048 pz MDS 2.1 %

No gr4 nephotoxicity (with 177Lu)



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control

Tumor

control

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Yao et al NEJM 2011

• Unresectable advanced and/or metastatic, Well differentiated pNET • Documented disease Progression in the last 12 Months* (Target n= 340; n=171 Were recruited before closure)

Placebo + BSC

ran

do

mis

ed

N= 86 (170)

N= 85 (170)

37.5 mg

continuous daily

sunitinib + BSC

Crossover to Sunitinib

at disease progression

(n=38)

Raymond E et al NEJM 2011

Primary End point: PFS

Kaplan Meier median

Sunitinib 11.4 mo

Placebo 5.5 months

Everolimus is indicated for the treatment of unresectable

or metastatic, well- or moderately-differentiated

neuroendocrine tumours of pancreatic origin in adults with

progressive disease.3

Sunitinib is indicated for the treatment of unresectable

or metastatic, well-differentiated pancreatic

neuroendocrine tumours (pNET) with disease

progression in adults.4

1 Yao et al NEJM 2011;364(6):514-23; 2 Raymond et al NEJM 2011;364(6):501-13; 3 Afinitor SPC (accessed 01/03/2016); 4 Sutent SPC (accessed 01/03/2016)

RADIANT-3 (everolimus) 1 SUN1111 (sunitinib) 2

TARGETED THERAPY | PRIMARY ENDPOINT

mPSF 6 mos mOS 28 mos

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

RA

N

D

O

MI

Z

E

Placebo

N=97

Stratified by:

• Prior SSA treatment (yes vs. no)

• Tumor origin (stratum A vs. B)*

• WHO PS (0 vs. 1)

45

Yao JC et al. Lancet 2015;

46

Yao JC et al. Lancet 2015;

Yao JC et al. ASCO meeting 2016;

— 67 —

GAZZETTA UFFICIALE DELLA REPUBBLICA ITALIANA Serie generale - n. 30228-12-2016

DETERMINA 14 dicembre 2016 .

Inserimento del medicinale everolimus (Afi nitor) nell’elenco dei medicinali erogabili a totale carico del Ser-vizio sanitario nazionale, ai sensi della legge 23 dicembre 1996, n. 648, per il trattamento di neoplasie neuroendocrine di origine polmonare e gastrointestinale (metastatico o non operabile), in progressione di malattia dopo analoghi della somatostatina. (Determina n. 1516).

IL DIRETTORE GENERALE

Visti gli articoli 8 e 9 del decreto legislativo 30 luglio 1999, n. 300;

Visto l’art. 48 del decreto-legge 30 settembre 2003 n. 269, convertito nella legge 24 novembre 2003, n. 326, che istituisce l’Agenzia italiana del farmaco ed in parti-colare il comma 13;

Visto il decreto del Ministro della salute di concerto con i Ministri della funzione pubblica e dell’economia e fi nanze in data 20 settembre 2004, n. 245 recante nor-me sull’organizzazione ed il funzionamento dell’Agenzia italiana del farmaco, a norma del comma 13 dell’art. 48 sopra citato, ed in particolare l’art. 19;

Visti il regolamento di organizzazione, del funziona-mento e dell’ordinamento del personale e la nuova dota-zione organica, defi nitivamente adottati dal consiglio di amministrazione dell’AIFA, rispettivamente, con delibe-razione 8 aprile 2016, n. 12, e con deliberazione 3 feb-braio 2016, n. 6, approvate ai sensi dell’art. 22 del de-creto 20 settembre 2004, n. 245, del Ministro della salute di concerto con il Ministro della funzione pubblica e il Ministro dell’economia e delle fi nanze, della cui pubbli-cazione sul proprio sito istituzionale è stato dato avviso nella Gazzetta Uffi ciale della Repubblica italiana - Serie generale - n. 140 del 17 giugno 2016;

Visto il decreto del Ministro della salute 17 novembre 2016, registrato dall’Uffi cio centrale del bilancio al regi-stro «visti semplici», foglio n. 1347 in data 18 novembre 2016, con il quale è stato nominato il dott. Mario Melaz-zini, direttore generale dell’Agenzia italiana del farmaco;

Visto il decreto del Ministro della salute 28 settembre 2004 che ha costituito la commissione consultiva tecnico-scientifi ca dell’Agenzia italiana del farmaco;

Vista la legge 23 dicembre 1996, n. 648, di conversione del decreto-legge 21 ottobre 1996, n. 536, relativa alle misure per il contenimento della spesa farmaceutica e la determinazione del tetto di spesa per l’anno 1996, pubbli-cata nella Gazzetta Uffi ciale n. 300 del 23 dicembre 1996;

Visto il provvedimento della Commissione unica del farmaco (CUF) datato 20 luglio 2000, pubblicato nella Gazzetta Uffi ciale n. 219 del 19 settembre 2000 con er-rata-corrige nella Gazzetta Uffi ciale n. 232 del 4 ottobre 2000, concernente l’istituzione dell’elenco dei medicina-li innovativi la cui commercializzazione è autorizzata in altri Stati ma non sul territorio nazionale, dei medicinali non ancora autorizzati ma sottoposti a sperimentazione clinica e dei medicinali da impiegare per una indicazio-ne terapeutica diversa da quella autorizzata, da erogarsi a totale carico del Servizio sanitario nazionale qualora non

esista valida alternativa terapeutica, ai sensi dell’art. 1, comma 4, del decreto-legge 21 ottobre 1996, n. 536, con-vertito dalla legge 23 dicembre 1996, n. 648;

Visto ancora il provvedimento CUF datato 31 gennaio 2001 concernente il monitoraggio clinico dei medicinali inseriti nel succitato elenco, pubblicato nella Gazzetta Uf-fi ciale n. 70 del 24 marzo 2001;

Considerati i dati derivanti dallo studio Radiant 4 in cui sono stati osservati vantaggi signifi cativi in PFS uni-camente per i pazienti con neoplasie neuroendocrine di origine polmonare e gastrointestinale (metastatico o non operabile), in progressione di malattia dopo analoghi del-la somatostatina;

Ritenuto opportuno consentire la prescrizione di detto medicinale a totale carico del Servizio sanitario nazionale per i pazienti affetti da neoplasie neuroendocrine di origi-ne polmonare e gastrointestinale (metastatico o non ope-rabile), in progressione di malattia dopo analoghi della somatostatina;

Tenuto conto della decisione assunta dalla Commissio-ne consultiva tecnico-scientifi ca (CTS) dell’AIFA nella riunione dell’11-13 luglio 2016 - Stralcio verbale n. 11;

Ritenuto, pertanto, di includere il medicinale everoli-mus (Afi nitor) nell’elenco dei medicinali erogabili a tota-le carico del Servizio sanitario nazionale istituito ai sensi della legge 23 dicembre 1996, n. 648, per il trattamento di neoplasie neuroendocrine di origine polmonare e ga-strointestinale (metastatico o non operabile), in progres-sione di malattia dopo analoghi della somatostatina;

Determina:

Art. 1.

Il medicinale everolimus (Afi nitor) è inserito, ai sensi dell’art. 1, comma 4, del decreto-legge 21 ottobre 1996, n. 536, convertito dalla legge 23 dicembre 1996, n. 648, nell’elenco istituito col provvedimento della Commissio-ne unica del farmaco, per le indicazioni terapeutiche di cui all’art. 2.

Art. 2.

Il medicinale di cui all’art. 1 è erogabile a totale carico del Servizio sanitario nazionale per il trattamento di ne-oplasie neuroendocrine di origine polmonare e gastroin-testinale (metastatico o non operabile), in progressione di malattia dopo analoghi della somatostatina, nel rispetto delle condizioni per esso indicate nell’allegato 1 che fa parte integrante della presente determinazione.



Syndrome

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Tumor

control

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n RR PFS OS

Raut CP, The Oncologist 2011

Strosberg, Cancer, 2011

Advanced p-NETs N=30

Capecitabine 750 mg/m2 po BID days 1-14 Temozolomide 200 mg/m2 po QD days 10-14 q28 days X 3

cycles

• Study design

- Retrospective

- pNETs only

• Endpoints:

- RR 70%

- mPFS 18 mos

- Overall well tolerated

No previous chemo Grade: 16 low 9 intermediate 5 unspecified

• Oxaliplatin-based chemotherapy can be active in advanced NETs irrespective of the primary sites and tumor grade

• The 80% DCR and 8-month PFS could justify a prospective study especially in

pancreatic primary tumor

E-Mail [email protected]

Original Paper

Neuroendocrinology 2016;103:806–814

DOI: 10.1159/000444087

Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors

Francesca Spada a Lorenzo Antonuzzo e Riccardo Marconcini f

Davide Radice b Andrea Antonuzzo f Sergio Ricci f Francesco Di Costanzo e

Annalisa Fontana g Fabio Gelsomino g Gabriele Luppi g Elisabetta Nobili h

Salvatore Galdy a Chiara Alessandra Cella a Angelica Sonzogni d Eleonora Pisa c

Massimo Barberis c Nicola Fazio a

a Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, b Biostatistics and Epidemiology Department,

c Histopathology and Molecular Diagnostics Unit, European Institute of Oncology, and d Fondazione IRCCS Istituto

Nazionale dei Tumori e Università degli Studi di Milano, Milan , e Medical Oncology 1, AOU Careggi Hospital,

Florence , f Department of Oncology 2, University Hospital, Pisa , g Department of Oncology and Hematology, General

Hospital, Modena , and h UOC of Oncology, General Hospital S. Orsola – Malpighi, Bologna , Italy

intestinal in 24, lung in 19 and unknown in 10% of patients.

The vast majority were G2 (2010 WHO classification). Eighty-

six percent of the patients were metastatic, and 87% were

pretreated and progressive to previous therapies. Sixty-five

percent of the patients received capecitabine/oxaliplatin

(CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leu-

covorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in

26% of the patients, half of them with pancreatic NETs, and

SD in 54%. With a median follow-up of 21 months, the me-

dian PFS and OS were 8 and 32 months with 70 and 45 events,

respectively. The most frequent G3 toxicities were neurolog-

ical and gastrointestinal. ERCC-1 immunohistochemical over-

expression was positive in 4/28 evaluated samples, with no

significant correlation with clinical outcome. Conclusion:

This analysis suggests that oxaliplatin-based chemotherapy

can be active with a manageable safety profile in advanced

NETs irrespective of the primary sites and tumor grade. The

80% DCR and 8-month PFS could justify a prospective study

in NETs with intermediate biological characteristics, especial-

ly with pancreatic primary tumors. © 2016 S. Karger AG, Basel

Key Words

Chemotherapy · Neuroendocrine tumor ·

Oxaliplatin · Pancreatic neuroendocrine tumors ·

Gastroenteropancreatic neuroendocrine tumors

Abstract

Purpose: The role of chemotherapy in low-/intermediate-

grade neuroendocrine tumors (NETs) is still debated. We

present the results of an Italian multicenter retrospective

study evaluating activity and toxicity of oxaliplatin-based

chemotherapy in patients with advanced NETs. Methods:

Clinical records from 5 referral centers were reviewed. Dis-

ease control rate (DCR) corresponding to PR + SD (partial re-

sponse + stable disease) at 6 months, progression-free sur-

vival (PFS), overall survival (OS) and toxicity were calculated.

Ki67 labeling index, grade of differentiation and excision-

repair-cross-complementing group 1 (ERCC-1) were analyzed

in tissue tumor samples. Results: Seventy-eight patients en-

tered the study. Primary sites were: pancreas in 46, gastro-

Received: March 10, 2015

Accepted after revision: January 17, 2016

Published online: January 21, 2016

Nicola Fazio or Francesca Spada Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit European Institute of Oncology, Via Ripamonti 435 IT–20141 Milan (Italy) E-Mail nicola.fazio @ ieo.it or francesca.spada @ ieo.it

© 2016 S. Karger AG, Basel0000–0000/16/1036–0806$39.50/0

www.karger.com/nen

Dow

nloa

ded

by:

85.1

19.4

6.8

- 9/

19/2

017

6:02

:36

PM

SB NET Treatment Algorithm: Post SSA treatment


PRRT

Qu

ale

seq

uen

za?

?

pNET Treatment Algorithm: Post SSA treatment


PRRT

• Gli studi clinici non rispondono alla domanda cosa fare nel singolo caso

• Espressione recettori somatostatina ≠ PRRT

• Fare il medico e stabilire la migliore la sequenza con senso clinico in ambito multidisciplinare

*Response assessment: Every 8 weeks for first 6 months; every 12 weeks thereafter

Primary endpoints: ORR per RECIST v1.1 (investigator review)

Secondary endpoints: PFS, OS, duration of response, and safety

KEYNOTE-028 (NCT02054806): Phase 1b Multicohort Study of Pembrolizumab for PD-L1+ Advanced Solid Tumors

Response

Assessment*

Pembrolizumab

10 mg/kg IV

Q2W

CR, PR, or SD

Treat for 24 months

or until

progressionb or

intolerable toxicity

Confirmed PDb or

unacceptable

toxicity

Discontinue

pembrolizumab

Patients

• Carcinoid tumors or

well or moderately

differentiated pNETs

• Failure of or inability to

receive standard

therapy

• ECOG PS 0 or 1

• ≥1 measurable lesion

• PD-L1 positivitya

• No autoimmune

disease or interstitial

lung disease

aAt least 1% modified proportion score or interface pattern (QualTek IHC using 22C3 antibody clone).bIf SD or better when pembrolizumab discontinued and subsequently have PD, patients may be eligible to resume pembrolizumab for ≥1 year.cIf clinically stable, patients are to remain on pembrolizumab until progressive disease is confirmed on a second scan performed ≥4 weeks later.

PD-L1 Screening: Carcinoid/pNET Cohorts

Not evaluable

(N = 9)

Patients Screened for PD-L1

Samples Evaluable for PD-L1

PD-L1–Positive Tumors

Patients treated as of January 10, 2017

aPatients with CNS metastases that were stable for ≥4 weeks could enroll.

24.5%

PD-L1+

Carcinoid, n = 179 pNET, n = 109



Carcinoid, N = 25 pNET, N = 16

Not evaluable

(N = 3)

20.6%

PD-L1+

Antitumor Activity (RECIST v1.1, Investigator Reviewa)

aOnly confirmed responses are included.Data cutoff date: February 20, 2017.

Carcinoid

(N = 25)

pNET

(N = 16)

Objective Response Rate, % (95% CI) 12% (3–31) 6% (0.2–30)

Best overall response, n (%)

Complete response 0 0

Partial response 3 (12%) 1 (6%)

Stable disease 15 (60%) 14 (88%)

≥6 months 8 (32%) 5 (31%)

Progressive disease 7 (28%) 1 (6%)

0 5 1 0 1 5 2 0 2 5

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

Pro

gre

ss

ion

-Fre

e S

urv

iva

l, %

16 7 4 2 2 0

N o . a t r is k

0 5 1 0 1 5 2 0 2 5

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

Pro

gre

ss

ion

-Fre

e S

urv

iva

l, %

25 16 8 4 2 0

N o . a t r is k

Progression-Free Survival(RECIST v1.1, Investigator Review)

Data cutoff date: February 20, 2017.

Carcinoid pNET

40% 27%44% 27%

Median (95% CI) 5.6 (3.5–10.7) Median (95% CI) 4.5 (3.6–8.3)

0 5 1 0 1 5 2 0 2 5 3 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

Ov

era

ll S

urv

iva

l, %

N o . a t r is k

16 14 14 12 7 0 0

0 5 1 0 1 5 2 0 2 5 3 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

Ov

era

ll S

urv

iva

l, %

N o . a t r is k

25 20 15 11 7 1 0

Overall Survival

Data cutoff date: February 20, 2017.

83% 65% 93% 87%

Median (95% CI) 21.1 (9.1–22.4) Median (95% CI) 21.0 (20.2–NR)

Carcinoid pNET

Is PDL-1 the right biomarker? Is G1-G2 NET the right disease?

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