NET

(1)

Lorenzo Antonuzzo

SC Oncologia Medica

Azienda Ospedaliero Universitaria Careggi

Firenze

(2)

Neuroendocrine tumors

Presented By Arturo Loaiza-Bonilla at 2017 Gastrointestinal Cancers Symposium

(3)

PANCREAS

Dasari et al. JAMA ONCOL 2017

(4)

2010 to 2017 WHO classif ication

• NETumor, G1

• NETumor, G2

• NECarcinoma, G3

• Small cell type

• Large cell type

Well differentiated NET

Poorly

Differentiated = 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

Poorly

Differentiated=NEC Well-diff NET of grade 3 are included in the 2017 WHO for Pan-NEN

Evaluation of the grade does not change in the new WHO

≤ 2%

2 – 20%

> 20%

≤ 2%

2 – 20%

> 20%

Ki 67

(5)

Treatment choice

• QoL

• Late toxiciy

Treatment (diagnostic) availability

Regulatory Authorities

Patient

AGE

Co m or bidity

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

(6)

TACE TAE RF

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

Syndrome control

Tumor control

news

^Paziente

Endocri nologia

Oncolo gia

Chir urgia

Gastroent erologia Medi

cina Nucle are Radiol

ogia Gene

tica Anato

mia Patolo

gica

Primary resection Metastasectomy Debulking

OLT

Interventional Radiology

Surgery

(7)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

Syndrome control

Tumor control

news

(8)

Kulke et al. JCO 2017

(9)

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

(10)

(11)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

Syndrome control

Tumor control

news

(12)

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

(13)

CLARINET OLE: data from open label extension study

Caplin et al Endocr Related Cancer 2016

(14)

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

(15)

(16)

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

(17)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

Syndrome control

Tumor control

news

(18)

90

Y

177

Lu + DTPA

DOTA + ocreotate

Peptide Receptors Radiolabelled Therapy (PRRT)

Adapted from Kaltsas et al. Endocr Related Cancer 2005

(19)

Van der Zwan et al Eur J Endocrinol 2014

(20)

Strosberg et al. NEJM Jan 2017

(21)

Population Characteristics at Enrolment<br />

Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium

(22)

Progression-Free Survival

(23)

Objective Responses<br />

(24)

Overall Survival (interim analysis)

(25)

Key Adverse Events: all grades and grades 3-4

(26)

MDS in 2.3% of pts Acute leukemia in 1.1%

Nephrotoxicity

Hematological toxicity

(27)

N =1048 pz MDS 2.1 %

No gr4 nephotoxicity

(with

¹⁷⁷

Lu)

(28)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

Syndrome control

Tumor control

news

(29)

(30)

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

ra n d o m is e d

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

(31)

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

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

RADIANT-3 (everolimus)

¹

SUN1111 (sunitinib)

²

TARGETED THERAPY | PRIMARY ENDPOINT

(32)

mPSF 6 mos mOS 28 mos

(33)

(34)

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)

(35)

45

Yao JC et al. Lancet 2015;

(36)

46

Yao JC et al. Lancet 2015;

Yao JC et al. ASCO meeting 2016;

(37)

— 67 —

GAZZETTA UFFICIALE DELLA REPUBBLICA ITALIANA Serie generale - n. 302 28-12-2016

DETERMINA 14 dicembre 2016 .

I nserimento 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 particolare 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 funzionamento e dell’ordinamento del personale e la nuova dota- zione organica, defi nitivamente adottati dal consiglio di amministrazione dell’AIFA, rispettivamente, con deliberazione 8 aprile 2016, n. 12, e con deliberazione 3 feb- braio 2016, n. 6, approvate ai sensi dell’art. 22 del decreto 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 medicinali 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, convertito 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 della somatostatina;

Ritenuto opportuno consentire la prescrizione di detto medicinale a totale carico del Servizio sanitario nazionale per i pazienti affetti da neoplasie neuroendocrine di origine polmonare e gastrointestinale (metastatico o non operabile), 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 everolimus (Afi nitor) nell’elenco dei medicinali erogabili a totale 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 gastrointestinale (metastatico o non operabile), in progressione 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 neoplasie neuroendocrine di origine polmonare e gastrointestinale (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.

(38)

• Somatostatin Analogs

• Interferon

• Others (PPI, diazoxide)

• Teloristat

• Somatostatin Analogs

• PRRT

• Targhet agents

• Chemotherapy

Syndrome control

Tumor control

news

(39)

n RR PFS OS

(40)

Raut CP, The Oncologist 2011

(41)

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

(42)

• 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 karger@karger.com

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 ê Annalisa Fontana ^g Fabio Gelsomino ^g Gabriele Luppi ^g Elisabetta Nobili ^h Salvatore Galdy â Chiara Alessandra Cella â Angelica Sonzogni ^d Eleonora Pisa ^c Massimo Barberis ^c Nicola Fazio â

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 median 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, especially 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 response + stable disease) at 6 months, progression-free survival (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

Downloaded by: 85.119.46.8 - 9/19/2017 6:02:36 PM

(43)

SB NET Treatment Algorithm: Post SSA treatment

PRRT

Q u ale se q u enz a??

(44)

pNET Treatment Algorithm: Post SSA treatment

PRRT

(45)

• 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

(46)

*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

progression^b or intolerable toxicity

Confirmed PD^b 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

• ≥1measurable lesion

• PD-L1 positivity^a

• 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 ≥1year.

cIf clinically stable, patients are to remain on pembrolizumab until progressive disease is confirmed on a second scan perform ed ≥4 w eeks later.

(47)

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 = 170 pNET, n = 106

Carcinoid, n = 35 pNET, n = 26

Carcinoid, N = 25 pNET, N = 16

Not evaluable (N = 3)

20.6%

PD-L1

⁺

(48)

Antitumor Activity

(RECIST v1.1, Investigator Review

^a

)

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%)

(49)

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 t h s

Progression-Free Survival, %

16 7 4 2 2 0

N o . a t r i s 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

Progression-Free Survival, %

25 16 8 4 2 0

N o . a t r is k

Progression-Free Survival

(RECIST v1.1, Investigator Review)

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

Overall Survival, %

N o . a t r i s 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

Overall Survival, %

N o . a t r i s k

25 20 15 11 7 1 0

Overall Survival

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?

(50)