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Lorenzo Antonuzzo SC Oncologia Medica
Azienda Ospedaliero Universitaria Careggi
Firenze
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Neuroendocrine tumors
Presented By Arturo Loaiza-Bonilla at 2017 Gastrointestinal Cancers Symposium
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PANCREAS
Dasari et al. JAMA ONCOL 2017
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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
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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
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TACE TAE RF
• Somatostatin Analogs • Interferon • Others (PPI, diazoxide) • Teloristat
• Somatostatin Analogs • PRRT • Targhet agents • Chemotherapy
Syndrome
control
Tumor
control
news
news
news Paziente
Endocrinologia
Oncologia
Chirurgia
Gastroenterologia Medi
cina Nucle
are
Radiologia
Genetica
Anatomia
Patologica
Primary resection Metastasectomy Debulking OLT
Interventional Radiology
Surgery
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• Somatostatin Analogs • Interferon • Others (PPI, diazoxide) • Teloristat
• Somatostatin Analogs • PRRT • Targhet agents • Chemotherapy
Syndrome
control
Tumor
control
news
news
news
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Kulke et al. JCO 2017
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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
Kulke et al. JCO 2017
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Kulke et al. JCO 2017
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• Somatostatin Analogs • Interferon • Others (PPI, diazoxide) • Teloristat
• Somatostatin Analogs • PRRT • Targhet agents • Chemotherapy
Syndrome
control
Tumor
control
news
news
news
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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
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CLARINET OLE: data from open label extension study
Caplin et al Endocr Related Cancer 2016
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Mean LAN treatment exposure: 43.5 m in LAN-LAN and 18.8 m in PBO-LAN
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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
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• Somatostatin Analogs • Interferon • Others (PPI, diazoxide) • Teloristat
• Somatostatin Analogs • PRRT • Targhet agents • Chemotherapy
Syndrome
control
Tumor
control
news
news
news
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90Y
177Lu +
DTPA
DOTA + ocreotate
Peptide Receptors Radiolabelled Therapy (PRRT)
Adapted from Kaltsas et al. Endocr Related Cancer 2005
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Van der Zwan et al Eur J Endocrinol 2014
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Strosberg et al. NEJM Jan 2017
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Population Characteristics at Enrolment<br />
Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium
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Progression-Free Survival
Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium
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Objective Responses<br />
Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium
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Overall Survival (interim analysis)
Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium
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Key Adverse Events: all grades and grades 3-4
Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium
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MDS in 2.3% of pts Acute leukemia in 1.1%
Nephrotoxicity
Hematological toxicity
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N =1048 pz MDS 2.1 %
No gr4 nephotoxicity (with 177Lu)
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• Somatostatin Analogs • Interferon • Others (PPI, diazoxide) • Teloristat
• Somatostatin Analogs • PRRT • Targhet agents • Chemotherapy
Syndrome
control
Tumor
control
news
news
news
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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
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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
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mPSF 6 mos mOS 28 mos
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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)
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45
Yao JC et al. Lancet 2015;
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46
Yao JC et al. Lancet 2015;
Yao JC et al. ASCO meeting 2016;
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— 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.
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• Somatostatin Analogs • Interferon • Others (PPI, diazoxide) • Teloristat
• Somatostatin Analogs • PRRT • Targhet agents • Chemotherapy
Syndrome
control
Tumor
control
news
news
news
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n RR PFS OS
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Raut CP, The Oncologist 2011
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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
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• 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:
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6.8
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SB NET Treatment Algorithm: Post SSA treatment
Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium
PRRT
Qu
ale
seq
uen
za?
?
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pNET Treatment Algorithm: Post SSA treatment
Presented By Jonathan Strosberg at 2017 Gastrointestinal Cancers Symposium
PRRT
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• 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
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*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.
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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+
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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%)
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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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