ESMO PRECEPTORSHIP PROGRAMME

Multidisciplinary management, standards of care and future perspectives

Lugano, Switzerland 13-14 April 2018

CHAIR: Nicola Fazio, Italy SPEAKERS: Pier Luigi Filosso, Italy George Pentheroudakis, Greece Andrea Frilling, United Kingdom

Rocio Garcia-Carbonero, Spain

Massimo Milione, Italy Marianne Pavel, Germany Aviral Singh, Germany Anders Sundin, Sweden Christos Toumpanakis, United Kingdom LEARNING OBJECTIVES

Ongoing• Toand learn about future best clinical practice clinical in the multid isciplinary management of gastroenteropancreatic (GEP) and thoracic neuroendocrine neoplasms (NEN) patients investigation in GEP NENs of Oncology • To learn about the biological and clinical principles of diagnostic and therapeutic strategy Institute • To understand the importance of terminology, pathological and clinical classification, morphological and functional characterization of disease European Nicola Fazio, M.D., Ph. D. • To learn how to manage the integration of several different therapies in patients with advanced disease

• To learn how to apply into clinical practice information coming from medical literature, guidelines and recommendations Division of Gastrointestinal Medical Oncology and

ACCREDITATION Neuroendocrine Tumors

EuropeanThe programme Institute of this event of has Oncology been accredited with 10 ESMO-MORA category 1 points. RecertificationMilan, is necessary Italy for medical oncologists to remain professionally certified by ESMO. Recertification guarantees that a certified medical oncologist has continued to update her/his knowledge and continues to possess the necessary skills and standards for the practice of medical oncology. For further details, please refer to esmo.org.

ACKNOWLEDGEMENTS

This event is supported by an unrestricted educational grant from

ORGANISATION AND CONTACTS

ESMO Head Office Education Department Via Luigi Taddei 4 6962 Lugano - Viganello Switzerland Email: [email protected] www.esmo.org

Disclosure!

Novartis, Ipsen, Pfizer, AAA, Merck Serono: consulting and advisory services!

Novartis, Merck Serono: Research funds (to the institution) ! Investigation lines in GEP NENs

• SSA

• Sequence

• PRRT

• High grade

• New drugs

• Immunotherapy Investigation lines in GEP NENs

• SSA

• Sequence

• PRRT

• High grade

• New drugs

• Immunotherapy Efficacy and Safety of Autogel® 120 mg Administered Every 14 Days in Well Differentiated, Metastatic or Locally Advanced, Unresectable Pancreatic or Midgut Neuroendocrine Tumours Having Progressed Radiologically While Previously Treated With Lanreotide Autogel® 120 mg Administered Every 28 Days CLARINET FORTE

Histopathologically confirmed, grade 1 or 2, metastatic or locally advanced, unresectable pNET (pNET cohort) or midgut NET (midgut cohort) with or without hormone related syndromes, with a proliferation index (Ki67) ≤20%.

Positive receptors type 2

100 patients European, prospective, multicentre, double-blind randomised study evaluating lanreotide Lanreotide as Maintenance Therapy in Patients With Non-Resectable Duodeno-Pancreatic Neuroendocrine Tumors (REMINET)

Inclusione criteria: Documented stable disease or objective response after first-line treatment (chemotherapy or biotherapy for 6 months), within 4 weeks (28 days) prior to randomisation

Treatment: Lanreotide 120 mg every 28 days until disease progression versus placebo Investigation lines in GEP NENs

• SSA

• Sequence

• PRRT

• High grade

• New drugs

• Immunotherapy GETNE-1206 (SEQTOR): Phase III Study in Patients With AdvancedGETNE 1206 (SEQTOR) pNET phase III trial

Compare efficacyin andpaents safety of with everolimusadvanced followed panNETsby chemotherapy with STZ + 5-FU upon progression, or theenrolling reverse sequence (chemotherapy with STZ + 5-FU followed by everolimus upon progression)

Arm A: Everolimus Everolimus

Progression

STZ + STZ + Arm B: 5-FU 5-FU

Primary end point: rate of second PFS at 84 weeks of treatment

Unpublished data. Clinicaltrials.gov ID, NCT02246127. 26 Investigation lines in GEP NENs

• SSA

• Sequence

• PRRT

• High grade

• New drugs

• Immunotherapy A prospective, randomised, Controlled, Open-label, Multicentre phase III study to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, - positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP- NET).

COMPETE trial 177Lu-edotreotide G1-G2 advanced progressive GEP NET

Rand. Phase III

Everolimus COMPETE: 177Lu-Edotreotide vs. Everolimus

4. Approval Status & Timelines

COMPETE Worldwide

Initiated & Sites Ready for Initiation Australia, Austria, France, Germany, Netherlands, South Africa, Switzerland, UK

Review in progress Italy, Poland

EC / CA submissions to be done US

COMPETE_Newsletter 4_Jan2018 4 Investigation lines in GEP NENs

• SSA

• Sequence

• PRRT

• High grade

• New drugs

• Immunotherapy Phase II trial Everolimus and Temozolomide in Advanced GEP NECs (G3)

Histologically proven neuroendocrine carcinoma with a Ki67 of 20-55%. Primary GEP NET or unknown primary where metastases are mainly abdominal Randomized phase II study of cisplatin and etoposide versus temozolomide and capecitabine in patients (pts) with advanced G3 non-small cell gastroenteropancreatic neuroendocrine carcinomas (GEPNEC): A trial of the ECOG-ACRIN Cancer Research Group (EA2142).

G3 (only large cell) GEP NEC CDDP / VP-16 Ki-67 21-100% First-line Rand. Phase II 126 pts

CAP / TEM Prospecve Internaonal Phase II Mul-centre Trial 177Lu-DOTA- (LuTate) PRRT Vs Capecitabine Temozolomide chemotherapy for Grade 3 GEP NEN (Ki67 20-55%) – LUCAT Trial PI: Grace Kong, Michael Michael, Rod Hicks Peter MacCallum Cancer Center, Melbourne, Australia • Primary objecve –PFS. • 56 paents • 1st or 2nd line Investigation lines in GEP NENs

• SSA

• Sequence

• PRRT

• High grade

• New drugs

• Immunotherapy Novel TKIs in GEP NETs

Compound VEGFR PDGFR FGFR CSF1R KIT FLT-3 RET MET

1 2 3 α β

Sunitinib ✔ ✔ ✔ ✔ ✔ ✔ ✔

Pazopanib ✔ ✔ ✔ ✔ ✔ ✔

Cabozantinib ✔ ✔ ✔ ✔ ✔ ✔

Lenvatinib ✔ ✔ ✔ ✔ ✔ ✔ ✔

Sulfatinib ✔ ✔ ✔ ✔ ✔ ✔

Sulfanib in GEP NET 81 NET pts (41 pNET)

Jia, ENETS 2017, Oral presentation Sulfanib in GEP NET

Jia, ENETS 2017, Oral presentation Cabozannib in GEP NET

PR 15% 41 SD 63% mPFS 31 mo Phase II trial PR 15% 20 pNETs SD 75% mPFS 22 mo

Chan et al., ASCO GI 2017, Poster TALENT trial Phase II with LENVATINIB in GEP NETs

§ Pancreatic G1/G2 cohort (n=55) Lenvatinib binds to RET, VEGFR and FGFR

§ Gastrointestinal G1/G2 cohort (n=55) Review of safety and effcacy of axitinib

This IC50 is 10-fold lower for the VEGF family of in y1.4 fold accumulation compared to single admin- receptors than for other TKIs such as pazopanib, suni- istration. The oral bioavaibility of axitinib is 58%. tinib, or sorafenib.26–28 Concerning other non-VEGF Although a low pH results in the highest solubility kinase receptors (PDGF, fbroblast growth of axitinib, studies have demonstrated that the effect factor, colony-stimulating factor), the IC50 of axi- of pH on absorption of axitinib was not clinically tinib was 1.6 to 1000 nmol/L (versus 6–880 nmol/L signifcant. As a measure of precaution, antacids with other agents).29 These results testify to the high or proton pump inhibitors should be administered potency and selectivity of axitinib against VEGFRs at times other than 2 h before and 2 h after drug (Table 1).26–28 Blockade of the VEGFR induces major dosing.11 Axitinib is highly bound (99%) to human changes of tumor vasculature in mouse models. In plasma proteins with preferential binding to albu- vivo, dynamic contrast enhanced magnetic resonance min and moderate binding to A1-acid glycoprotein. imaging (DCE-MRI), which is an imaging technique The plasma half-life ranges between 2.5 and 6.1 h that can measure the density, integrity, and leakiness and a steady-state is attained within 15 days. Linear of tissue vasculature, showed that axitinib decreases correlations have been reported between dose and the tumor blood fow/permeability. Maximum reduc- maximum plasma concentration, in addition to area tion in tumor endothelial transfer constant (Ktrans)— under plasma concentration-time curve.16 The mean an indicator of vascular leakage to the extracellular apparent volume of distribution in patients receiving space—was observed on day 7 after dosing and was 5 mg twice daily was 160L.11 Axitinib is primarily correlated with decreased micro-vessel density, cel- metabolized in the liver by cytochrome P450 (CYP) lular viability, and tumor growth. 3A4 and to a lesser extent by CYP1A2, CYP2C19, uridine diphosphate glucuronosyl-transferase (UGT) Metabolism and pharmacokinetic profle 1A1, and the drug transporters P-glycoprotein. Two Pharmacokinetic analyses have been obtained from metabolites are produced: an N-glucuronide metabo- polled data of 17 trials, in both healthy volunteers lite and a sulfoxide. Both are 400-fold less potent and cancer patients.11 A two-compartment disposi- against VEGFR-2 in vitro than axitinib.11 Less than tion model with frst-order absorption and lag-time one percent of the absorbed drug remained unchanged adequately describes the axitinib concentration- in the urine. Otherwise, a recent meta-analysis found time profle. After a single dose of 5 mg in the fed no statistically signifcant associations between the state, axitinib is rapidly absorbed with peak plasma polymorphism of genes encoding these enzymes and concentrations occurring at 2–6 h post dosing. The the transporters and axitinib pharmacokinetics.31 As median time (tmax) ranged from 2.5–4.1 h. The rate observed in a phase 1 trial, axitinib pharmacokinetics of the drug’s absorption was higher in the fasting are affected by CYP inducers (rifampicin, phenytoin, state with a peak concentration occurring 1–2 h after etc.) and inhibitors (ketoconazole, etc.). They may also dosing.30 Moreover, Pithavala et al30 demonstrated in be affected by drugs that are substrates or inhibitors healthy volunteers that axitinib XLI Form flm-coated of P-glycoprotein. Specifc data on patients with mild immediate-release (FCIR) could be administered to moderate hepatic impairment have been obtained regardless of the fasting or fed state without signif- through a phase I study, and showed an association cant impact on its pharmacokinetics.30 Twice daily between drug exposure and hepatic impairment, thus administration of 5 mg of axitinib was associated justifying the need for dose reduction in patients with

Table 1. Inhibitory concentrations (IC50 in nmol) for targets with multitargeted TKIs.

Drug VEGFR1 VEGFR2 VEGFR3 PDGFR] PDGFR^ c-Kit RET RAF FLT3 Axitinib9 0.1 0.2 0.1–0.3 5 1.6 1.7 1000 NA 1000 Pazopanib24 10 30 47 71 84 74 1000 NA 1000 Sunitinib25 10 10 10 5–10 10 13 100–200 NA 1–10 Sorafenib26 NA 90 20 50–60 50–60 68 100–150 5–10 46

Abbreviation: NA, Not available.

Clinical Medicine Insights: Oncology 2013:7 271

AXITINIB A PHASE II/III RANDOMIZED DOUBLE-BLIND STUDY OF SANDOSTATIN LAR IN COMBINATION WITH AXITINIB VERSUS SANDOSTATIN LAR WITH PLACEBO IN PATIENTS WITH ADVANCED G1-G2 NEUROENDOCRINE TUMOURS (WHO 2010) OF NON-PANCREATIC ORIGIN

N=!253! Arm$A$

Axitinib!+!

Nonpancreatic!G1@G2!NETs! ! Sandostatin!LAR! with!progression!of!disease!in! the!previous!12!mo! ! ! N ECOG!PS!0@2! Age!≥!18!years!

With!or!without!previous! *!RANDOMIZATION Placebo!+! chemotherapy! Sandostatin!LAR! Ki67!

CDK4/6 controls cell cycle progression from G1 to S phase by regulating the activity of Rb

Prada et al, Neuroendocrinology 2016 Fig. 1. Proposed and simplified modeTang of L. action et al., Clinof the Cancer CDK4/6 Res inhibitor 2012 LEE011 on the cell cycle. a Activated CyclinD-CDK4/6-Rb axis leads to G1/S cell cycle progression via the phosphorylation of Rb and subsequent activation of the transcription factor E2F. b Blocking the CyclinD-CDK4/6-Rb axis leads to G1 phase cell cycle arrest through either the endogenous CDK4/6 inhibitor p16 or the small molecule CDK4/6 inhibitor LEE011. Downloaded by: Ist.Europeo di Oncologia 193.204.98.2 - 2/24/2017 8:43:52 AM Ribociclib in NET: preclinical study Neuroendocrinology (DOI:10.1159/000463386) © 2017 S. Karger AG, Basel 23

GOT-1

H727 QGP-1

BON-1

RibociclibFig. 2. sensitivity The effect of wasdifferent associated concentrations with of LEE011 high expressionon cell survival ofof 4cyclin-1 different and Rb NET cell lines after 144 h of incubation. Human neuroendocrine pancreatic BON1, Ribociclib/Everolimus or 5-FU combinations were superior to the single-agent therapies, pancreatic islet QGP1, bronchopulmonary H727 and midgut GOT1 cells were by downregulating mTOR and MEK pathways incubated with LEE011 in a concentration range of 1 nM to 10 μM for 144 h. The calculated means and standard deviation of at least three independent experiments are shown. Statistically significant differences in the results in comparison to Control cells treated with DMSO for 50 nM to 10 μM are representedPrada et by al, p<0.001 Neuroendocrinology = ***. 2016 Downloaded by: Ist.Europeo di Oncologia 193.204.98.2 - 2/24/2017 8:43:52 AM Abstract 429O

A phase II trial of palbociclib in metastatic grade 1/2 pancreatic neuroendocrine tumors: the PALBONET study on behalf of the Spanish Taskforce Group of Neuroendocrine Tumors (GETNE)

Enrique Grande1, Alexandre Teulé2, Teresa Alonso-Gordoa1, Paula Jiménez-Fonseca3, Marta Benavent4, Jaume Capdevila5, Ana CustodioPatient6, Ruth Vera7, Javier disposition Munárriz8, Adelaida La Casta-Muñoa9, Rocío García-Carbonero10

1H. U. Ramón y Cajal; 2ICO. Hospital Duran i Reynals; 3H. U. Central de Asturias; 4H. U. Virgen del Rocío; 5H. U. Vall d’Hebron; 6H. U. La Paz; 7Complejo Hospitalario de Navarra; 8H. U. Castellón; 9H. U. Donostia; 10H. U. 12 de Octubre Overall responseNo. of patients r(%)ate Patients treated 21 Median numberProgression of treatment cycles administered [rangefree] N survival3 [2–15] % PartialMedian responsefollow up (PR) time, months [range] 0 12.3 [7.5-19.30]

1.0 StableReason disease “off” study* (SD) 11 55 Disease progression 17 (81) ProgressionToxicity disease (PD) 9 1 (4.8) 45 0.8 ClinicalDeath benefit rate (PR + SD) 11 1 (4.8) 55 Withdrew consentmPFS: 2.6 months (95% CI 0–14.4) 0 (0) StableOther disease ≥ 3 months 7 1 (5) 35 0.6 *OnlyStable20 patients diseasewere ≥followed 6 monthsup for treatment administration; patient #306 was lost6 to follow up after cycle 1 day301.

0.4 * 20 patients were evaluable for response; 1 patient lost follow up after cycle 1 day 1 Cumulative survival Cumulative 0.2

0.0

0 5 10 15 20 25 Time (months) A Phase II Study of LEE011 (Ribociclib) in Patients with Advanced Neuroendocrine Tumors of Foregut Origin (CLEE011 XUS02T) US only Research lines in GEP NENs

• SSA

• PRRT

• High grade

• New drugs

• Immunotherapy Yao, ENETS 2017, Oral presentations ElevatION NET-201: An Open-Label Phase II Study to Evaluate the Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-Differentiated, Non-Functional NET of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-Differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC) Who Have Progressed on Prior Treatment J.C. Yao1, N. Fazio2, M.E. Pavel3, J. Strosberg4, E. Bergsland5, P. Ruszniewski6, M. Voi7, C. Wu7, E. Degtyarev8, P. Aimone8, S. Singh9 1University of Texas/MD Anderson Cancer Center, Houston, Texas, USA; 2European Institute of Oncology, Milan, Italy; 3Dept. of Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany; 4Department of Medicine, Moffitt Cancer Center, Tampa, Florida, USA; 5UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, USA; 6Gastroenterology and Pancreatology Department, Beaujon Hospital, Clichy, France; 7Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 8Novartis Pharmaceuticals AG, Basel, Switzerland; 9Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Figure 2. Study Design Introduction Well-diferentiated NET group Study Flow Study Enrollment Þ .POPDMPOBMBOUJCPEZ N"C JOIJCJUPSTPGJNNVOFDIFDLQPJOUT JODMVEJOHBOUJQSPHSBNNFEDFMM EFBUIQSPUFJO 1% BOEJUTMJHBOET1%Ƽ- IBWFCFDPNFFTUBCMJTIFEUSFBUNFOUPQUJPOTJO Patients: Total (N=110)* Norway PDR001 400 mg Q4W, flat Thoracic (lung and thymus origin) cohort GI cohort Germany  Þ "EWBODFE OPOGVODUJPOBM  Sweden WBSJPVTTPMJEUVNPST dose until: Þ "UMFBTUUXPQSJPSTZTUFNJDSFHJNFOT XIJDI Screen period: Day -28 to Day -1 well-diferentiated NET of Þ 5IZNVTPSJHJOBUMFBTUPOFQSJPSTZTUFNJD Netherlands Þ "MUIPVHINBOZBEWBODFTXJUIDIFDLQPJOUJOIJCJUPSTIBWFCFFONBEFJOPUIFSUVNPSUZQFT UIF GI Cohort NVTUJODMVEFFWFSPMJNVT pancreatic or GI origin (grade UIFSBQZBDDPSEJOHUPJOWFTUJHBUPS×TDIPJDF (n=30) Þ $POôSNFE1%QFS Þ 1SJPSTZTUFNJDUIFSBQJFTNBZJODMVEF Canada Austria EBUBHFOFSBUFEJOOFVSPFOEPDSJOFUVNPSTPDR001 /&5T BSFMJNJUFE in GEP and1 or 2) orLung thoracic (typical or NET/NEC Þ -VOHPSJHJOBUMFBTUPOFQSJPSTZTUFNJD Belgium atypical ) origin RECIST 1.1 TPNBUPTUBUJOBOBMPHT 1FQUJEF3FDFQUPS Italy Þ 1%JTBSFDFQUPS FYQSFTTFEPOBDUJWBUFE5DFMMTBOEPUIFSMZNQIPDZUFT XIJDIOFHBUJWFMZ Pancreatic Cohort UIFSBQZJTSFRVJSFE XIJDINVTUJODMVEF France or Þ 5PYJDJUZ 3BEJPOVDMJEF5IFSBQZ 1335 BOEPS Treatment period: Japan SFHVMBUFT5DFMMGVODUJPO (n=30) FWFSPMJNVT United Israel DIFNPUIFSBQZ Þ 1PPSMZEJźFSFOUJBUFE Þ 1BUJFOUXJUIESBXBM PDR001 -400 mg Q4W States – #JOEJOHPG1%CZ1%Ƽ-BOE1%Ƽ-SFTVMUTJOUIFJOIJCJUJPOPG5DFMMGVODUJPO BOEUIF GEP-NEC Spain Phase II multi-cohort internationalThoracic Cohortstudy QSPUFDUJPOPGUVNPSDFMMTGSPNBUUBDLCZDZUPUPYJD5DFMMT3 Switzerland Þ 1SJPSUSFBUNFOUSFRVJSFEXJUI (n=30) /PEPTFNPEJôDBUJPOT pNET cohort 4 – 5VNPSTDBOFWBEFUIFJNNVOFTZTUFNCZVQSFHVMBUJOHFYQSFTTJPOPG1%Ƽ- everolimus in lung and GI allowed NETs. Prior sunitinib and/or Þ "UMFBTUUXPQSJPSTZTUFNJDSFHJNFOT XIJDINVTU Þ 1%Ƽ-PWFSFYQSFTTJPOIBTCFFOBTTPDJBUFEXJUIQPPSFSQSPHOPTJTJOTPNFUVNPSUZQFT5–7 FWFSPMJNVTSFRVJSFEJOQ/&5 GEP-NEC Cohort Dose may be interrupted JODMVEFFWFSPMJNVTBOEPSTVOJUJOJC End of treatment (EOT) (n=20) for up to 12 weeks Þ *OQSFDMJOJDBMNPEFMT 1%CMPDLBEFIBTCFFOTIPXOUPSFTUPSFFGGFDUPS5DFMMGVODUJPO MFBEJOH Þ (&1/&$QBUJFOUTOFFEFEUP Þ 1SJPSTZTUFNJDUIFSBQJFTNBZJODMVEF UP5DFMMQSPMJGFSBUJPO JOUFSGFSPOγTFDSFUJPO BOEJODSFBTFEDZUPMZUJDGVODUJPO  have progressed on or after TPNBUPTUBUJOBOBMPHT 1335 BOEPS Australia their last treatment *Target enrollment Primary analysis: 1 year after DIFNPUIFSBQZ Þ 1%3JTBIJHIBGGJOJUZ IVNBOJ[FE*H(BOUJCPEZEJSFDUFEBHBJOTU1%UIBUCMPDLTUIF LPFT  CJOEJOHPG1%Ƽ-BOE1%Ƽ-UP1%  Figure 1  Þ &$0(TUBUVT Final analysis: after all patients Safety Follow-up Efficacy follow-up: period: Until PD per irRECIST; unless Þ *OBQIBTFPDR001*USJBMPG1%3 N"CbindsDIFDLQPJOU JOIJCJUPSto PD-1UBSHFUJOH1% soDPOEVDUFE JOQBUJFOUT Þ .FBTVSBCMFEJTFBTFBTQFS have discontinued study RECIST 1.1 treatment and have completed Poorly-diferentiated GEP-NEC group 30, 60, 90, 120, 150 days PD prior to EOT XJUINVMUJQMFTPMJEUVNPSUZQFT BQBUJFOUXJUIIJTUPMPHJDBMMZDPOGJSNFENFUBTUBUJDBUZQJDBM the safety follow up period Conclusions blockingQVMNPOBSZDBSDJOPJE EFNPOTUSBUFEboth BOPD-L1QBSUJBMSFTQPOTF andXJUI BDDPSEJOH PD-L2UP3&$*45 W  SFTPMVUJPOPGMJWFSBOEQMFVSBMNFUBTUBTFT &$0( &BTUFSO$PPQFSBUJWF0ODPMPHZ(SPVQ(&1Ƽ/&$ HBTUSPFOUSPQBODSFBUJDOFVSPFOEPDSJOFDBSDJOPNB(* HBTUSPJOUFTUJOBM Þ 5IJTQIBTF** PQFOMBCFM NVMUJDFOUFSTUVEZIBTFOSPMMFEQBUJFOUTJO6OJUFE4UBUFT  1% QSPHSFTTJWFEJTFBTFQ/&5 QBODSFBUJDOFVSPFOEPDSJOFUVNPS28 FWFSZXFFLT3&$*45 3FTQPOTF&WBMVBUJPO$SJUFSJB*O GEP-NEC cohort &VSPQF $BOBEB "VTUSBMJB *TSBFM BOE+BQBO /$5 UPJOWFTUJHBUFUIFSPMFPG Figure 1. Mechanism of Action of PDR001 4PMJE5VNPST § Well differentiated: End of post treatment follow-up JNNVOPUIFSBQZJO/&5BGUFSQSJPSUSFBUNFOU Study Endpoints Primary endpoint § GI cohort (n=30) Þ "UMFBTUPOFQSJPSDIFNPUIFSBQZ References Þ 0WFSBMM3FTQPOTF3BUF 033 QFS3&$*45BOE#MJOEFE*OEFQFOEFOU3FWJFX$PNNJUUFF SFHJNFOBDDPSEJOHUP*OWFTUJHBUPS×T  5PQBMJBO4- FUBMN Engl J Med Survival follow-up #*3$ § Pancreatic cohort (n=30) DIPJDF  1BSEPMM%.Nat Rev Cancer Key secondary endpoint  $IFO- FUBMJ Clin Invest. Þ %VSBUJPOPG3FTQPOTF %03 QFS3&$*45BOE#*3$ Study Success  %POH) FUBMNat Med Þ 3BEJPMPHJDBMEPDVNFOUBUJPOPGEJTFBTFQSPHSFTTJPO  (BP2 FUBMClin Cancer Res. Additional secondary§ endpointsThoracic cohort (n=30) Þ 5IFTUVEZEFTJHOJTCBTFEPOUIFEVBMDSJUFSJBDPOTJTUJOHPGÙTUBUJTUJDBMTJHOJGJDBODFÚBOEÙDMJOJDBM – 8FMMEJGGFSFOUJBUFE/&5EJTFBTFQSPHSFTTJPOXIJMFPOPSBGUFSUIFMBTUUSFBUNFOU SFMFWBODFÚPGUIFQSJNBSZFOEQPJOU  5IPNQTPO3) FUBMProc Natl Acad Sci USAWW Þ %JTFBTF$POUSPM3BUF %$3 QFS3&$*45BOE#*3$ QSPHSFTTJPONVTUIBWFCFFOPCTFSWFEXJUIJONPOUITQSJPSUPTUBSUPGTUVEZUSFBUNFOU  )JOP3 FUBMCancer Þ 5JNFUP3FTQPOTF 553 QFS3&$*45BOE#*3$ Group 1: Well-differentiated NET: JFNBYJNVNPGXFFLTGSPNEPDVNFOUBUJPOPGQSPHSFTTJPOVOUJMTUVEZFOUSZ `%JTFBTF Þ 1SPHSFTTJPOGSFF4VSWJWBM 1'4 QFS3&$*45BOE#*3$  8POH3. FUBMInt ImmunoM NVTUTIPXFWJEFODFPGQSPHSFTTJPOCBTFEPOTDBOTQFSGPSNFEOPUNPSFUIBOPOFZFBSBQBSU Þ 5IFSFTVMUTJOUIJTHSPVQXJMMCFDPOTJEFSFEBTVDDFTTJGCPUIDPOEJUJPOTBSFNFU Þ &GGJDBDZFOEQPJOUTCBTFEPOJNNVOFSFTQPOTFDSJUFSJBQFSJNNVOFSFMBUFE3&$*45BOE#*3$  ;IPV2 FUBMJ Immunol – BSFTQPOTFSBUFPGBUMFBTUJTPCTFSWFE DMJOJDBMSFMFWBODF JS033 JS%03 JS%$3 JS553 JS1'4 – 1PPSMZEJGGFSFOUJBUFE(&1Ƽ/&$EJTFBTFQSPHSFTTJPOXIJMFPOPSBGUFSQSJPSUSFBUNFOU 8BOH8 FUBMInt Immunol. Þ $IBOHFTGSPNCBTFMJOFJODISPNPHSBOJO"BOEOFVSPOTQFDJGJDFOPMBTF Þ "UMFBTUPOFNFBTVSBCMFMFTJPOBTTFTTFECZ$5BOEPS.3*BDDPSEJOHUP3&$*45 – UXPTJEFE$*GPS033FYDMVEFTUIFWBMVF TUBUJTUJDBMTJHOJGJDBODF  .BOHTCP4. FUBMJ Immunother Þ 1IBSNBDPLJOFUJD 1, QBSBNFUFST Þ *OUIFBCTFODFPGIJTUPSJDBMDPNQBSBUPSJOUIJTTFUUJOH SFTQPOTFSBUFTPGBQQSPYJNBUFMZ .LSUJDIZBO. FUBMEur J Immunol Þ (MPCBMIFBMUITUBUVT2VBMJUZPG-JGF 2P- TDPSFPGUIF&035$2-2Ƽ$BOEUIFJOEFYTDPSF Key Exclusion Criteria JOXFMMEJGGFSFOUJBUFE/&5SFQPSUFEJOQMBDFCPBSNTPGSBOEPNJ[FETUVEJFTJOFBSMJFSMJOFTPG 3PTFOCMBUU+ FUBMJ Immunother PGUIF&2%-§ Poorly differentiated: Þ 8FMMEJGGFSFOUJBUFE (SBEFOFVSPFOEPDSJOFUVNPSTQPPSMZEJGGFSFOUJBUFEOFVSPFOEPDSJOF USFBUNFOUBSFDPOTJEFSFEBTBWBMJEIJTUPSJDBMSFGFSFODF /BJOH" FUBMJ Clin OncolTVQQMBCTUS Þ "OUJESVHBOUJCPEJFT "%" QSFWBMFODFBUCBTFMJOFBOE"%"JODJEFODFPOUSFBUNFOU DBSDJOPNBPGBOZPSJHJO PUIFSUIBO(&1Ƽ/&$ JODMVEJOH/&$PGVOLOPXOPSJHJO  – 8JUIQBUJFOUT BUMFBTUSFTQPOEFSTOFFEUPCFPCTFSWFE JFBSFTQPOTFSBUFPGXJUI The poster was previously presented at 14th Annual ENETS Conference; March 8 - 10, 2017, Þ ZFBSBOEZFBSPWFSBMMTVSWJWBMSBUFT BEFOPDBSDJOPJE BOEHPCMFUDFMMDBSDJOPJE $*<>  Þ 'SFRVFODZBOETFWFSJUZ§ GEPPGBEWFSTFFWFOUT cohort "&T (n=20) Barcelona. 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A multicohort phase II study of durvalumab plus tremelimumab for the treatment of patients (PTS) with advanced neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or lung origin (the DUNE trial-GETNE1601-).

Single-arm Phase II 126 pts

Durvalumab § Well differentiated: § GI cohort (n=30) § Pancreatic cohort (n=30) § Thoracic cohort (n=30)

§ Poorly differentiated: Tremelimumab § GEP cohort (n=20) European Institute of Oncology, IEO, Milan, Italy ENETS Center of Excellence for GEP NETs IEO NET MDT