Ongoing and future clinical investigation in GEP NENs

European Institute of Oncology

Nicola Fazio, M.D., Ph. D.

Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors

European Institute of Oncology Milan, Italy

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

• To learn about best clinical practice in the multidisciplinary management of gastroenteropancreatic (GEP) and thoracic neuroendocrine neoplasms (NEN) patients

• To learn about the biological and clinical principles of diagnostic and therapeutic strategy

• To understand the importance of terminology, pathological and clinical classification, morphological and functional characterization of disease

• 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

ACCREDITATION

The programme of this event has been accredited with 10 ESMO-MORA category 1 points. Recertification is necessary 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: courses@esmo.org 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 Lanreotide 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 somatostatin 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)

Treatment: Lanreotide 120 mg every 28 days until disease progression

versus placebo

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

Investigation lines in GEP NENs

•  SSA

•  Sequence

•  PRRT

•  High grade

•  New drugs

•  Immunotherapy

GETNE-1206 (SEQTOR): Phase III Study in Patients With Advanced pNET

Unpublished data. Clinicaltrials.gov ID, NCT02246127.

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

Progression

Everolimus

STZ +

5-FU

Everolimus

STZ +

5-FU

Arm A:

Arm B:

Compare efficacy and safety of everolimus followed by chemotherapy with STZ + 5-FU upon progression, or the reverse sequence (chemotherapy with STZ + 5-FU followed by everolimus upon progression)

26

GETNE  1206  (SEQTOR)  phase  III  trial    in  pa;ents  with  advanced  panNETs  

enrolling  

Investigation lines in GEP NENs

•  SSA

•  Sequence

•  PRRT

•  High grade

•  New drugs

•  Immunotherapy

177Lu-edotreotide

Everolimus

Rand. Phase III

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, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin

(GEP- NET).

G1-­‐G2  advanced  progressive  GEP  NET  

COMPETE trial

COMPETE_Newsletter 4_Jan2018 4

COMPETE: 177Lu-Edotreotide vs. Everolimus

4. Approval Status & Timelines

COMPETE Worldwide

EC / CA submissions to be done Æ US

Review in progress Æ Italy, Poland

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

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).

CDDP / VP-16

CAP / TEM

Rand. Phase II 126 pts

G3  (only  large  cell)  GEP  NEC  Ki-­‐67  21-­‐100%  

First-­‐line  

Prospec;ve  Interna;onal  Phase  II  Mul;-­‐centre  Trial  177Lu-­‐DOTA-­‐octreotate  (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  objec;ve  –PFS.  • 56  pa;ents  

• 1st  or  2nd  line  

Investigation lines in GEP NENs

•  SSA

•  Sequence

•  PRRT

•  High grade

•  New drugs

•  Immunotherapy

Compound VEGFR PDGFR FGFR CSF1R KIT FLT-3 RET MET

1 2 3 α β

Sunitinib ✔ ✔ ✔ ✔ ✔ ✔ ✔

Pazopanib ✔ ✔ ✔ ✔ ✔ ✔

Cabozantinib ✔ ✔ ✔ ✔ ✔ ✔

Lenvatinib ✔ ✔ ✔ ✔ ✔ ✔ ✔

Sulfatinib ✔ ✔ ✔ ✔ ✔ ✔

Novel  TKIs  in  GEP  NETs  

SulfaTnib  in  GEP  NET  81 NET pts (41 pNET)

Jia, ENETS 2017, Oral presentation

Jia, ENETS 2017, Oral presentation

SulfaTnib  in  GEP  NET  

41 carcinoids

20 pNETs Phase II trial

Chan et al., ASCO GI 2017, Poster

PR 15% SD 75% mPFS 22 mo

PR 15% SD 63% mPFS 31 mo

CabozanTnib  in  GEP  NET  

TALENT trial Phase II with LENVATINIB in GEP NETs

Lenvatinib binds to RET, VEGFR and FGFR

§  Gastrointestinal G1/G2 cohort (n=55)

§  Pancreatic G1/G2 cohort (n=55)

Review of safety and efficacy of axitinib

Clinical Medicine Insights: Oncology 2013:7 271

This IC50 is 10-fold lower for the VEGF family of receptors than for other TKIs such as pazopanib, suni-tinib, or sorafenib.26–28 Concerning other non-VEGF tyrosine kinase receptors (PDGF, fibroblast growth factor, colony-stimulating factor), the IC50 of axi-tinib was 1.6 to 1000 nmol/L (versus 6–880 nmol/L with other agents).29 These results testify to the high potency and selectivity of axitinib against VEGFRs (Table 1).26–28 Blockade of the VEGFR induces major changes of tumor vasculature in mouse models. In vivo, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), which is an imaging technique that can measure the density, integrity, and leakiness of tissue vasculature, showed that axitinib decreases the tumor blood flow/permeability. Maximum reduc-tion in tumor endothelial transfer constant (Ktrans)—an indicator of vascular leakage to the extracellular space—was observed on day 7 after dosing and was correlated with decreased micro-vessel density, cel-lular viability, and tumor growth.

Metabolism and pharmacokinetic profilePharmacokinetic analyses have been obtained from polled data of 17 trials, in both healthy volunteers and cancer patients.11 A two-compartment disposi-tion model with first-order absorption and lag-time adequately describes the axitinib concentration-time profile. After a single dose of 5 mg in the fed state, axitinib is rapidly absorbed with peak plasma concentrations occurring at 2–6 h post dosing. The median time (tmax) ranged from 2.5–4.1 h. The rate of the drug’s absorption was higher in the fasting state with a peak concentration occurring 1–2 h after dosing.30 Moreover, Pithavala et al30 demonstrated in healthy volunteers that axitinib XLI Form film-coated immediate-release (FCIR) could be administered regardless of the fasting or fed state without signifi-cant impact on its pharmacokinetics.30 Twice daily administration of 5 mg of axitinib was associated

in 1.4 fold accumulation compared to single admin-istration. The oral bioavaibility of axitinib is 58%. Although a low pH results in the highest solubility of axitinib, studies have demonstrated that the effect of pH on absorption of axitinib was not clinically significant. As a measure of precaution, antacids or proton pump inhibitors should be administered at times other than 2 h before and 2 h after drug dosing.11 Axitinib is highly bound ( 99%) to human plasma proteins with preferential binding to albu-min and moderate binding to 1-acid glycoprotein. The plasma half-life ranges between 2.5 and 6.1 h and a steady-state is attained within 15 days. Linear correlations have been reported between dose and maximum plasma concentration, in addition to area under plasma concentration-time curve.16 The mean apparent volume of distribution in patients receiving 5 mg twice daily was 160L.11 Axitinib is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP1A2, CYP2C19, uridine diphosphate glucuronosyl-transferase (UGT) 1A1, and the drug transporters P-glycoprotein. Two metabolites are produced: an N-glucuronide metabo-lite and a sulfoxide. Both are 400-fold less potent against VEGFR-2 in vitro than axitinib.11 Less than one percent of the absorbed drug remained unchanged in the urine. Otherwise, a recent meta-analysis found no statistically significant associations between the polymorphism of genes encoding these enzymes and the transporters and axitinib pharmacokinetics.31 As observed in a phase 1 trial, axitinib pharmacokinetics are affected by CYP inducers (rifampicin, phenytoin, etc.) and inhibitors (ketoconazole, etc.). They may also be affected by drugs that are substrates or inhibitors of P-glycoprotein. Specific data on patients with mild to moderate hepatic impairment have been obtained through a phase I study, and showed an association between drug exposure and hepatic impairment, thus 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 1000Pazopanib24 10 30 47 71 84 74 1000 NA 1000Sunitinib25 10 10 10 5–10 10 13 100–200 NA 1–10Sorafenib26 NA 90 20 50–60 50–60 68 100–150 5–10 46

Abbreviation: NA, Not available.

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

!

*!RANDOMIZATION!

N!

Arm$A$

Arm$B$

Axitinib!+!Sandostatin!LAR!

Placebo!+!Sandostatin!LAR!

Nonpancreatic!G1@G2!NETs!with!progression!of!disease!in!the!previous!12!mo!!ECOG!PS!0@2!Age!≥!18!years!With!or!without!previous!chemotherapy!Ki67!<!20%!!!

N=!253!

CDK 4/6 inhibitors in NETs

 

  Neuroendocrinology (DOI:10.1159/000463386)  © 2017 S. Karger AG, Basel 22  

 

Fig. 1. Proposed and simplified mode of action of the CDK4/6 inhibitor 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.

Down

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CDK 4/6 inhibition in NET: preclinical studies with ribociclib and pabociclib

Prada et al, Neuroendocrinology 2016 Tang L. et al., Clin Cancer Res 2012

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

activity of Rb

 

  Neuroendocrinology (DOI:10.1159/000463386)  © 2017 S. Karger AG, Basel 23  

 

 

Fig. 2. The effect of different concentrations of LEE011 on cell survival of 4 different

NET cell lines after 144 h of incubation. Human neuroendocrine pancreatic BON1,

pancreatic islet QGP1, bronchopulmonary H727 and midgut GOT1 cells were

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 represented by p<0.001 = ***.

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:52

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Ribociclib sensitivity was associated with high expression of cyclin-1 and Rb

Ribociclib/Everolimus or 5-FU combinations were superior to the single-agent therapies, by downregulating mTOR and MEK pathways

Prada et al, Neuroendocrinology 2016

BON-1

QGP-1 H727

GOT-1

Ribociclib in NET: preclinical study

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 Custodio6, Ruth Vera7, Javier 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

Abstract 429O

Overall response rate

N %

Partial response (PR) 0 0

Stable disease (SD) 11 55

Progression disease (PD) 9 45

Clinical benefit rate (PR + SD) 11 55

Stable disease ≥ 3 months 7 35

Stable disease ≥ 6 months 6 30

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

Patient disposition

No. of patients (%)

Patients treated 21

Median number of treatment cycles administered [range] 3 [2–15]

Median follow up time, months [range] 12.3 [7.5-19.3]

Reason “off” study*Disease progressionToxicityDeathWithdrew consentOther

17 (81)1 (4.8)1 (4.8)0 (0)1 (5)

*Only 20 patients were followed up for treatment administration; patient #306 was lost to follow up after cycle 1 day 1.

Progression free survival

mPFS: 2.6 months (95% CI 0–14.4)

Cum

ulat

ive

surv

ival

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25

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

PDR001 in GEP and Lung NET/NEC Phase II multi-cohort international study

PDR001 binds to PD-1 so blocking both PD-L1 and PD-L2

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

§  Poorly differentiated: §  GEP cohort (n=20)

Introduction

–3

– 4

5–7

γ

Figure 1

Figure 1. Mechanism of Action of PDR001

MethodsStudy Design

Figure 2

Figure 2. Study Design

*Target enrollment Primary analysis: 1 year after LPFT Final analysis: after all patients have discontinued study treatment and have completed the safety follow up period

Total (N=110)*

Thoracic Cohort (n=30)

GI Cohort (n=30)

Pancreatic Cohort(n=30)

GEP-NEC Cohort(n=20)

PDR001 400 mg Q4W, flat dose until:

RECIST 1.1

allowed

Dose may be interrupted for up to 12 weeks

Patients:

well-differentiated NET of pancreatic or GI origin (grade 1 or 2) or thoracic (typical or atypical carcinoid) origin or

GEP-NEC

everolimus in lung and GI NETs. Prior sunitinib and/or

have progressed on or after their last treatment

RECIST 1.1

Study EndpointsPrimary endpoint

Key secondary endpoint

Additional secondary endpoints

Key Inclusion Criteria

–

–

–

–

Thoracic (lung and thymus origin) cohort GI cohort

pNET cohort

Well-differentiated NET group

Poorly-differentiated GEP-NEC group

GEP-NEC cohort

–

–

Key Exclusion Criteria

α

–––

–

– –

–

End of treatment (EOT)

Safety Follow-upperiod:

30, 60, 90, 120, 150 days

Efficacy follow-up:Until PD per irRECIST; unless

PD prior to EOT

Treatment period:PDR001 -400 mg Q4W

Screen period: Day -28 to Day -1

Study Flow

End of post treatment follow-up

Survival follow-up

Study Success

Group 1: Well-differentiated NET:

–

–

–

–

Group 2: Poorly-differentiated GEP-NEC:

–

–

–

–

–

–

Canada

Australia

Austria

Israel

Italy

Austria

Israel

Italy

Belgium

France

Germany

Netherlands

Norway

Study Enrollment

Spain

SwitzerlandSwitzerland

United States

Japan

SwedenSweden

Conclusions

ReferencesN Engl J Med

Nat Rev CancerJ Clin Invest.Nat Med

Clin Cancer Res.Proc Natl Acad Sci USA

CancerInt Immuno

J ImmunolInt Immunol.

J ImmunotherEur J Immunol

J ImmunotherJ Clin Oncol

The poster was previously presented at 14th Annual ENETS Conference; March 8 - 10, 2017, Barcelona.

Presented at the IASLC -Chicago Multidisciplinary Symposium in Thoracic Oncology September 14-16, 2017

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 TreatmentJ.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

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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-).

Durvalumab

Tremelimumab

Single-arm Phase II 126 pts

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

§  Poorly differentiated: §  GEP cohort (n=20)

European Institute of Oncology, IEO, Milan, Italy

ENETS Center of Excellence for GEP NETs

IEO NET MDT