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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: [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 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.
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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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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