IARTCremona, 06-06-2018

Quale spazio per la terapia biologica ?

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

Unit of Gastrointestinal Medical Oncology and

Neuroendocrine Tumors

European Institute of Oncology

Milan, Italy

VEGFR

PI3K

Akt

mTORC-1

PDGFREndothelial cell

Pericytes

PLC

PKC

SSTRs

Jak/STAT

RAS

RAF

MEK

ERK

IGF1-R

NET tumor cells

EVEROLIMUS

SUNITINIB SSA

SSA

Everolimus /

Sunitinib

Chemotherapy

PRRT

Liver-directed

treatments

Primary tumor

removal

Therapies for patients with advanced NET

‘70 ’80 ’90 2011

STZ in

pNET

Octreotide

IFN in carcinoid

syndrome

Lanreotide

in carcinoid

syndrome

Sunitinib

Everolimus

in pNET

PRRT in

GEP NET

Pasireotide

Liver-directed:

TACE/TAE

TARF/TARE

Bevacizumab

TMZ

Therapies for patients with advanced NETs

FDA/EMA Approved

Not FDA/EMA approved

2015

Lanreotide in

GEP

Octreotide in

midgut

2016

Everolimus in

non functioning

Lung and GI

Telotristatin refractory carcinoid

syndrome diarrhea

2017

Oxaliplatin

STZ: streptozotocin; TMZ: Temozolomide; IFN: Interferon; GEP: Gastroenteropancreatic; TACE: Trans-Arterial-Chemoembolization; TAE: Trans-arterial-embolization; TARE: Trans-arterialradioembolization

Oncological scientific societes NEN scientific societes

Italian NEN guidelines

NET guidelinesfrom several different scientific societes

Advanced pancreatic NET

trialPresented/pub

lishedtherapy PFS exp. arm PFS PLB arm setting

CLARINETCaplin, NEJM

2014

LAN A vs.

PLBNot reached 12 mo Well-diff

RADIANT-3Yao, NEJM

2011EVE vs. PLB 11.4 mo 5.4 mo Well-diff

NCT00510068Raymond,

NEJM 2011SUN vs. PLB 11 .4 mo 5.5 mo Well-diff

Phase III trial-related evidence in pNET

Yao, NEJM 2011

Raymond, NEJM 2011

Everolimus 11.4 m

Placebo 5.4 m

Sunitinib 11.4 m

Placebo 5.5 m

340 pts planned

171 enrolled

Early stop due to

significant difference

in deaths, SAEs, and

PFS

2006 Phase I

2008 Phase II

2011 Phase III

Preclinical

In the RIP1-Tag2 transgenic mouse model of pancreatic islet cell carcinoma,

sunitinib:

– reduced tumor burden and increased survival

– reduced endothelial cell population (VEGFR inhibition)

– reduced pericyte coverage (PDGFR inhibition)

Phase I

A study of sunitinib in solid tumors included 4 patients with

non-pancreatic NET, inducing:

– 1 confirmed PR (rectal NET with bulky peritoneal metastases; he

received sunitinib 75 mg/day 4/2 weekly)

– 1 minor response/SD

Pietras K & Hanahan D. J Clin Oncol 2005;23:939–52;

Yao V, et al. EORTC-NCI-AACR, Prague, 2007, Abstract 78

Faivre S, et al. J Clin Oncol 2006;24:25–35;

Sunitinib in NET:

preclinical and phase I experience

105 pts

with NET

(small cell excluded)

65 pts

With pNET

40 pts

with NET

from other origin

46

Non functioning

19 functioning

prior SSA

50%

prior SSA

30% Kulke et al., JCO 2008

2003 → 2005

Phase II trial

50 mg/day 4/6 weeks

PR m TTP

Pancreatic 16.7 % 7.7 mo

Non

pancreatic2.4 % 10.2 mo

Kulke et al., JCO 2008

Phase II trial

Phase III, Randomized, Double-Blind Study of Sunitinib

vs. Placebo in Patients with Advanced, Progressive,

Well-Differentiated Pancreatic Endocrine Tumors

R

A

N

D.

Accrual goal = 340

pts

Sunitinib 37.5 mg/day orally,

continuous daily dosing

(CDD)*

Arm A

Placebo

Arm B

1:1

Primary endpoint: PFS

Secondary endpoints:

OS, ORR, TTR, duration of response,

safety, patient-reported outcomes

Open-label sunitinib

protocol (NCT00443534 or

NCT00428220)

Crossover

Progression of disease

Non functioning, well differentiated, advanced pancreatic NET

Lanreotide

1

Everolimus

or

Sunitinib

CLARINET trialRADIANT-3 trial

A6181111 trial

2

or

Octreotide

Metastatic panNET:

Everolimus→ Sunitinib or Sunitinib→ Everolimus?

Criterion

Regulatory features ✖

Evidence ✖

Biological

background

✖

Clinical wisdom ✔

Everolimus Investigation in NETs

RADIANT (RAD001 in Advanced Neuroendocrine

Tumors)

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

RADIANT-3

RADIANT-2

RADIANT-1

EVE+OCT RAMSETE LUNA

EVE+OCT 1ST Line

ITMO

RADIANT-4

Phase III

Phase II

No validate predictive biomarker for sunitinib and everolimus so far

Martins et al., Targeted Oncol 2017

REVIEW ARTICLE

Predictive Markers of Response to Everolimus and Sunitinibin Neuroendocrine Tumors

Diana Martins1&Francesca Spada1

&Ioana Lambrescu1&Manila Rubino1

&

Chiara Cella1&Bianca Gibelli 2 &Chiara Grana3

&Dario Ribero4&Emilio Bertani 4 &

DavideRavizza5&Guido Bonomo6

&Luigi Funicelli 7&Eleonora Pisa8

&Dario Zerini 9 &

Nicola Fazio1&IEO ENETS Center of Excellence for GEP NETs

# Springer International Publishing Switzerland 2017

Abstract Neuroendocrine tumors (NETs) represent a large

and heterogeneous group of malignancies with various bio-

logical and clinical characteristics, depending on the site of

origin and the grade of tumor proliferation. In NETs, as in

other cancer types, molecularly targeted therapies have radi-

cally changed the therapeutic landscape. Recently two

targeted agents, the mammalian target of rapamycin inhibitor

everolimus and the tyrosine kinase inhibitor sunitinib, have

both demonstrated significantly prolonged progression free

survival in patients with advanced pancreatic NETs. Despite

these important therapeutic developments, there are still sig-

nificant limitationsto theuseof theseagentsdueto thelack of

accuratebiomarkers for predicting tumor responseand effica-

cy of therapy. In this review, we provide an overview of the

current clinical data for theevaluation of predictive factorsof

response to/efficacy of everolimus and sunitinib in advanced

pancreatic NETs. Surrogate indicators discussed include cir-

culating and tissue markers, as well as non-invasive imaging

techniques.

Key Points

Everolimus and sunitinib are widely investigated

targeted cancer therapies, and they are both globally

approved by regulatory authorities for the treatment of

pancreatic NETs.

The establishment of predictive markers of response to

everolimus and sunitinib in NETs is of extreme importance

for their efficient use.

Most efforts to define predictive biomarkers have failed,

with the exception of chromogranin-A and neuron-specific

enolase for advanced pancreatic NETs treated with

everolimus.

1 Introduction

Neuroendocrine tumors (NETs) comprise a heterogeneous

group of malignanciesoriginating from the diffuseendocrine

system. Even though NETsareconsidered a raremalignancy,

representing about two new cases per 100.000 persons per

year, their incidenceand prevalenceseem to berising steadily

[1]. Someof thepossible reasons for the increasing incidence

* Nicola Fazio

nicola.fazio@ieo.it

1 Unit of Gastrointestinal Medical Oncology and Neuroendocrine

Tumors, European Instituteof Oncology, IEO, 20141 viaRipamonti,

435 Milan, Italy

2 Division of Otolaryngology-Head and Neck Surgery, European

Instituteof Oncology, IEO, Milan, Italy

3 Division of Nuclear Medicine, European Instituteof Oncology, IEO,

Milan, Italy

4 Division of Hepatobiliopancreatic Surgery, European Instituteof

Oncology, IEO, Milan, Italy

5 Division of Endoscopy, European Instituteof Oncology, IEO,

Milan, Italy

6 Division of Interventional Radiology, European Instituteof

Oncology, IEO, Milan, Italy

7 Division of Radiology, European Instituteof Oncology, IEO,

Milan, Italy

8 Division of Pathology, European Institute of Oncology, IEO,

Milan, Italy

9 Division of Radiotherapy, European Instituteof Oncology, IEO,

Milan, Italy

Targ Oncol

DOI 10.1007/s11523-017-0506-5

Dual modulation of Mcl-1 and mTOR by sunitinib determines the

response of cancer cells

Elgendy et al., JCI 2016

Comparison of patient samples prior and post sunitinib treatment

suggests that increasing Mcl-1 levels and mTORC1 activity

correlates with resistance to sunitinib in patients

Resistance  

Suni,nib  

Beyond  c

e

ll  type-­

specific  threshold  

 

 GSK3b

 

 ERK

 

 Mcl-­1

 

 mTOR

 

Sensi,vity  

 

Suni,nib  

(higher  doses)  

 GSK3b

 

 ERK

 

 Mcl-­1

 

 mTOR

 

Combinatorial  treatment  

 

Rapalogs/  Starva4on  

   

 

Mcl-­­1  inhibitors  

Sensi4za4on  

 

Suni4nib  

 GSK3b

 

 ERK

 

 Mcl-­­1

 

 mTOR

 

Everolimus —> Sunitinib vs. Sunitinib —> Everolimus

in renal cancer

RECORD-3 trial

Everolimus —> Sunitinib was not non-inferior

to the opposite sequence

An Italian real world analysis of sunitinib in panNET

• 73 pts with advanced pNET

• 82% with prior Everolimus

PR 19 %

SD 53 %

PFS 11 mo

mOS 36 mo

• (71% >/= 3 lines)

Confirmed activity and toxicity profile

even beyond Everolimus and/or PRRT

Panzuto et al., Pancreatology Nov 2017

Presented at the 14th Annual European Neuroendocrine Tumor Society (ENETS) Conference, March 8–10, 2017, Barcelona, Spain

CONCLUSIONS n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of 24.5%

(95% CI, 16.7–33.8) observed in this phase IV trial support the

outcomes of the pivotal phase III trial of sunitinib in pNETs and

confirm its activity in this setting.

n OS data were not mature at the time of the primary analysis.

n AEs were consistent with the known safety profile of sunitinib.

n The study confirmed sunitinib is an efficacious and safe treatment

option in progressive, locally advanced and/or metastatic, well-

differentiated, unresectable pNETs.

The Efficacy and Safety of Sunitinib in Patients With Advanced

Well-Differentiated Pancreatic Neuroendocrine Tumors: Focus on Response RateE Raymond1, MH Kulke2, S Qin3, X Yu4, M Schenker5, A Cubillo6, W Lou7, J Tomasek8, E Thiis-Evensen9, K Fernandez10, B Rosbrook11, N Fazio12

1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Fudan University Shanghai Cancer Center, Shanghai, China; 5Centrul de

Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 6Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 7Zhongshan Hospital, Fudan University, Shanghai, China; 8Masarykuv

onkologicky ustav/Klinika komplexní onkologické péče, Brno, Czech Republic; 9Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 10Pfizer Inc, Cambridge, MA, USA; 11Pfizer Inc, San Diego, CA, USA; 12IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy

REFERENCES1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA.2. Raymond E, et al. N Engl J Med 2011;364:501-13.3. Faivre S, et al. Ann Oncol 2016; Nov 10 [Epub ahead of print]. 4. Sutent® (sunitinib malate) prescribing information. New York, NY: Pfizer Inc; 2015.

ACKNOWLEDGMENTSWe thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators who participated in this trial, including: M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane (Japan); J. Sufliarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfizer. Medical writing support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientific Solutions, and was funded by Pfizer. Previously presented in part at the 2017 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CA

For information on this poster, contact Eric Raymond, eraymond@hpsj.fr

Copyright © 2017

INTRODUCTION • Pancreatic neuroendocrine tumors (pNETs) are rare tumors. Of an

estimated 53,070 new cases of pancreatic cancers expected in the US in

2016, pNETs account for fewer than 5%.1

• Due to their relatively indolent nature, the majority of patients are

diagnosed with metastatic pNETs, for whom treatment options are

limited.

• pNETs are highly vascularized tumors; aberrant expression of vascular

endothelial growth factor (VEGF) and its receptors, which play vital roles

in tumor angiogenesis, has been observed.

• Sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) of angiogenesis,

showed a significant increase in progression-free survival (PFS) over

placebo in well-differentiated, advanced and/or metastatic pNETs in a

pivotal phase III clinical trial (ClinicalTrials.gov NCT00428597).2

• The trial was terminated early after more-serious adverse events (AEs) and

deaths were observed in the placebo arm and a difference in PFS favored

the sunitinib arm (hazard ratio [HR] 0.42; 95% confidence interval [CI],

0.26–0.66; P<0.001; median: 11.4 vs 5.5 months).

– The median (95% CI) 5-year overall survival (OS) was 38.6 (25.6–56.4)

months for sunitinib and 29.1 (16.4–36.8) months for placebo (HR 0.73;

95% CI, 0.50–1.06; P=0.094), with 69% of placebo patients having

crossed over to sunitinib.3

• In 2010 and 2011, sunitinib was approved by the European Medicines

Agency and US Food and Drug Administration (FDA), respectively, for the

treatment of patients with progressive, locally advanced and/or metastatic,

well-differentiated, unresectable pNETs.4

OBJECTIVES • This phase IV clinical trial (ClinicalTrials.gov NCT01525550) was

conducted as post-approval commitments to the FDA and other

regulatory agencies to confirm the efficacy and safety of sunitinib in

advanced and/or metastatic, well-differentiated, unresectable pNETs.

METHODSStudy Design

• This multinational, single-arm, open-label, phase IV clinical trial is ongoing.

• The primary endpoint is investigator-assessed PFS per the Response

Evaluation Criteria in Solid Tumors (RECIST) v1.0.

• Secondary endpoints include PFS assessed by the independent radiologic

review and per Choi criteria, time to tumor progression (TTP), objective

response rate (ORR), OS, and safety.

Key Eligibility Criteria

• Histologically or cytologically confirmed, well-differentiated, unresectable or

metastatic pNETs with documented progression within 12 months of study

enrollment.

• Not amenable to surgery, radiation, or combined modality therapy with

curative intent.

• Presence of ≥1 measurable target lesion per RECIST v1.0.

• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.

• No pre-existing uncontrolled hypertension (ie, blood pressure >150/100

mmHg despite medical therapy).

• No prior treatment with TKIs, anti-VEGF, or other angiogenesis inhibitors.

Treatment and Assessments

• Patients received 37.5 mg sunitinib orally once a day on a continuous daily

dosing regimen.

– Sunitinib dose could be increased to 50 mg daily any time after 8 weeks

of treatment initiation in patients without treatment response who

experienced only grade 1 or lower nonhematologic or grade 2 or lower

hematologic treatment-related AEs.

– Dose could be temporarily interrupted or reduced to 25 mg daily to

manage severe toxicity.

• Somatostatin analogs for control of symptoms were permitted at the

investigator’s discretion.

• Radiologic tumor assessments were conducted at screening, Cycle 2

Day 1, Cycle 3 Day 1, and every 2 cycles thereafter; tumor responses were

evaluated per RECIST v1.0 criteria.

• Safety was monitored throughout the study and AEs were graded according

to the National Cancer Institute Common Terminology Criteria for Adverse

Events v3.0.

Statistical Analyses

• More than 80 patients were to be enrolled: 40 treatment-naïve (defined

as those who never received systemic antitumor therapy; somatostatin

analogs for symptomatic control were allowed) and 40 previously treated

patients.

• Median PFS and 95% CI were estimated using the Kaplan–Meier method

for the entire population as well as separately for treatment-naïve and

previously treated patients.

• Descriptive statistics were used to summarize other parameters.

RESULTSPatients

• Of 123 patients screened, 106 (61 treatment-naïve and 45 previously

treated) were enrolled at 25 centers in 15 countries (Figure 1).

• Patient demographics and baseline characteristics are summarized in

Table 1.

• More than half (n=64/106, 60.4%) of patients had a nonfunctioning tumor

and 17.9% had a functioning tumor (unknown for 21.7% of patients).

Figure 1: Trial Profile

123 patients screened

106 patients enrolled

61 txt-naïve patients treated 45 previously treated patients treated

39 previously treated patients discontinued txt

23 Objective progression/relapse

8 Adverse events

1 Refusal of txt for reason other than AE

2 Global health deterioration

1 Death

4 Other

43 txt-naïve patients discontinued txt

26 Objective progression/relapse

6 Adverse events

4 Refusal of txt for reason other than AE

2 Global health deterioration

1 Death

4 Other

Efficacy analysis: 61 txt-naïve patients

Safety analysis: 61 txt-naïve patients

45 previously treated patients

45 previously treated patients

AE=adverse event; txt=treatment

• In regard to prior locoregional treatment, 18.9% of patients had

trans-arterial chemoembolization; radiofrequency ablation (3.8%);

or trans-arterial embolization, percutaneous injections, or microwave

ablation (2.8% each).

• Median (range) treatment duration in the total population was 11.7 months

(0.2–40.3): 12.2 months (0.2–35.9) in treatment-naïve vs 10.2 months

(0.5–40.3) in previously treated patients.

Efficacy

• Median (95% CI) PFS as assessed by investigators was 13.2 months

(10.9–16.7); median (95% CI) PFS was similar in treatment-naïve and

previously treated patients (13.2 months [7.4–16.8] and 13.0 months

[9.2–20.4], respectively).

• Median (95% CI) PFS per Choi criteria was 18.7 months (5.6–not estimable)

and 16.5 months (7.4–22.9) in treatment-naïve and previously treated

patients, respectively (Figure 2).

• Median (95% CI) PFS as assessed by independent radiological review

was 11.1 months (7.4–16.6), in treatment-naive patients 11.1 months

(5.5–16.7), and in previously treated patients 9.5 months (7.4–18.4).

– 7 patients were censored due to lack of adequate baseline assessments.

Table 1: Demographics and Patient Baseline Characteristics

CharacteristicsTreatment-Naïve

n=61Previously Treated

n=45Total

N=106

Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)

Gender, n (%)

Male 30 (49.2) 33 (73.3) 63 (59.4)

Female 31 (50.8) 12 (26.7) 43 (40.6)

Race, n (%)

White 32 (52.5) 35 (77.8) 67 (63.2)

Black 2 (3.3) 0 2 (1.9)

Asian 27 (44.3) 10 (22.2) 37 (34.9)

ECOG PS, n (%)

0 39 (63.9) 29 (64.4) 68 (64.2)

1 22 (36.1) 16 (35.6) 38 (35.8)

No. of involved disease sites,* n (%)

1 24 (39.3) 9 (20.0) 33 (31.1)

2 19 (31.1) 22 (48.9) 41 (38.7)

3 11 (18.0) 8 (17.8) 19 (17.9)

4 3 (4.9) 3 (6.7) 6 (5.7)

>4 4 (6.6) 3 (6.7) 7 (6.6)

Tumor site,* n (%)

Liver 57 (93.4) 41 (91.1) 98 (92.5)

Pancreas 22 (36.1) 25 (55.6) 47 (44.3)

Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4)

Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9)

Lung 3 (4.9) 3 (6.7) 6 (5.7)

Other 10 (16.4) 10 (22.2) 20 (18.9)

Any prior systemic chemotherapy, n (%)

0 45 (100) 45 (42.5)

Prior SSA, n (%) 24 (39.3) 27 (60.0) 51 (48.1)

Ki-67 index, mean (SD) 6.7 (5.0) 8.4 (7.2) 7.4 (6.0)* Included both target and nontarget sites; sites with multiple lesions were counted once.

ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs

Figure 2: Kaplan–Meier Estimates of PFS Based on the Independent Third-Party

Radiology According to Choi Criteria PFS in Treatment-Naïve and Previously Treated

Patients With pNETs

PFS D

istribution Function

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 5 10 15 20 25

Time (Months)No. at risk:

Treatment-naïve

Previously treated

61

45

29

25

22

17

11

11

6

8

4

5

1

4

0

2

0

0

0

0

30 35 40 45

Treatment-naïve 61 25 18.7 (5.6–NE)

Previously treated 45 24 16.5 (7.4–22.9)

n Events mPFS (95% CI), mo

CI=confidence interval; mPFS=median progression-free survival; PFS=progression-free survival; NE=not estimable;

pNET=pancreatic neuroendocrine tumor

• ORR (95% CI) was 24.5% (16.7–33.8) according to the investigator

assessment.

• The ORR (95% CI) per Choi criteria was higher than the ORR per RECIST:

52.5% (39.3–65.4) and 55.6% (40.0–70.4) in treatment-naïve and

previously treated patients, respectively (Table 2).

•

Table 2: Best Observed Response Based on Independent Third-Party Radiology

According to Choi Criteria in Treatment-Naïve and Previously Treated Patients

With pNETs

Treatment-Naïve

n=61Previously Treated

n=45

Best overall response, n (%)

Complete response 0 1 (2.2)

Partial response 32 (52.5) 24 (53.3)

Stable disease 12 (19.7) 17 (37.8)

Progressive disease 9 (14.8) 2 (4.4)

Indeterminate 8 (13.1) 1 (2.2)

ORR,* n (%) 32 (52.5) 25 (55.6)

95% CI 39.3–65.4 40.0–70.4* Complete response + partial response.

CI=confidence interval; ORR=objective response rate; pNET=pancreatic neuroendocrine tumor; RECIST=Response Evaluation Criteria in

Solid Tumors

Median (95% CI) TTP was 14.5 months (11.0–16.7); median (95% CI) TTP

in treatment-naïve and previously treated patients was similar

(14.8 [7.5–16.8] and 14.5 [9.2–20.4] months, respectively).

– According to the Choi criteria, the median (95% CI) TTP was 18.7 months

(5.6–not estimable) for treatment-naïve patients and 16.7 months

(7.4–30.9) for previously treated patients.

• OS data were not mature at the time of data cutoff date (March 19, 2016);

29 (27.4%) patients had died and median (95% CI) OS was 37.8 months

(33.0–not estimable).

Safety

• Most-common treatment-emergent, all-grade AEs experienced by all patients

treated with sunitinib included neutropenia, diarrhea, and leukopenia

(Table 3).

– No major differences were observed in the incidence of AEs reported by

treatment-naïve vs previously treated patients, except dyspepsia, nausea,

and neutropenia.

• Percentage of treatment-naïve and previously treated patients who

experienced Grade 3 or 4 AEs was comparable; serious AEs were also

comparable: 24.6% (n=15) vs 24.4% (n=11), respectively.

• 15 (24.6%) treatment-naïve and 5 (11.1%) previously treated patients had

sunitinib dose reductions due to AEs; 8 (13.1%) and 10 (22.2%) patients,

respectively, discontinued treatment due to AEs.

Table 3: Treatment-Emergent, All-Causality Adverse Events

Adverse Events,* n (%)

Treatment-Naïven=61

Previously Treatedn=45

TotalN=106

All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4

Neutropenia 37 (60.7) 13 (21.3) 22 (48.9) 10 (22.2) 59 (55.7) 23 (21.7)

Diarrhea 32 (52.5) 7 (11.5) 22 (48.9) 3 (6.7) 54 (50.9) 10 (9.4)

Leukopenia 25 (41.0) 4 (6.6) 21 (46.7) 3 (6.7) 46 (43.4) 7 (6.6)

Fatigue 19 (31.1) 1 (1.6) 14 (31.1) 0 (0.0) 33 (31.1) 1 (0.9)

Hand–foot syndrome 19 (31.1) 5 (8.2) 14 (31.1) 2 (4.4) 33 (31.1) 7 (6.6)

Thrombocytopenia 18 (29.5) 6 (9.8) 14 (31.1) 2 (4.4) 32 (30.2) 8 (7.5)

Hypertension 16 (26.2) 4 (6.6) 11 (24.4) 2 (4.4) 27 (25.5) 6 (5.7)

Abdominal pain 16 (26.2) 2 (3.3) 10 (22.2) 3 (6.7) 26 (24.5) 5 (4.7)

Dysgeusia 14 (23.0) 0 (0.0) 11 (24.4) 0 (0.0) 25 (23.6) 0 (0.0)

Nausea 11 (18.0) 0 (0.0) 14 (31.1) 1 (2.2) 25 (23.6) 1 (0.9)

Dyspepsia 7 (11.5) 0 (0.0) 14 (31.1) 0 (0.0) 21 (19.8) 0 (0.0)

Headache 12 (19.7) 0 (0.0) 9 (20.0) 0 (0.0) 21 (19.8) 0 (0.0)

Stomatitis 13 (21.3) 2 (3.3) 6 (13.3) 1 (2.2) 19 (17.9) 3 (2.8)

Vomiting 8 (13.1) 1 (1.6) 10 (22.2) 1 (2.2) 18 (17.0) 2 (1.9)

Asthenia 10 (16.4) 0 (0.0) 7 (15.6) 2 (4.4) 17 (16.0) 2 (1.9)

Abdominal pain upper 5 (8.2) 1 (1.6) 7 (15.6) 1 (2.2) 12 (11.3) 2 (1.9)

ALT increased 2 (3.3) 1 (1.6) 9 (20.0) 0 (0.0) 11 (10.4) 1 (0.9)

AST increased 4 (6.6) 1 (1.6) 7 (15.6) 1 (2.2) 11 (10.4) 2 (1.9)

Constipation 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)

Dizziness 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)

Hypophosphatemia 2 (3.3) 2 (3.3) 7 (15.6) 3 (6.7) 9 (8.5) 5 (4.7)

Myalgia 2 (3.3) 0 (0.0) 7 (15.6) 0 (0.0) 9 (8.5) 0 (0.0)Adverse events are listed by highest to lowest % for Total/All Grades patients.

* Adverse events reported by ≥15% in any treatment group per MedDRA crit eria.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities

Presented at the 2017 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI), January 19–21, 2017, San Francisco, CA

CONCLUSIONS n Median PFS of 13.2 months (95% CI, 10.9–16.7) and ORR of 24.5% (95% CI, 16.7–33.8) observed in this phase IV trial support the outcomes of the pivotal phase III trial of sunitinib in pNETs and confi rm its activity in this setting.

n OS data were not mature at the time of the primary analysis.

n AEs were consistent with the known safety profi le of sunitinib.

n The study confi rmed sunitinib is an effi cacious and safe treatment option in progressive, locally advanced and/or metastatic, well-differentiated, unresectable pNETs.

The Effi cacy and Safety of Sunitinib in Patients With Advanced Well-Differentiated Pancreatic Neuroendocrine TumorsEric Raymond1, Matthew H Kulke2, Shukui Qin3, Michael Schenker4, Antonio Cubillo5, Wenhui Lou6, Jiri Tomasek7, Espen Thiis-Evensen8, Jianming Xu9, Karoly Racz10, Adina E Croitoru11, Mustafa Khasraw12, Eva Sedlackova13, Ivan Borbath14, Paul Ruff15, Paul E Oberstein16, Tetsuhide Ito17, Kathrine C Fernandez18, Brad Rosbrook19, Nicola Fazio20 1Paris Saint-Joseph Hospital Group, Paris, France; 2Dana-Farber Cancer Institute, Boston, MA, USA; 3PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; 4Centrul de Oncologie Sf. Nectarie, Oncologie Medicala, Craiova, Romania; 5Hospital Universitario Madrid Sanchinarro, Centro Integral Oncológico Clara Campal, Madrid, Spain; 6Zhongshan Hospital, Fudan University, Shanghai, China; 7Masaryk Memorial Cancer

Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Oslo University Hospital, Department of Gastroenterology, Rikshospitalet, Oslo, Norway; 9No.307 Hospital, Academy of Military Medical Sciences, Beijing, China; 10Semmelweis University, Faculty of Medicine, 2nd Department of Internal Medicine, Budapest, Hungary; 11Fundeni Clinical Institute, Department of Medical Oncology, Bucharest, Romania; 12Andrew Love Cancer Center, Geelong Hospital, Victoria, Australia; 13Všeobecné Fakultní Nemocnice v Praze Onkologická Klinika, Praha, Czech Republic; 14Cliniques Universitaires Saint-Luc, King Albert II Institute Cancerology and Hematology, Brussels, Belgium; 15University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa; 16Columbia University Medical Center, Division of Hematology/Oncology,

New York, NY, USA; 17Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; 18Pfi zer Inc, Cambridge, MA, USA; 19Pfi zer Inc, San Diego, CA, USA; 20IEO, European Institute of Oncology, Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, Milan, Italy

380

REFERENCES1. American Cancer Society. Cancer Facts & Figures 2016. Atlanta, GA.2. Raymond E, et al. N Engl J Med 2011;364:501-13.3. Faivre S, et al. Ann Oncol 2016; Nov 10 [Epub ahead of print].

4. Sutent® (sunitinib malate) prescribing information. New York, NY: Pfi zer Inc; 2015.

ACKNOWLEDGMENTSWe thank the participating patients and their families, as well as the global network of research nurses, trial coordinators, and operations staff for their contributions, and investigators who participated in this trial, including: M. Michael (Australia); X. Yu, Y. Shen and L. Jia (China); P. Hammel (France); S. Skrikhande (India); C. Morizane (Japan); J. Sufl iarsky (Slovakia); and G. Khan (United States). This study was sponsored by Pfi zer. Medical writing

support was provided by Mariko Nagashima, PhD, and Anne Marie Reid, PhD, of Engage Scientifi c Solutions, and was funded by Pfi zer.

For information on this poster, contact Eric Raymond, eraymond@hpsj.fr

Copyright © 2017

INTRODUCTION • Pancreatic neuroendocrine tumors (pNETs) are rare tumors. Of an estimated

53,070 new cases of pancreatic cancers expected in the US in 2016, pNETs

account for fewer than 5%.1

• Due to their relatively indolent nature, the majority of patients are diagnosed

with metastatic pNETs, for whom treatment options are limited.

• pNETs are highly vascularized tumors; aberrant expression of vascular

endothelial growth factor (VEGF) and its receptors, which play vital roles in tumor

angiogenesis, has been observed.

• Sunitinib, a multi-targeted tyrosine kinase inhibitor (TKI) of angiogenesis,

showed a signifi cant increase in progression-free survival (PFS) over placebo in

well-differentiated, advanced and/or metastatic pNETs in a pivotal phase III

clinical trial (ClinicalTrials.gov NCT00428597).2

• The trial was terminated early after more-serious adverse events (AEs) and deaths

were observed in the placebo arm and a difference in PFS favored the sunitinib arm

(hazard ratio [HR] 0.42; 95% confi dence interval [CI], 0.26–0.66; P<0.001; median:

11.4 vs 5.5 months).

– The median (95% CI) 5-year overall survival (OS) was 38.6 (25.6–56.4) months for

sunitinib and 29.1 (16.4–36.8) months for placebo (HR 0.73; 95% CI, 0.50–1.06;

P=0.094), with 69% of placebo patients having crossed over to sunitinib.3

• In 2010 and 2011, sunitinib was approved by the European Medicines Agency

and US Food and Drug Administration (FDA), respectively, for the treatment of

patients with progressive, locally advanced and/or metastatic, well-differentiated,

unresectable pNETs.4

OBJECTIVES • This phase IV clinical trial (ClinicalTrials.gov NCT01525550) was conducted

as post-approval commitments to the FDA and other regulatory agencies to

confi rm the effi cacy and safety of sunitinib in advanced and/or metastatic,

well-differentiated, unresectable pNETs.

METHODSStudy Design

• This multinational, single-arm, open-label, phase IV clinical trial is ongoing.

• The primary endpoint is investigator-assessed PFS per the Response Evaluation

Criteria in Solid Tumors (RECIST) v1.0.

• Secondary endpoints include PFS assessed by the independent radiological review,

time to tumor progression (TTP), objective response rate (ORR), OS, and safety.

Key Eligibility Criteria

• Histologically or cytologically confi rmed, well-differentiated, unresectable or

metastatic pNETs with documented progression within 12 months of study

enrollment.

• Not amenable to surgery, radiation, or combined modality therapy with curative

intent.

• Presence of ≥1 measurable target lesion per RECIST v1.0.

• Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.

• No pre-existing uncontrolled hypertension (ie, blood pressure >150/100 mmHg

despite medical therapy).

• No prior treatment with TKIs, anti-VEGF, or other angiogenesis inhibitors.

Treatment and Assessments

• Patients received 37.5 mg sunitinib orally once a day on a continuous daily-dosing

regimen.

– Sunitinib dose could be increased to 50 mg daily any time after 8 weeks of

treatment initiation in patients without treatment response who experienced

only grade 1 or lower nonhematologic or grade 2 or lower hematologic

treatment-related AEs.

– Dose could be temporarily interrupted or reduced to 25 mg daily to manage

severe toxicity.

• Somatostatin analogs for control of symptoms were permitted at the investigator’s

discretion.

• Radiologic tumor assessments were conducted at screening, Cycle 2 Day 1, Cycle 3

Day 1, and every 2 cycles thereafter; tumor responses were evaluated per RECIST

v1.0 criteria.

• Safety was monitored throughout the study and AEs were graded according to the

National Cancer Institute Common Terminology Criteria for Adverse Events v3.0.

Statistical Analyses

• More than 80 patients were to be enrolled: 40 treatment-naïve (defi ned as

those who never received systemic antitumor therapy; somatostatin analogs for

symptomatic control were allowed) and 40 previously treated patients.

• Median PFS and 95% CI were estimated using the Kaplan–Meier method for the

entire population as well as separately for treatment-naïve and previously treated

patients.

• Descriptive statistics were used to summarize other parameters.

RESULTSPatients

• Of 123 patients screened, 106 (61 treatment-naïve and 45 previously treated) were

enrolled at 25 centers in 15 countries (Figure 1).

Figure 1: Trial Profi le

123 patients screened

106 patients enrolled

61 txt-naïve patients treated 45 previously treated patients treated

39 previously treated patients discontinued txt

23 Objective progression/relapse

8 Adverse events

1 Refusal of txt for reason other than AE

2 Global health deterioration

1 Death

4 Other

43 txt-naïve patients discontinued txt

26 Objective progression/relapse

6 Adverse events

4 Refusal of txt for reason other than AE

2 Global health deterioration

1 Death

4 Other

Efficacy analysis: 61 txt-naïve patients

Safety analysis: 61 txt-naïve patients

45 previously treated patients

45 previously treated patients

AE=adverse event; txt=treatment

• Patient demographics and baseline characteristics are summarized in Table 1.

• More than half (n=64/106, 60.4%) of patients had a nonfunctioning tumor and

17.9% had a functioning tumor (unknown for 21.7% of patients).

• In regard to prior locoregional treatment, 18.9% of patients had trans-arterial

chemoembolization; radiofrequency ablation (3.8%); or trans-arterial embolization,

percutaneous injections, or microwave ablation (2.8% each).

• Median (range) treatment duration in the total population was 11.7 months

(0.2–40.3): 12.2 months (0.2–35.9) in treatment-naïve vs 10.2 months (0.5–40.3)

in previously treated patients.

Effi cacy

• Median PFS as assessed by investigators was 13.2 months (95% CI, 10.9–16.7);

median PFS was similar in treatment-naïve and previously treated patients

(13.2 months [95% CI, 7.4–16.8] and 13.0 months [95% CI, 9.2–20.4],

respectively; Figure 2).

• Median PFS as assessed by independent radiological review was 11.1 months

(95% CI, 7.4–16.6), in treatment-naive patients 11.1 months (95% CI, 5.5–16.7),

and in previously treated patients 9.5 months (95% CI, 7.4–18.4).

– 7 patients were censored due to lack of adequate baseline assessments.

Table 1: Demographics and Patient Baseline Characteristics

Characteristics

Treatment-naïven=61

Previously Treatedn=45

TotalN=106

Age, years, mean (SD) 55.4 (8.9) 53.5 (9.1) 54.6 (9.0)

Gender, n (%)

Male 30 (49.2) 33 (73.3) 63 (59.4)

Female 31 (50.8) 12 (26.7) 43 (40.6)

Race, n (%)

White 32 (52.5) 35 (77.8) 67 (63.2)

Black 2 (3.3) 0 2 (1.9)

Asian 27 (44.3) 10 (22.2) 37 (34.9)

ECOG PS, n (%)

0 39 (63.9) 29 (64.4) 68 (64.2)

1 22 (36.1) 16 (35.6) 38 (35.8)

No. of involved disease sites,* n (%)

1 24 (39.3) 9 (20.0) 33 (31.1)

2 19 (31.1) 22 (48.9) 41 (38.7)

3 11 (18.0) 8 (17.8) 19 (17.9)

4 3 (4.9) 3 (6.7) 6 (5.7)

>4 4 (6.6) 3 (6.7) 7 (6.6)

Tumor site,* n (%)

Liver 57 (93.4) 41 (91.1) 98 (92.5)

Pancreas 22 (36.1) 25 (55.6) 47 (44.3)

Lymph node, distant 16 (26.2) 13 (28.9) 29 (27.4)

Lymph node, regional 13 (21.3) 7 (15.6) 20 (18.9)

Lung 3 (4.9) 3 (6.7) 6 (5.7)

Other 10 (16.4) 10 (22.2) 20 (18.9)

Any prior systemic chemotherapy, n (%) 0 45 (100) 45 (42.5)

Prior SSA, n (%) 24 (39.3) 27 (60.0) 51 (48.1)

Ki-67 index, mean (SD) 6.7 (5.0) 8.4 (7.2) 7.4 (6.0)

* Included both target and nontarget sites; sites with multiple lesions were counted once.

ECOG PS, Eastern Cooperative Oncology Group performance status; SD=standard deviation; SSA=somatostatin analogs

Figure 2: Kaplan–Meier Estimates of PFS in Treatment-Naïve and Previously Treated

Patients With pNETs, Assessed by Investigators

PFS D

istrib

utio

n F

unctio

n

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 5 10 15 20 25

Time (Months)No. at risk:

Treatment-naïve

Previously treated

61

45

41

29

32

20

14

10

8

8

6

4

0

4

0

2

0

1

0

0

30 35 40 45

Treatment-naïve 61 37 13.2 (7.4–16.8)

Previously treated 45 28 13.0 (9.2–20.4)

n Events mPFS (95% CI), mo

CI=confi dence interval; mPFS=median progression-free survival; PFS=progression-free survival; pNETs=pancreatic neuroendocrine tumors

• ORR was 24.5% (95% CI, 16.7–33.8) according to the investigator assessment

(Table 2).

•

Table 2: Best Observed Response by RECIST, Assessed by Investigators

Treatment-naïve

n=61

Previously Treatedn=45

TotalN=106

Best overall response, n (%)

Complete response 2 (3.3) 1 (2.2) 3 (2.8)

Partial response 11 (18.0) 12 (26.7) 23 (21.7)

Stable disease 40 (65.6) 29 (64.4) 69 (65.1)

Progressive disease 7 (11.5) 2 (4.4) 9 (8.5)

Indeterminate 1 (1.6) 1 (2.2) 2 (1.9)

ORR,* n (%) 13 (21.3) 13 (28.9) 26 (24.5)

95% CI 11.9–33.7 16.4–44.3 16.7–33.8

* Complete response + partial response.

CI=confi dence interval; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors

Median TTP was 14.5 months (95% CI, 11.0–16.7); median TTP in treatment-naïve

and previously treated patients was similar (14.8 [95% CI, 7.5–16.8] and 14.5

[95% CI, 9.2–20.4] months, respectively).

• OS data were not mature at the time of data cutoff date (March 19, 2016); 29 (27.4%)

patients had died and median OS was 37.8 months (95% CI, 33.0–not estimable).

Safety

• Most-common treatment-emergent, all-grade AEs experienced by all patients treated

with sunitinib included neutropenia, diarrhea, and leukopenia (Table 3).

– No major differences were observed in the incidence of AEs reported by treatment-

naïve vs previously treated patients, except dyspepsia, nausea, and neutropenia.

• Percentage of treatment-naïve and previously treated patients who experienced

Grade 3 or 4 AEs was comparable; serious AEs were also comparable: 24.6% (n=15) vs

24.4% (n=11), respectively.

• 15 (24.6%) treatment-naïve and 5 (11.1%) previously treated patients had sunitinib

dose reductions due to AEs; 8 (13.1%) and 10 (22.2%) patients, respectively,

discontinued treatment due to AEs.

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Table 3: Treatment-Emergent, All-Causality Adverse Events

Adverse Events,* n (%)

Treatment-naïven=61

Previously Treatedn=45

TotalN=106

All Grades

Grade 3/4

All Grades

Grade 3/4

All Grades

Grade 3/4

Neutropenia 37 (60.7) 13 (21.3) 22 (48.9) 10 (22.2) 59 (55.7) 23 (21.7)

Diarrhea 32 (52.5) 7 (11.5) 22 (48.9) 3 (6.7) 54 (50.9) 10 (9.4)

Leukopenia 25 (41.0) 4 (6.6) 21 (46.7) 3 (6.7) 46 (43.4) 7 (6.6)

Fatigue 19 (31.1) 1 (1.6) 14 (31.1) 0 (0.0) 33 (31.1) 1 (0.9)

Hand–foot syndrome 19 (31.1) 5 (8.2) 14 (31.1) 2 (4.4) 33 (31.1) 7 (6.6)

Thrombocytopenia 18 (29.5) 6 (9.8) 14 (31.1) 2 (4.4) 32 (30.2) 8 (7.5)

Hypertension 16 (26.2) 4 (6.6) 11 (24.4) 2 (4.4) 27 (25.5) 6 (5.7)

Abdominal pain 16 (26.2) 2 (3.3) 10 (22.2) 3 (6.7) 26 (24.5) 5 (4.7)

Dysgeusia 14 (23.0) 0 (0.0) 11 (24.4) 0 (0.0) 25 (23.6) 0 (0.0)

Nausea 11 (18.0) 0 (0.0) 14 (31.1) 1 (2.2) 25 (23.6) 1 (0.9)

Dyspepsia 7 (11.5) 0 (0.0) 14 (31.1) 0 (0.0) 21 (19.8) 0 (0.0)

Headache 12 (19.7) 0 (0.0) 9 (20.0) 0 (0.0) 21 (19.8) 0 (0.0)

Stomatitis 13 (21.3) 2 (3.3) 6 (13.3) 1 (2.2) 19 (17.9) 3 (2.8)

Vomiting 8 (13.1) 1 (1.6) 10 (22.2) 1 (2.2) 18 (17.0) 2 (1.9)

Asthenia 10 (16.4) 0 (0.0) 7 (15.6) 2 (4.4) 17 (16.0) 2 (1.9)

Abdominal pain upper 5 (8.2) 1 (1.6) 7 (15.6) 1 (2.2) 12 (11.3) 2 (1.9)

ALT increased 2 (3.3) 1 (1.6) 9 (20.0) 0 (0.0) 11 (10.4) 1 (0.9)

AST increased 4 (6.6) 1 (1.6) 7 (15.6) 1 (2.2) 11 (10.4) 2 (1.9)

Constipation 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)

Dizziness 3 (4.9) 0 (0.0) 7 (15.6) 0 (0.0) 10 (9.4) 0 (0.0)

Hypophosphatemia 2 (3.3) 2 (3.3) 7 (15.6) 3 (6.7) 9 (8.5) 5 (4.7)

Myalgia 2 (3.3) 0 (0.0) 7 (15.6) 0 (0.0) 9 (8.5) 0 (0.0)

Adverse events are listed by highest to lowest % for Total/All Grades patients.

* Adverse events reported by ≥15% in any treatment group per MedDRA crit eria.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; MedDRA=Medical Dictionary for Regulatory Activities

TTP (mo) 14.8 14.5 TTP (mo) 18.7 16.7

RECIST-based Choi-based

Raymond et al., ENETS 2017, Poster session

Manuscript under review

Sunitinib in panNET: data about first-line and cytoreductive effect

SSA

1

Everolimus

or Sunitinib

2

PRRT

4

Chemotherapy

5

Sunitinib

or Everolimus

3

Clinical trials

TAE / TACE / TARE

Liver surgery

RT

Primary tumor

removal

Metastatic indolent SSTR-2 + pancreatic NET

Minimal consensus statement:

Everolimus or sunitinib are generally recommended after failure of SSA or

chemotherapy in pancreatic NET.

Everolimus and sunitinib ………….. can be considered a first line therapy,

especially if SSA is not an option, and if systemic chemotherapy is not clinically

required, not feasible or not tolerated.

Advanced panNETs

2016 ENETS guidelines

Pavel et al., Neuroendocrinology Jan 2016

1

Chemotherapy

Everolimus

or

Sunitinib PRRT

Sunitinib

or

Everolimus

2 4 53

Advanced well differentiated panNET

According to ENETS guidelines

SSA

Prior therapy EVE PBO

Surgery n.r. n.r.

Radiotherapy 23 % 20 %

Chemotherapy 50 % 50 %

SSA 49 % 50 %

Yao et al., NEJM 2011

Everolimus in panNETs:

Prior chemotherapy

Raymond et al., NEJM 2011

Concomitant SSA treatment, n (%) of patients

Started prior to study and continued

Started during study

17 (20.5)

15 (18.1)

2 (2.4)

18 (22.0)

12 (14.6)

6 (7.3)

Sunitinib in panNETs:

Prior chemotherapy

Advanced

pancreatic NET G3

Type A = well diff. + Ki-67 21-55 %

Type B = poorly diff. + Ki-67 21-55%

Type C = poorly diff. + Ki-67 > 55%

Milione et al., Neuroendocrinology Mar 2016

Overall survival of 136 patients with GEP

NEC according to subtype

 

  Neuroendocrinology (DOI:10.1159/000445165)  © 2016 S. Karger AG, Basel 20  

 

Table 1. Clinico-pathological features of 136 patients with NEC ALL Type A Type B Type C

Total 136 24 30 82

Gender Men 81 15 15 51

Women 55 9 15 31 Tumor site

Esophagus 5 0 1 4 Stomach 28 5 6 17

Duodenum 5 0 3 2 Ileum cecum appendix 17 4 3 10

Colon rectum 46 4 8 34 Pancreas 33 11 9 13

Gallbladder 2 0 0 2 Mitotic count /10HPF

<20 44 17 24 3 20-29 18 7 3 8 30 74 0 3 71

CD117 Negative 63 7 12 44 Positive 20 1 4 15 Missing 53 16 14 23

MMRd Absent 61 5 11 45

Present 6 2 2 2 Missing 69 17 17 35

Angio-invasion Absent 39 12 13 14

Present 67 7 12 48 Missing 30 5 5 20

Lymphocytic Infiltration Absent 94 14 19 61

Present 29 7 3 19 Missing 13 3 8 2

Stage (ENETS) I-II 9 2 1 6 III 45 7 15 23 IV 82 15 14 53

MMRd: mismatch repair protein defect.

 

Do

wnlo

ad

ed b

y:

EN

ET

S

19

8.1

43

.45.3

3 -

3/6

/20

16 1

2:0

0:5

9 P

M

Milione et al., Neuroendocrinology Mar 2016

• panNEC = 24% of the total population

• 30% of pNEC were NET G3 (or type A)

• Pancreas as the most frequent primary site among NET G3

GEP NEC heterogeneity: possible clinical implications

WD = well differentiated; PD = poorly differentiated

mPFS = 6 mo

mOS = 28 mo

Everolimus in panNET G3

Panzuto et al., Pancreas 2017

15 pts with panNET (all well/moderately differentiated) and 20-55% Ki-67

All pre-treated, mostly with chemotherapy

Clinical and biomarker evaluations of sunitinib in patients (pts) with

advanced well-differentiated grade 3 (G3) and poorly differentiated

neuroendocrine neoplasms (PD-NEN).

Dreyer et al., POSTER ASCO GI 2016

7/26 pts (23%) had SD or PR

3 pts were NET G3

Sunitinib in NET/NEC G3

IEO patient with liver mets from

moderately differentiated pancreatic NET, Ki67 40%

Resistant to platinum-based chemotherapy

1 month of Sunitinib 37.5 mg/d

Pancreatic “NET G3”

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 patients with advanced panNETs

enrolling

Therapies sequencing in non-functioningmetastatic midgut NET: evidence

1 2

1

PRRT

2

Everolimus

3

Clinical trials

TAE / TACE / TARE

Liver surgery

RT

Primary tumor

removal

Metastatic SSTR-2 positive midgut NET

SSA

Sequence of therapies in refractory carcinoid syndrome

SSA dose/schedule

adjustmentPRRT IFN

Locoregional

treatments

diarrhea

SSA dose/schedule

adjustmentPRRT IFN

Locoregional

treatments

diarrhea

EVE

New TKIs

Novel TKIs in GEP NETs

Phase III

Phase III

Phase III

CDK 4/6 inhibitors

 

  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.

Dow

nloa

ded

by:

Ist.E

urop

eo d

i Onc

olog

ia

193.

204.

98.2

- 2

/24/

2017

8:4

3:52

AM

CDK 4/6 inhibition in NET:

preclinical studies with RIBOCICLIB and PALBOCICLIB

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

Immune checkpoint inhibitors

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)

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(anti-PD-L1)

Tremelimumab(anti-CTLA-4)

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