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PANCREATIC

NEUROENDOCRINE TUMORS

DECEMBER 12, 2017

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THE Q&A PANEL

Pancreatic Neuroendocrine TumorsDaniel M. Halperin, MD

Assistant Professor

Gastrointestinal Medical Oncology

The University of Texas MD Anderson Cancer Center

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Disclosures• Consultant for Novartis, AbbVie.

• Research funded by Ipsen, Genentech, Novartis, Tarveda, Dicerna (prior).

• I will discuss off-label and/or investigational use.

Disclosures (cont.)• No webinar is a substitute for a personal consultation with a trusted

physician.

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Overview• Basics of the pancreas and pancreatic neuroendocrine neoplasms (NENs)

• Epidemiology

• Clinical presentations

• Basic biology

• Modern treatment approaches

• Future investigational directions

This is not conventional pancreas cancer

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Pancreas Anatomy/Physiology 101Exocrine

• Acinar cells produce digestive enzymes, delivered to the GI tract by ducts.

Endocrine

• Islet cells secrete hormones into blood.

Bardeesy and DePinho, Nat Rev Cancer. 2002 Dec;2(12):897-909.

Rising Incidence of Pancreatic NETs

Dasari et al., JAMA Oncol. 2017 Oct 1;3(10):1335-1342

Pancreatic

Adenocarcinoma

12.5/100,000

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Rising Prevalence of Pancreatic NETs

Dasari et al., JAMA Oncol. 2017 Oct 1;3(10):1335-1342

NET Framework• NETs arise from endocrine cells distributed

throughout the aerodigestive tract, including the pancreas.

• Classified in four dimensions:

• Primary Site

• Grade

• Stage

• Functional Status (hormonal secretion)

• Frequently express somatostatin receptors

Histology of NET. A: H&E; B: CgA

Halperin and Yao, MD Anderson Manual of Medical Oncology, 3e.

Histology of adenocarcinoma

Hruban and Fukushima, Modern Pathology (2007) 20, S61–S70.

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Grading NENs (2017)Grade

1 NET < 2 mitoses/10 HPF, Ki-67 <3%

2 NET 2-20 mitoses/10 HPF, Ki-67 3-20%

3 NET Well-differentiated

>20 mitoses/10 HPF, Ki-67 >20%

3 NEC Poorly-differentiated

>20 mitoses/10 HPF, Ki-67 >20%

Grade is dependent on appearance and rate of cellular division

Grade, Stage, Primary Site

Yao et al., J Clin Oncol 2008; 26:3063

Primary Tumor

Site

Median Survival

(months)

Appendix NA

Cecum 98

Colon 14

Lung 24

Pancreas 60

Rectum 33

Small Intestine 103

Stomach 29

Dasari et al., JAMA Oncol. 2017 Oct 1;3(10):1335-1342

Grade 1-2 Grade 3 Metastatic Grade 1-2 NET

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Functional StatusGastrinoma

(gastrin)

Glucagonoma

(glucagon)

Insulinoma

(insulin)

VIPoma

(vasoactive

intestinal peptide)

Reflux

Ulcers

Diarrhea

Diabetes

Dementia

Dermatitis

DVT

Low blood

sugar

Confusion

Improvement

with eating

Weight gain

Diarrhea

Adapted with permission from James Yao

Non-functional Presentations• Completely incidental

• Symptoms from primary tumor

Painless jaundice from pancreatic head tumor obstructing biliary drainage

Bleeding gastric varices from pancreatic tail tumor occluding splenic vein

• Symptoms from metastatic disease

Right upper quadrant pain from liver metastases

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Genetics/Genomics• Most pancreatic NETs are not inherited or

associated with a familial syndrome

• MEN1

• DAXX/ATRX

• TSC2, NF1

• VHL

• BRCA2

Scarpa et al., Nature 2017; 543:65

Alternative Lengthening of Telomeres in pNET• Loss of DAXX or ATRX results in

telomerase-independent elongation of telomeres, conferring cellular immortality.

Heaphy et al., Science 2011

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Chromosomal instability in pancreatic NETs

Yao et al, J Clin Oncol 34, 2016 (suppl; abstr e23284)

Summary• Pancreatic NETs arise from endocrine islet cells.

• NET grade, stage, and primary site all contribute to clinical course and treatment options.

• Pancreatic NETs can cause dramatic syndromes of hormone hypersecretion.

• But they usually do not.

• New data are accumulating regarding the mutations that tend to be present in pancreatic NETs.

• Most pancreatic NETs are not part of a familial/inherited syndrome.

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Management

Management Principles• Removal of localized and limited metastatic disease

• Advanced disease

Control of hormone secretion

Control of tumor growth

Minimize toxicity

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Cut when you can (should?)• Surgical series suggest overall

survival is better in patients undergoing surgery.

• Surgery appears to have survival advantage over observation or HAE.

• However, while almost anything canbe cut out, the question is frequently whether it should.

Bacchetti et al., Int J Hepatol 2013: 235040

Does everyone need active therapy?

2013 2017

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Lanreotide in GEP-NET• CLARINET

• Lanreotide: a somatostatin analogue binding SSTRs 2,5.

• Patients with SSA-avid GEP-NETs, Ki67 < 10%.

• Lanreotide vs. placebo.

Caplin et al., N Engl J Med 2014;371:224

cys

phe

lys

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D-

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tyr

lys

D-

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NH2

Octreotide Lanreotide

Lanreotide toxicities• Characteristic toxicities:

• Diarrhea (steatorrhea)

• Flatulence

• Cholelithiasis

• Hyperglycemia

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Streptozocin in pNET• Streptozocin: “islet-specific” alkylator.

• Initially tested in 4 pNET and 4 carcinoid patients at NCI.

• 1 CR for 1 year in pNET patient.

• 3 subsequent prospective randomized studies confirmed efficacy.

• However, radiographic response rates with doublets were < 10 %.

• The triplet of FAS has been reported to yield a response rate of 40%.

• Characteristic toxicities include neutropenia, hair loss, nausea/vomiting, possible cardiac toxicity

Moertel et al., N Engl J Med 1980; 303:1189 Moertel et al., N Engl J Med 1992; 326:519

mOS 2.2 vs 1.5 yrs

p<0.004

Temozolomide• Widely used but off-label (not FDA approved for NET)

• Range of response rates reported, probably approaching 30-40%

• Prospective randomized study of temozolomide +/- capecitabine is ongoing

• Characteristic toxicities include unusual infections, nausea, thrombocytopenia

Strosberg et al., Cancer 2011

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Everolimus in pNET• RADIANT-3

• Everolimus: PO mTOR inhibitor.

• Patients with G1-2 advanced pNETs, PD within 12 months.

• Everolimus vs. placebo.

Yao et al., N Engl J Med 2011;364:514

Everolimus toxicities• Characteristic toxicities:

• Stomatitis

• Rash (capelike)

• Pneumonitis

• Lymphopenia and infections

• Hyperglycemia

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Sunitinib in pNET• Sunitinib: PO VEGFR inhibitor

• Patients with G1-2 advanced pNETs, PD within 12 months.

• Sunitinib vs. placebo.

Raymond et al., N Engl J Med 2011;364:501

Sunitinib toxicities• Characteristic toxicities:

• Diarrhea

• Hair color changes

• Hypertension

• PPEDE

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Liver-directed treatment optionsStudy Patients

n

Device used Toxicity ORR

(RECIST 1.0)

Survival times and rates

Kennedy et al. 148 Yttrium-90(resin) 33% (grade III), fatigue

(6.5%)

63% Median: 70m

King et al. 58 Yttrium-90(resin)

plus 5-FU

Radiation gastritis (2 pts), duodenal

ulcer (1 pts)

39% Median: 36m

Cao et al. 58 Yttrium-90(resin)

plus 5-FU

Not reported 39.2% Median: 36m

Memon et al. 40 Yttrium-90(glass) Fatigue (63%,), nausea/vomiting

(40%), grade III, IV(bilirubin, 8%;

albumin, 2%; lymphocyte, 38%)

WHO: 64.0%;

EASL: 71.4%

Median: 34.4m

Loewe et al. 23 HAE Not reported 73% Median: 69m;

Gupta et al 49 HAE (42) vs

TACE (27)

Overall complications: TACE, 20%;

bland, 12% [HRS, Sepsis, abscess]

HAE: 25%

TACE: 50%

Median

NET:

TACE, 33.8m; HAE, 33.2m;

pNET:

TACE, 31.5m; HAE, 18.2m

Dong & Carr 123 TACE Abdominal pain (44%), diarrhoea

(30%), weight loss (22%)

62% Mean: 3.3y

Kennedy et al., HPB 2015

The Systemic Therapy Ladder

Observation

Somatostatin Analogues

(Octreotide/Lanreotide)

Targeted therapies

(Everolimus, Sunitinib)

Chemotherapy

(Streptozocin, Temozolomide)

Tolerability

Response Rate

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Therapeutic Approach

Unresectable

pNET

High Volume

Low Volume

Consider

Cytotoxic

Indolent

Progressive

Observation

SSA

Everolimus

Sunitinib

Liver-directed

Therapy

Have we moved the needle?

Primary Tumor

Site

Median Survival

(months)

Appendix NA

Cecum 98

Colon 14

Lung 24

Pancreas 60

Rectum 33

Small Intestine 103

Stomach 29

Metastatic/Distant Grade 1-2 NET

Yao et al., J Clin Oncol 2008; 26:3063 Dasari et al., JAMA Oncol. 2017 Oct 1;3(10):1335-1342

(All grades)

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Investigational Strategies• Chemotherapy

Temozolomide +/- capecitabine (NCT01824875)

• Molecularly-targeted therapy

Everolimus + ribociclib (NCT03070301)

Cabozantinib

• Immunotherapy

PDR001 (NCT02955069)

Atezolizumab + bevacizumab (NCT03074513)

• Receptor-targeted therapy

177Lu-DOTATATE

177Lu-DOTA-JR11 (NCT02609737)

PEN-221 (NCT02936323)

Cabozantinib (phase II)

Courtesy of Jennifer A. Chan, MD; GI ASCO 2017

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

Carcinoid

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

pNET

Prior everolimus and/or sunitinib

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Pembrolizumab in PD-L1+ NET25% pNET

PD-L1+

Mehnert et al., ESMO 2017

PRRT in midgut NET• NETTER-1

• 177Lu-DOTA-Octreotate (DOTATATE): a radioactive isotope conjugated to somatostatin analogue.

• Patients with G1-2 midgut NET, PD on octreotide LAR 30, somatostatin-avid.

• DOTATATE vs. octreotide LAR 60mg.

• Toxicity profile includes myelosuppression, nausea.

PFS HR 0.209 [95% CI 0.129-0.33]; P<0.0001

Strosberg et al., NEJM 2017; 376:125-135

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Symptomatic Control

pNET Syndromes and Medical Management

Tumor Signs/Symptoms Medical

Management

Insulinoma Hypoglycemia with

confusion,

diaphoresis,

weakness

Frequent small

meals, dextrose,

diazoxide, everolimus

Gastrinoma Refractory PUD,

diarrhea

PPI, SSA

Glucagonoma Rash (necrotizing

migratory erythema),

diabetes, DVT

SSA

VIPoma Profound secretory

diarrhea, electrolyte

dyscrasias

SSA

Adapted with permission from Halperin, Kulke, Yao. Annu Rev Med 2015; 66:1

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Octreotide

Kvols et al., NEJM 1986Rubin et al., JCO 1999

• Octreotide LAR is FDA

approved for control of

carcinoid syndrome

(20mg) and VIPoma.

• Agonist of SSTRs 2, 5.

Liver-directed therapy for hormone reduction

Mitty et al., Radiology 1985

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Surgical Debulking• R1 or R0 resection of liver metastases

+/- primary tumor and nodal metastases

Wilson and Butterick. Ann Surg 1959

Osborne et al., Ann Surg Onc 2006

Investigational: PRRT• 177Lutitium conjugated to octreotate

for receptor-targeted tumor irradiation.

Khan et al., J Nuc Med 2011

177Lu arm

average % of

patients

60mg Oct arm

average % of

patients

Global Health

Status

Improvement 28%** 15%

Worsening 18% 26%

DiarrheaImprovement 39%** 23%

Worsening 19% 23%

PainImprovement 41% 28%

Worsening 17% 25%

FlushingImprovement 42% 38%

Worsening 22% 19%

Strosberg et al., J Nucl Med May 1, 2017 vol. 58 no. supplement 1 244

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Grade 3 NEC is not NET

Grading NENs (2017)Grade

1 < 2 mitoses/10 HPF, Ki-67 <3%

2 2-20 mitoses/10 HPF, Ki-67 3-20%

3 NET Well-differentiated

>20 mitoses/10 HPF, Ki-67 >20%

3 NEC Poorly-differentiated

>20 mitoses/10 HPF, Ki-67 >20%

Grade is dependent on appearance and rate of cellular division

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Grade 3 NEN Genomics

GeneSCLC (N =

593)

Pancreas (N

= 123)

Colon (N =

92)

Other GI (N

= 59)

TP53 90%P,C,O 18%S,C,O 59%S,P 49%S,P

RB1 67% P,C,O 10% S,C,O 34%S,P 29% S,P

CDKN2A 3%P,O 21%S,C 5%P,O 25%S,C

MEN1 1%P 33%S,C,O 3%P 2%P

CDKN2B 1%P,O 16%S,C 1%P,O 19%S,C

DAXX 0%P 20%S,C,O 0%P 0%P

APC 2%C 3%C 47%S,P,O 8%C

KRAS 4%C 7%C 37%S,P,O 3%C

CCNE1 4%O 2%O 1%O 17%S,P,C

S, P, C or O: Statistically significant difference compared toS= SCLC, P= Pancreas, C= colon, O= Other GI

Bergsland et al., GI ASCO 2016

Grade 3 NEC has a distinct natural history

Yao et al., J Clin Oncol 2008; 26:3063

Grade 1-2 Grade 3

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Cisplatin/Etoposide for Grade 3 NEC

Mitry et al., Br J Cancer (1999) 81(8), 1351–1355.

Investigational Strategies• Chemotherapy

FOLFIRINOX (NCT03042780)

EP vs. CAPTEM (NCT02595424)

• Immunotherapy

PDR001 (NCT02955069)

Pembrolizumab (NCT02939651)

Avelumab (NCT03147404)

• Receptor-targeted therapy

PEN-221 (NCT02936323)

Rova-T (NCT02709889)

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Take Home Points• Pancreatic NETs are not conventional pancreas cancer (adenocarcinoma)

• Pancreatic NECs are not conventional pancreatic NETs.

• Pancreatic NETs are increasing in incidence.

• Patients are living longer than ever.

• Much progress has been made in developing new effective therapy.

• Current challenges include:

Choosing from the standard therapy menu.

Choosing from the investigational menu.

Thank you for your participation.

If you have questions, please contact

Patient Central at

877-2-PANCAN or e-mail patientcentral@pancan.org.

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