Selection of Appropriate Treatment · The Increasing Incidence of NETs Yao JC, et al. J Clin Oncol....

Expert Review in Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs):

Selection of Appropriate Treatment

Reference Slide Deck

Neuroendocrine Tumors (NETs): A Diverse Group of Malignancies

• Tumors arising from enterochromaffin cells located in neuroendocrine tissue throughout the body1

• NETs can be functional or nonfunctional and include a heterogeneous group of neoplasms2,3

– Gastroenteropancreatic neuroendocrine tumors (GEP-NETs)3

– Islet cell tumors2

– Typical/atypical/poorly differentiated lung carcinoid2

– Small cell carcinoma of the lung2,3

– Pheochromocytoma/paraganglioma2,3

– Medullary thyroid carcinoma

– Merkel cell carcinoma2,3

– Kidney, bladder, breast, prostate, thymus…

1. Caplin ME, et al. Lancet. 1998;352(9130):799-805. 2. NCCN Clinical Practice Guidelines in Oncology™: Neuroendocrine Tumors V2.2016.

Available at: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed November 11, 2016. 3. Modlin IM, et al.

Gastroenterology. 2005;128(6):1717-1751.

The Increasing Incidence of NETs

Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072.

Lung and bronchus

Small intestine

Rectum

Stomach

Pancreas

Appendix

Colon

Cecum

Year

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0

1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003

Inc

ide

nc

e p

er

10

0 0

00

• Annual age-adjusted incidence of NETs in the US population by anatomic location

The Gastrointestinal Tract (GI) Is the Most Common Primary Location of NET (US SEER Data)

58%15%

27%Digestivesystem

Lung

Other/unknown

Percent distribution (%)

17.2 Rectum

13.4 Jejunum/ileum

6.4 Pancreas

6.0 Stomach

4.0 Colon

3.8 Duodenum

3.2 Cecum

3.0 Appendix

0.8 Liver


NETs Are the Second Most Prevalent Type of GI Malignancy

1. National Cancer Institute: SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/archive/csr/1975_2004/.

Accessed: September 8, 2016. 2. Modlin IM, et al. Cancer. 2003;97(4):934-959.

Colorectal1 Stomach1 Pancreas1 Esophagus1 Hepatobiliary1GEP-NET2

100,000

Prevalence in SEER Database

1,100,000

1,200,000

0

2 times more prevalent than pancreatic cancer

Neuroendocrine Tumors (NETs) Are Heterogeneous With a Wide Spectrum of Characteristics

Öberg KE, et al. Cancer Metastasis Rev. 2011;30 Suppl 1:3-7.

Localized

Metastatic

Symptomatic

Asymptomatic

Indolent Aggressive

Functioning

Nonfunctioning

Well-differentiated

Poorly differentiated

NET

NETs Are Often Advanced at the Time of Diagnosis

0,4

2,75

9,25

18,5

0 5 10 15 20

Local

Regional

Metastatic

Poorly differentiatedmetastatic

Median Survival, Years

Well and moderately

differentiated

18.5

9.25

2.75

0.4

Yao JC, et al. J Clin Oncol. 2008;26(18):3063-3072. Soga J. Cancer. 2005;104(6):1180-1187. Alexiev BA, et al. Diagn

Pathol. 2007;2:28. Modlin IM, et al. Lancet. 2008;9(1):61-72.

Carcinoids M1 at Dx SV 5 and M1

Small intestine 70% 55%

Colon 71% 20%

Appendix 10% 34%

Rectum 15% 30%

Pancreatic NETs 50%-60% 30%-50%

Correlation of Primary Tumor Site With Survival


Known prognostic factors include:

• Location of primary tumor

• Extent of disease

• Tumor stage

• Degree of differentiation/

proliferative index

• Tumor grade

• Patient age

• Performance status

65% of patients with advanced NETs will not be alive in 5 years

Distant metastases

1.0

0.8

0.6

0.4

0.2

Su

rviv

al P

rob

ab

ility

012 24 36 48 60 72 84 96 108 120

Time, months

ColonLungPancreasRectumSmall bowel

Prognostic Value of Ki67<2% 15% 75%

Pape UF, et al. Endocr Relat Cancer. 2008;15(4):1083-1097.

Scarpa A, et al. Mod Pathol. 2010;23(6):824-833.Ekeblad S, et al. Clin Cancer Res. 2008;14(23):7798-7803.

Grade Mitotic Count (10 HPF)

Ki-67 Index (%)

G1 2 ≤2

G2 2-20 3-20

G3 20 20

Prognostic Value of Differentiation

Poorly differentiated histology


HistologyWell- and moderately-differentiated histology

High Complexity for NETs ClassificationDifferentiation Grade Mitotic Count Ki67 Index Traditional ENETS; WHO

Well differentiated

Low grade

(G1)

<2 per 10 high

power fields

(HPFs)

≤2% Carcinoid, islet

cell, pancreatic

(neuro)endocrine

tumor

Neuroendocrine

tumor; grade 1

Intermediate

grade (G2)

2-20 per 10

HPFs

3%-20% Carcinoid, islet

cell, pancreatic

(neuro)endocrine

tumor

Neuroendocrine

tumor; grade 2

Poorly

differentiated

High grade

(G3)>20 per 10 HPFs >20%

Small cell

carcinoma

Neuroendocrine

tumor; grade 3,

small cell

Large cell

neuroendocrine

carcinoma

Neuroendocrine

tumor; grade 3,

large cell

Well-Differentiated Poorly-Differentiated

Grade (ENETS) Low (G1) Intermediate (G2) High (G3)

Ki67 index (%) ≤2 3-20 >20

Anatomic imaging More rapid growth on serial imaging

Functional imaging Octreoscan SPECT

or SSTR PET-positive

FDG PET-positive

Prognosis Indolent (slowly growing) Aggressive

Bosman FT, eds. WHO Classification of Tumours of the Digestive System. 4th Ed. Lyon, France: The International Agency for

Research on Cancer; 2010. Rindi G, et al. Virchows Arch. 2006;449(4):395-401. Rindi G, et al. Virchows Arch. 2007;451(4)757-762.

Jensen RT, et al. Neuroendocrinology. 2006;84(3):173-182.

Integrating Grade and Tumor Burden

Treatment goals: Tumor control and QoL

Tumor Aggressiveness (eg, Ki67)

Tumor

Burden

High

Low

Moderate(up to Ki67 = 20%)

Low

Advanced, unresectable, well to moderately differentiated NETs:

Primary treatment goals

Tumor response/control &

QoLTumor response/control

Rapid Tumor

Response

QoL & tumor controlTumor control &

QoLTumor control/response

QoL & tumor

controlTumor control & QoL

Tumor control

& QoL

Syndromes With Nonspecific Symptoms Caused by Hormones and Peptides Secreted by

Functional NETs*

*There are many other hormones, syndromes, and symptoms that can be caused by NETs. These are some of the most common.

Modlin IM, et al. Lancet Oncol. 2008;9(1):61-72. Kaltsas GA, et al. Endocr Rev. 2004;25(3):458-511. Barakat MT, et al.

Endocr Relat Cancer. 2004;11(1):1-18.

NET Location

Hormone

/peptide

Associated

syndrome

GastrinSerotonin InsulinVasoactive

intestinal peptideGlucagon

Carcinoid

syndrome

Zollinger-Ellison

syndrome

Hypoglycemia

syndrome

Verner-Morrison

syndrome

Diarrhea

Flushing

Cramping Rash

Glucose intolerance /

diabetes

Weight

lossWheezing

Ulcers

Weight

gain

Insulin

resistance

Hypo-

glycemia

Small bowel Pancreas

Carcinoid Syndrome

CNS, central nervous system; PCPA, parachlorophenylalanine

1. Kulke MH, et al. N Engl J Med. 1999;340(11):858-868. 2. Rubin J, et al. J Clin Oncol. 1999;17(2):600-606. 3. Strosberg,

et al. Gastrointest Cancer Res. 2013;6(3):81-85. 4. Engelman K, et al. N Engl J Med. 1967;277(21):1103-1108.

• Tumoral release of serotonin and other vasoactive substances into the systemic circulation causes carcinoid syndrome1

• Treatment with somatostatin analogs (SSAs) is associated with improved symptom control, but patients may not maintain adequate control of symptoms2,3

• Inhibition of serotonin synthesis with PCPA was previously shown to provide symptom control, but its utility was limited by CNS side effects4

Urinary 5-Hydroxyindoleacetic Acid (5-HIAA)

• Measured in a 24-hour urine

specimen

• Arises in the setting of hepatic

metastases or due to direct drainage

into systemic circulation

• Severity of carcinoid syndrome may

correlate with urinary 5-HIAA levels

• High levels have prognostic value

and are associated with:

- Reduced survival

- Progressive carcinoid heart

disease

Kocha W, et al. Curr Oncol. 2010;17(3):49-64. Feldman JM, et al. Clin Chem. 1986;32(5):840-844. Formica V, et al. Br J

Cancer. 2007;96(8):1178-1182. de Herder WW. Best Pract Res Clin Endocrinol Metab. 2007;212(1):33-41. Strosberg JR,

et al. Clincal features of the carcinoid syndrome. Available at: www.uptodate.com. Last update: July 2015.

When to Treat?Factors to Consider in Nonfunctioning GI NETs

Tumor factors to consider

• Signs and symptoms

– Pain, weight loss, etc

• Tumor volume

– What is the risk if tumor

grows?

• Tumor aggressiveness

– Growth rate, Ki 67, marker

levels

Treatment factors

• Short-term risks, long-term risks

• Reversibility of AEs

• Patient

– Functional status, organ

function

– Preferences

Risk from treatment

Risk from tumor

progression

MIBG, meta-iodobenzylguanidine; mTOR, mammalian target of rapamycin; PRRT, peptide-receptor radiotherapy; TKI,

tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor

Salazar R, et al. Neuroendocrinology. 2012;95(2):71-73. National Comprehensive Cancer Network. NCCN Clinical Practice

Guidelines in Oncology (NCCN® Guidelines): Neuroendocrine tumors. v2.2016. Available at:

https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed October 7, 2016.

Surgery Debulking / Locoregional Therapy

• Resection of primary tumor

• Cytoreductive surgery of unresectable

tumor

• Curative (rarely), ablative (very often)

• Radiofrequency ablation (RFA)

• Embolization / chemoembolization /

radioembolization

Medical Therapy Nuclear Medicine and Irradiation

• Somatostatin analogs (SSAs)

• Interferon-α

• Targeted therapies

– mTOR inhibitors

– VEGFR inhibitors

– Other TKIs

• Chemotherapy

• Tumor-targeted, radioactive therapy:

PRRT using, eg

– MIBG

– 90Y-DOTATOC

– 177Lu –DOTATATE

• External irradiation (for bone, brain-

metastases)

• Brachytherapy (for liver metastases)

Treatment Options for NETs

Factors Influencing the Therapeutic Decision in NETs

Type of NET

(pancreatic vs GI)

TNM stage and grade

(G1/G2 vs G3)

ResectabilityFunctioning vs non-

functioning tumor

Patient performance status

and comorbidities

Availability of different

therapeutic modalities

Patient preference and

convenience

Uptake on somatostatin

receptor scintigraphy

ENETS Guidelines for 1st-Line Treatment

Drug Functionality Grading Primary Site SSTR

status

Special Considerations

Octreotide +/- G1 Midgut + Low tumor burden

Lanreotide +/- G1/G2 (~10%) Midgut, pancreas + Low and high (>25%) liver tumor

burden

IFN-alpha 2b +/- G1/G2 Midgut If SSTR negative

STZ/5-FU +/- G1/G2 Pancreas Progressive in short-term* or high tumor

burden or symptomatic; if STZ is

contraindicated or not available

TEM/CAP +/- G2 Pancreas Atypical carcinoid and/or SSTR

negative

Everolimus +/- G1/G2 Lung Insulinoma or contraindication for CTX

Pancreas Insulinoma or contraindication for CTX

Midgut If SSTR negative

Sunitinib +/- G1/G2 Pancreas Contraindication for CTX

PRRT +/- G1/G2 Midgut +

(required)

Extended disease; extrahepatic

disease, eg, bone metastasis

Cisplatin†/

etoposide

+/- G3 Any All poorly differentiated NEC

Pavel M, et al. Neuroendocrinology. 2016;103(2):172-185.

* ≤6-12 months; †Cisplatin can be replaced by carboplatin

AC, atypical carcinoid; AJCC; American Joint Committee on Cancer; CS, carcinoid syndrome; ENETS, European Neuroendocrine Tumor Society; ESMO; European

Society for Medical Oncology; EVE, everolimus; GEP, gastroenteropancreatic; GI NETs, gastrointestinal neuroendocrine tumors; LAN, lanreotide; LAR, long-acting

repeatable; m, metastatic; NANETS, North American Neuroendocrine Tumor Society; NEC, neuroendocrine carcinomas; NET, neuroendocrine tumors; NF,

nonfunctional; OCT, octreotide; pNET, pancreatic NET; SC, subcutaneous; STZ, streptozotocin; TC, typical carcinoid; UICC, Union for International Cancer Control;

WHO, World Health Organization

CLARINETLAN GEP

NET16,17,29

2014/15

1980 2000 2005

STZ combination:

Survival benefit pNET2

1992

1900

RADIANT-4EVE NF GI and

lung NET15,19

2015/16

TELESTARtelotristat etiprate

CS20

NDA filed 3/30/16

NETTER-1177Lu-Dotatate

midgut NET18RADIANT-2

EVE + OCT, LAR in mNET w/CS14

2010/11

Sunitinib phase IIIpNET13,31,34

2015

PROMIDOCT LAR:

Antitumor

activity9,31

2009

LANsymptom

control24

1998

OCT LARcarcinoid

tumors23,26,28

US

approva

l

US/EU

approva

l

EU

approva

l

Tre

atm

en

ts

ELECTLAN:

Symptom

control27

2010

OCT

SCCS 25,30

1988/89

RADIANT-3EVE in pNET 11,12,32,33

2015

STZ pNET36

1982

New Options in NETs Treatment

Somatostatin Analogs

1. Susini C, et al. Ann Oncol. 2006;17(12):1733-1742. 2. Öberg KE, et al. Gastroenterology. 2010;139(3):742-753.

Overview

• Synthetic derivatives of somatostatin1

• Bind to somatostatin receptors

(SSTRs)1

• Similar to endogenous somatostatins

but with1:

– Increased affinity for specific SSTRs

– Longer half-life and greater stability

– Longer duration of action in the

body

• Have different SSTR affinity profiles2

– Octreotide and lanreotide have high

affinity for SSTR2 and lower

affinities for SSTR3 and SSTR5

– Pasireotide has high affinity for

SSTR1-3, and SSTR5

SSTR1

SSTR2

SSTR3

SSTR4

SSTR5

Octreotide

and

Lanreotide2 Pasireotide2

PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR 30 mg

• Primary endpoint: Time to tumor progression (blinded central review)

• Secondary endpoints: Objective response rate, survival, quality of life, safety

Patients with midgut NETs

• Treatment naïve

• Histologically confirmed

• Locally inoperable or

metastatic

• Well differentiated

• Measurable (CT/MRI)

• Functioning or

nonfunctioning

Octreotide LAR

30 mg IM

every 28 days

Placebo IM

every 28 days

RA

ND

OM

IZA

TIO

N (

1:1

)

Treatment until

CT/MRI

documented

tumor

progression or

death

Month 3 6 9 12 15 18

CT, computed tomography; IM, intramuscular; MRI, magnetic resonance imaging

Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663.

Phase III randomized, double-blind, placebo-controlled study

Tumor Control in NET: Octreotide LAR Significantly Prolongs TTP

Octreotide LAR 30 mg: 42 patients/26 events

Median TTP = 14.3 months (95% CI 11.0-28.8)

Placebo: 43 patients/40 events

Median TTP = 6.0 months (95% CI 3.7-9.4)

Time, Months

Pro

po

rtio

n o

f P

ati

en

ts

Wit

ho

ut

Pro

gre

ss

ion

0

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42 48 54 60 66 72 78

66% reduction in the risk of tumor progression

HR = 0.34; 95% CI: 0.20-0.59; P = .000072

PROMID: Well-differentiated midgut NET

HR, hazard ratio; TTP, time to progression


Octreotide LAR 30 mg Achieved Superior Tumor Response at 6 Months (WHO)

Octreotide

LAR 30 mg (n = 42)

Placebo

(n = 43)

Complete response, n 0 0

Partial response, n 1 1

Stable disease, n 28 16

Progressive disease, n 10 23

Unknown, n 3 3

Wilcoxon-Mann-Whitney test: P = .0079

WHO, World Health Organization


Octeotride LAR: Safety Profile• No treatment-related deaths

• Serious AEs (SAEs) were observed in 11 octreotide LAR–treated and 10 placebo-treated patients

• Most common SAEs affected

- GI tract (octreotide LAR, n = 6; placebo, n = 8)

- Hematopoietic system (octreotide LAR, n = 5; placebo, n = 1)

- General health status (fatigue and fever; octreotide LAR, n = 8; placebo, n = 2)

• Treatment discontinuation due to AEs occurred 5 octreotide LAR recipients and no placebo recipients

• WHO grade 2-4 adverse events were observed more often in the octreotide LAR arm and included diarrhea and flatulence

• Bile stones were recorded six times (octreotide LAR recipients n = 5)


CLARINET: Study Design

PFS, progression-free survival

Caplin ME, et al. N Engl J Med. 2014;371(3):224-233.

Study design:

• Phase III, 96-week, randomized, double-blind, placebo-controlled, multicenter study (14 countries: United States, India, and 12 European countries)

• Primary endpoint: Progression-free survival, defined as time to disease progression or death

Population:

• N = 204 adults with well or moderately differentiated, progressing, metastatic, and/or locally advanced unresectable GEP NETs, and Ki67 <10%

Treatments:

• Lanreotide autogel 120 mg (fixed dose) vs placebo every 28 days

1:1

12-24 weeks

1 12 24 36 48 72 96

(baseline)Study Visits, Weeks

Scan 1 Scan 2

Lanreotide autogel SC 120 mg q28 days

Placebo SC q28 days

Primary Endpoint = PFS

Tumor Control in NETs: Lanreotide Autogel Significantly Prolongs PFS


Lanreotide Autogel 120 mg

32 events/101 patients

Median, not reached

Placebo

60 events/103 patients

Median, 18.0 months (95% CI 12.1-24.0)

53% reduction in the risk of tumor progression

HR = 0.47; 95% CI 0.30-0.73; P = .0002

0 3 6 9 12 18 24 27

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

Ali

ve

an

d W

ith

No

Pro

gre

ss

ion

, %

Time, Months

62%

22%

CLARINET: Well/moderately differentiated nonfunctioning GEP NET

PFS According to Subgroups


Event Lanreotide (n = 101) Placebo (n = 103)

Diarrhea 26 (26) 9 (9)

Abdominal pain 14 (14) 2 (2)

Cholelithiasis 10 (10) 3 (3)

Flatulence 8 (8) 5 (5)

Injection-site pain 7 (7) 3 (3)

Nausea 7 (7) 2 (2)

Vomiting 7 (7) 0

Headache 5 (5) 2 (2)

Lethargy 5 (5) 1 (1)

Hyperglycemia 5 (5) 0

Decreased level of pancreatic enzymes 5 (5) 0

Lanreotide Autogel: Safety ProfileStudy Treatment-Related Adverse Events in ≥5% of Patients


Trial (Prospective/

Retrospective)

Primary/

Number

Prior

SSA

? Intervention Symptoms DCR ORR

Biochemical

Response Toxicity

Anthony 1993 (P) NET (14) N Octreotide 500-2000 mcg tid

lanreotide 750-3000 mcg tid

N 46% 31% NA No major AE

di Bartolomeo

1996 (P)

SBNET/PN

ET (58)

N Octreotide 500 mcg tid (n =

23)

or 1000 mcg tid (n = 35)

Diarrhea improved

in 40%,

flushing in 50%

50% 3% 77% (u5HIAA) Gallstones (4%),

Steatorrhea (4%)

Filosso 2002 (P) Bronchial

NET (7)

N Octreotide 1500 mcg/d All improved 100% 42% 100% Nil

Eriksson 1997 (P) SBNET/PN

ET(19)

N Lanreotide 750 mcg qid to

3 mg qid

Flushing better

(P = .06)

NA NA 58% 4 ceased due to AE

(gallstone, diarrhea)

Faiss 1999 (P) Foregut

NET (30)

Y Lanreotide 5 mg tds Improved on the

whole

36% 6% Decreased

(CgA/u5HIAA)

Fatigue (30%), steatorrhea

(6%), cholelithiasis (3%)

Strosberg 2014 (R) Metastatic

NET (239)

Y Octreotide 40-133 mg/month 70% to 80%

reported

improvement in

flushing/diarrhea

NA NA NA NA

Welin 2004(P) Midgut

NET (12)

N Octreotide 160 mg/m2 weeks NA 75% 0% CgA 33%,

u5HIAA 16%

Gallstone (8%), fever (50%)

Al-Efraij 2014 (R) Metastatic

NET (27)

Y Octreotide 40-60 mg Diarrhea 62%,

flushing 76%,

palpitation 100%

29% 0% CgA 31%,

u5HIAA 23%

NA

Weber 2012 (R) Metastatic

NET (337)

Y Octreotide 40-60 mg Diarrhea 62%,

56% flushing

NA NA NA NA

Modica 2015 (R) Metastatic

NET (21)

Y Octreotide LAR (15),

lanreotide (6)

63% improved 53% 5% NA Abdominal discomfort (5%),

gallstones (5%), T2DM (5%)

Albertelli 2016 (P) Metastatic

NET (35)

Y Lanreotide ATG 180 mg NA NA NA NA 21% SAE

(cholelithiasis/cholecystitis)

Trials Investigating Somatostatin Analogs

Somatostatin Dose Escalation

• No official dose-finding studies have been

performed

• There may be a value in dose escalation in

indolent tumors

• Those with carcinoid syndrome may also

benefit from dose escalation

• The NETTER-1 trial included a double dose

octreotide (60 mg)

CLARINET FORTE Trial Design

Primary Endpoint: Median PFS

Secondary Endpoints: TTP, OS, ORR, DCR, best overall response, median duration

of SD, total number of stools and flushing episodes, change in QOL from baseline,

change in tumor biomarker concentrations from baseline

120 mg lanreotide

every 14 days

NETs grade 1 or 2,

metastatic or locally

advanced

unresectable

pancreatic or

intestinal

neuroendocrine tumor

progressing on

standard dose of

lanreotide

US National Institutes of Health. https://clinicaltrials.gov/ct2/show/NCT02651987. Accessed November 1, 2016.

RADIANT-2 Study Design

Multiphasic CT or MRI performed every 12 weeks

Everolimus 10 mg/d +

Octreotide LAR 30 mg/28

days

n = 216

Placebo +

Octreotide LAR 30 mg/28

days

n = 213

Treatment

until

disease

progression

R

A

N

D

O

M

I

Z

E

Patients with

advanced NET

and a history of

symptoms

attributed to

carcinoid

syndrome,

N = 429

1:1

Crossover

Primary endpoint:• PFS (RECIST)

Secondary endpoints:• Tumor response, OS, biomarkers, safety, PK

Enrollment January 2007 - March 2008

Phase III, Double-Blind, Placebo-Controlled Trial

OS, overall survival; PK, pharmacokinetics

Pavel ME, et al. Lancet. 2011;378(9808):2005-2012.

RADIANT-2: PFS by Central Review*

Time, MonthsNo. of patients still at riskE + OP + O

216

213

202

202

167

155

129

117120

106

102

84

81

72

69

65

63

57

56

50

50

42

42

35

33

24

22

18

17

11

11

9

4

3

1

1

1

0

0

0

* Independent adjudicated central review committee

• P-value is obtained from the one-sided log rank test

• Hazard ratio is obtained from unadjusted Cox model

E + O = Everolimus + Octreotide LAR

P + O = Placebo + Octreotide LAR

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Perc

en

tag

e E

ven

t-F

ree

Kaplan-Meier median PFS

Everolimus + Octreotide LAR: 16.4 months

Placebo + Octreotide LAR: 11.3 months

Hazard ratio = 0.77; 95% CI [0.59 -1.00]

P value = .026

Total events = 223

Censoring times

E + O (n/N = 103/216)

P + O (n/N = 120/213)

Pavel ME, et al. Lancet. 2011;378(9808):2005-2012.

RADIANT-4: Study Design

*Two strata: Stratum A appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary

Stratum B lung, stomach, rectum, and colon except cecum

Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary

analysis.

Endpoints:

• Primary: PFS (central)

• Key Secondary: OS

• Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK

Everolimus 10 mg/day

N = 205Treated until

centrally

confirmed

PD or

intolerable

toxicity

Patients with advanced,

progressive, nonfunctional

NET of lung or GI origin

(N = 302)

• Absence of active

symptoms or any history of

carcinoid syndrome

• Pathologically confirmed

advanced disease

• Radiologic disease

progression in ≤6 months

2:1

R

A

N

D

O

M

I

Z

E

Placebo

N = 97

Stratified by:

• Prior SSA treatment (yes vs no)

• Tumor origin (stratum A vs B)*

• WHO PS (0 vs 1)

Yao JC, et al. Lancet. 2016;387(10022):968-977.

0 2 4 6 8 10 12 15 18 21 24 27 30

Months

0

10

20

30

40

50

60

70

80

90

100

Pro

ba

bil

ity o

f P

rog

res

sio

n-F

ree

Su

rviv

al

(%) Kaplan-Meier median PFS

Everolimus: 11.0 months (95% CI, 9.2-13.3)

Placebo: 3.9 months (95% CI, 3.6-7.4)

HR = 0.48 (95% CI, 0.35-0.67); P<.00001

Censoring times

Everolimus (n/N = 113/205)

Placebo (n/N = 65/97)


RADIANT-4: Everolimus for Advanced Neuroendocrine Tumors of the Lung or GI Tract:

Centrally Confirmed PFS

RADIANT-4: Everolimus for Advanced Neuroendocrine Tumors of the Lung or GI-Tract:

Investigator-Assessed PFS

P value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.

205 171 148 132 108 93 75 59 33 15 5 0

97 70 47 35 27 25 21 19 10 6 4 0Placebo

Everolimus

Months

0

10

20

30

40

50

60

70

80

90

100

Pro

ba

bil

ity o

f P

rog

res

sio

n-F

ree

Su

rviv

al,

%

No. of patients still at risk

Kaplan-Meier median PFS

Everolimus: 14.0 months (95% CI, 11.24-17.71)

Placebo: 5.5 months (95% CI, 3.71-7.39)

HR = 0.39 (95% CI, 0.28-0.54); P<.00001

Censoring times

Everolimus (n/N = 98/205)

Placebo (n/N = 70/97)

2 4 6 8 10 12 15 18 21 24 270 30

0

0


RADIANT-4: PFS HR by Stratification FactorsCentral Review

Hazard ratio obtained from unstratified Cox model.

SSA, somatostatin analogs; WHO PS, World Health Organization performance status

Prior SSA treatment

Yes

No

Tumor origin*

Midgut

Non midgut

WHO PS

0

1

157

145

153

149

216

86

Hazard Ratio (95% CI)No.Subgroups

0.52 (0.34-0.81)

0.60 (0.30-0.94)

0.63 (0.40-1.02)

0.43 (0.28-0.66)

0.58 (0.41-0.84)

0.50 (0.28-0.91)

0.1 0.4 1 10

Everolimus Better Placebo Better

*Based on prognostic level, grouped as:

Stratum A (better prognosis) - appendix,

cecum, jejunum, ileum, duodenum, and NET of

unknown primary)

Stratum B (worse prognosis) - lung, stomach,

rectum, and colon except cecum)


RADIANT-4: Activity in Less Favorable Subgroups

None

≤10%

>10%-25%

>25%

Hazard Ratio (95% CI)

Liver Tumor Burden

48

180

37

35

No.

0.49 (0.20-1.20)

0.67 (0.45-1.00)

0.62 (0.20-1.93)

0.18 (0.06-0.50)

0.1 0.4 1 10

Everolimus Better Placebo Better

Grade 1

Grade 2

194

107

0.57 (0.39-0.84)

0.49 (0.29-0.83)

Treatment naïve*

Yes

No

117

185

0.65 (0.39-1.08)

0.51 (0.35-0.76)

Prior chemotherapy

Yes

No

Baseline CgA

>2xULN

≤2xULN

77

225

139

138

0.35 (0.19-0.64)

0.60 (0.42-0.86)

0.40 (0.25-0.62)

0.70 (0.45-1.11)

Tumor grading


RADIANT-4: Adverse Events

Presented are drug-related adverse events in ≥15% of patients (safety set)

*Includes stomatitis, aphthous stomatitis, mouth ulceration, and tongue ulceration†Includes all infections‡Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis

Everolimus

N = 202

Placebo

N = 98

Drug-related adverse events All grades Grade 3/4 All grades Grade 3/4

Stomatitis* 63% 9% 19% 0

Diarrhea 31% 7% 16% 2%

Fatigue 31% 3% 24% 1%

Infections† 29% 7% 4% 0

Rash 27% 1% 8% 0

Peripheral edema 26% 2% 4% 1%

Nausea 17% 1% 10% 0

Anemia 16% 4% 2% 1%

Decreased appetite 16% 1% 6% 0

Asthenia 16% 1% 5% 0

Noninfectious pneumonitis‡ 16% 1% 1% 0

Dysgeusia 15% 1% 4% 0


RADIANT-4 QoL: Time to Definitive Deterioration ≥7 Points on the FACT-G Total Score

Pavel M, et al. J Clin Oncol. 2016;34(suppl): Abstract e15657

Midgut NET: NETTER-1Phase III Study of 177Lu-Dotatate + Octreotide vs High-Dose

Octreotide

Strosberg J et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6.

Midgut NET

Octreoscan

positive

Progression

within 3

years

n = 115

Dose 1

n = 115

Treatment and assessments

Tumor burden assessment (RECIST criteria) every 12 weeks

5 years

of

follow-

up

Dose 2 Dose 3 Dose 4

4 administrations of 7.4 GBq of 177Lu-Dotatate

every 8 weeks + octreotide 30 mg

Octreotide LAR 60 mg every 4 weeks

N = 229 (ITT)

Number of events: 90 177Lu-Dotatate: 23

Octreotide 60 mg LAR: 67

NETTER-1: PFS

HR 0.209; 95% CI: 0.129-0.338

P<.0001

Octreotide LAR 60 mg

Median PFS: 8.4 months

177Lu-Dotatate

Median PFS: Not reached

0 5 10 15 20 25 30

1.0

0.8

0.6

0.4

0.2

0


NETTER-1: Objective Response Rate

177-Lu-Dotatate

(n = 101)

Sandostatin LAR

60 mg (n = 100)

Complete response (n) 1 0

Partial response (n) 17 3

Objective response rate 18% 3%

Confidence interval (95%) 10%-25% 0%-6%

Statistical significance P = .0008

All patients (n = 116) (n = 113)

Progressive disease 5 (4%) 27 (24%)

Stable disease 77 (66%) 70 (62%)


NETTER-1: Most Common Adverse Events177Lu-Dotatate + 30 mg OCT

LAR

(n = 111)

60 mg OCT LAR

(n = 110)

All Grades Grade 3-4 All Grades Grade 3-4

Nausea 59% 4% 12% 2%

Vomiting 47% 7% 10% 0%

Fatigue/asthenia 40% 2% 25% 2%

Diarrhea 29% 3% 19% 2%

Musculoskeletal pain 29% 2% 20% 1%

Abdominal pain 26% 3% 26% 5%

Thrombocytopenia 25% 2% 1% 0%

Lymphopenia 18% 9% 2% 0%

Decreased appetite 18% 0% 8% 3%

Strosberg JR, et al. J Clin Oncol. 2016;34(suppl 3): Abstract 194.

Sunitinib Phase III: PFS by Investigator Review

Median PFS

Sunitinib 11.4 months (95% CI 7.4, 19.8)

Placebo 5.5 months (95% CI 3.6, 7.4)

HR = 0.42 (95% CI 0.26, 0.66)

P<.001

86 39 19 4 0 0

85 28 7 2 1 0

Number at risk

Sunitinib

Placebo

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n o

f P

ati

en

ts

0 5 10 15 20 25Time, Months

Events

Sunitinib 30/86

Placebo 51/85

Raymond E, et al. N Engl J Med. 2011;364(6):501-513. Blumenthal GM, et al. Oncologist. 2012;17(8):1108-1113.

Phase III Trial: Sunitinib vs Placebo in pNET

Raymond E, et al. N Engl J Med. 2011;364:501-513.

Event Sunitinib (n = 83) Placebo (n = 82)

All grades Grade 1 or 2 Grade 3 or 4 All grades Grade 1 or 2 Grade 3 or 4

Number of patients (%)

Diarrhea 49 (59) 45 (54) 4 (5) 32 (39) 30 (37) 2 (2)

Nausea 37 (45) 36 (43) 1 (1) 24 (29) 23 (28) 1 (1)

Asthenia 28 (34) 24 (29) 4 (5) 22 (27) 19 (23) 3 (4)

Vomiting 28 (34) 28 (34) 0 25 (30) 23 (28) 2 (2)

Fatigue 27 (32) 23 (28) 4 (5) 22 (27) 15 (18) 7 (8)

Hair-color changes 24 (29) 23 (28) 1 (1) 1 (1) 1 (1) 0

Neutropenia 24 (29) 14 (17) 10 (12) 3 (4) 3 (4) 0

Abdominal pain 23 (28) 19 (23) 4 (5) 26 (32) 18 (22) 8 (10)

Hypertension 22 (26) 14 (17) 8 (10) 4 (5) 3 (4) 1 (1)

Palmar-plantar

erythrodysesthesia19 (23) 14 (17) 5 (6) 2 (2) 2 (2) 0

Anorexia 18 (22) 16 (19) 2 (2) 17 (21) 16 (20) 1 (1)

Stomatitis 18 (22) 15 (18) 3 (4) 2 (2) 2 (2) 0

TELESTAR: Phase III Study Design

*Including a blinded titration step of one week of 250 mg TID

BM, bowel movement; TID, three times daily

Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELESTAR: Inclusion/Exclusion Criteria

Key Inclusion Criteria

• Well-differentiated metastatic NET

• Documented carcinoid syndrome with ≥4 BMs/day

• Currently receiving stable-dose (≥3 months) SSA therapy

• Minimum SSA dose:

Octreotide LAR 30 mg or lanreotide depot 120 mg, every 4 weeks

• Higher dose/frequency allowed

Key Exclusion Criteria

• >12 BMs/day

• Evidence of Clostridium difficile or other enteric infection

• Previous tumor-directed therapy (≤4 weeks prior to screening)

• History of short bowel syndrome


TELESTAR: Reduction in Daily BM Frequency Averaged Over Double-Blind Treatment Phase

Hodges-Lehman estimator of treatment differences estimated a reduction

versus placebo of

• -0.81 BMs daily for telotristat etiprate 250 mg dose (P<.001)

• -0.69 for telotristat etiprate 500 mg dose (P<.001)Kulke MH, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 37LBA.

TELESTAR: Reduction in Mean Daily BM Frequency at Baseline and Week 12

All patients continue SSA therapy throughout study period. Data included only

patients for whom both baseline and week 12 assessments were available.


TELESTAR: Mean Absolute Change in Urinary 5-HIAA (mg/24 h) From Baseline to Week 12

All patients continue SSA therapy throughout study period. Data included only patients for whom both baseline and week 12 assessments were available.

• Wilcoxon rank-sum test showed significant differences for each telotristat etiprate dose vs placebo (P<.001)


TELESTAR: Adverse Events (AEs) of Interest

• Events of depression and nausea were mild or moderate and did not lead

to treatment discontinuation

Category, n (%)

Placeboa

(n = 45)

Telotristat

Etipratea

250 mg (n = 45)

Telotristat

Etipratea

50 mg (n = 45) Total

Nausea 5 (11.1) 6 (13.3) 13 (28.9) 24 (17.8)

Severe nausea 1 (2.2) 1 (2.2) 0 2 (1.5)

Discontinuation due to nausea 1 (2.2) 0 0 1 (0.7)

Depression 3 (6.7) 1 (2.2) 6 (17.7)) 10 (7.4)

Depressed mood 0 1 (2.2) 2 (4.4) 3 (2.2)

Severe depression or

depressed mood0 0 0 0

Discontinuation due to

depression or depressed mood0 0 0 0

aAll patients continue SSA therapy throughout study period


TELECAST: A Phase III Companion Trial to TELESTAR

250 mg telotristat

etiprate TID (n = 25)

500 mg telotristat

etiprate TID (n = 25)

Placebo TID (n = 26)

R

A

N

D

O

M

I

Z

E

N = 76

Treated

with SSA

with <4

BM/day or

not treated

with SSA

Primary endpoint: Safety and percentage change from baseline in urinary 5-HIAA

Secondary endpoint: change from baseline in number of bowel movements, stool consistency, number of cutaneous flushing episodes, abdominal pain, and change in the frequency of rescue short-acting, somatostatin analog used to treat carcinoid syndrome symptoms

Pavel M, et al. Presented at: North American Neuroendocrine Tumor Society (NANETS); October 1, 2016;

Jackson, Wyoming. Abstract C8.

TELECAST ResultsPlacebo Treatment

Treatment description Placebo Telotristat

etiprate 250 mg

P value vs

Placebo

Telotristat

etiprate 500 mg

P value vs

Placebo

Number of patients 26 25 25

Number of evaluable patients N/A N/A N/A

Placebo-adjusted change in urinary 5-HIAA

from baseline to week 12

(Endpoint = primary)

N/A -54.0%

(P<.001)

-89.7%

(P<.001)

Placebo-adjusted change in daily BM

frequency from baseline to week 12

(Endpoint = secondary)

N/A -0.45 events/day

(P = .004)

-0.54 events/day

(P<.001)

≥30% reduction in BM frequency

for at least 50% of the days

(Endpoint = secondary)

0% 40%

(P = .001)

40%

(P = .001)

Pavel M, et al. Presented at: North American Neuroendocrine Tumor Society (NANETS); October 1, 2016;

Jackson, Wyoming. Abstract C8.

Treatment Landscape for Advanced NETs 2016

*RADIANT-3 requires documentation of progressive disease (PD) in the prior 12 months. RADIANT-4 requires documentation of PD

during prior 6 months.

Rinke A, et al. J Clin Oncol. 2009;27(28):4656-4663. Caplin ME, et al. N Engl J Med. 2014;371(3):224-233. Strosberg

J, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA6. Raymond E, et al. N Engl J Med. 2011;364(6):501-513. Yao

JC, et al. J Clin Oncol. 2008;26(26):4311-4318. Yao JC, et al. N Engl J Med. 364(6):514-523. Yao JC, et al. Lancet.

2016;387(10022):968-977.

Site Octreotide Lanreotide177Lu-

DOTATATEStreptozocin Sunitinib Everolimus

Disease statusTreatment

naïveStable

Progressive

over 3 yearsHistorical

Progressive

over 12

months

Progressive

over 6

months*

Lung RADIANT-4

Stomach CLARINET RADIANT-4

Duodenum CLARINET RADIANT-4

Pancreas CLARINET Historical Phase III RADIANT-3*

Small bowel

AppendixPROMID CLARINET NETTER-1 RADIANT-4

Colon CLARINET RADIANT-4

Rectum CLARINET RADIANT-4

Unknown 1° RADIANT-4

GEP NETs represent a heterogeneous disease with multiple facets and increasing incidence; typical features include high somatostatin receptor expression and relatively slow growth

Careful consideration of primary site, disease extent, histology (grade/Ki67), symptoms, performance status, and functional imaging findings needed to optimize treatment decisions at each point in the disease

Somatostatin analogs are the backbone of systemictreatments

Effective second-line and further line antiproliferative treatments include everolimus, sunitinib, PRRT andtelotistat etiprate (if approved) for symptom control of carcinoid syndrome

Selection of Appropriate Treatment · The Increasing Incidence of NETs Yao JC, et al. J Clin Oncol....

Documents

Transcript of Selection of Appropriate Treatment · The Increasing Incidence of NETs Yao JC, et al. J Clin Oncol....