2016 Capital Area carcinoid Survivors (CACS) Lecture Neuroendocrine Cancer Therapy -

Where are we in 2016?

Edward M. Wolin, M.D. Director, Neuroendocrine Tumor Program

Montefiore Einstein Center for Cancer Care New York, NY

Incidence of GEP-NETs

0

1

2

3

4

5

6

1973

1975

1977

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

2005

2007

2009

2011

SEER 9 1973 - 1991

SEER 13 1992 – 1999

SEER 18 2000 – 2011

YaoJC,HassanM,PhanA,etal,JClinOncol.2008;26:3063-3072

NETPrevalenceintheUnitedStates

YaoJC,HassanM,PhanA,etal,JClinOncol.2008;26:3063-3072

Classification of NET by Site

Carcinoid Tumors

Pancreatic NETs • Insulinoma • Glucagonoma • VIPoma • Pancreatic polypeptidoma

Foregut • Thymus • Esophagus • Lung • Stomach • Duodenum

Midgut • Appendix • Ileum • Cecum • Ascending colon

Hindgut • Distal large bowel • Rectum

GradingofGEP-NET

DIFFERENTIATIONGINETs

Grade NameofNeoplasm

ProliferaDveRate

Well-differenDated

G1,Lowgrade

Neuroendocrinetumor <2mitoses/10hpfAND<3%Ki67index

G2Intermediategrade Neuroendocrinetumor 2-20mitoses/10hpf

OR3-20%Ki67index

Poorly-differenDated

G3Highgrade

Neuroendocrinecarcinoma,smallcelltypeNeuroendocrinecarcinoma,largecelltype

>20mitoses/10hpfOR>20%Ki67index

Bosman,2010.

FuncUonalCarcinoids

PancreaUcNET–FuncUonalvs.Non-FuncUonal

Non-funcDonal

40-90%MayormaynotsecretepancreaDc

polypepDde

FuncDonal

Insulinoma(70%)Glucagonomas(15%)Gastrinomas(5-10%)SomatostaDnomas

(5-10%)VIPomas,ACTH(Rare)

PaUent-ReportedTimeBetweentheFirstSymptomandaDiagnosisofNET

53%required>2yearsforadiagnosisofNETand34%

required>5years

EdwardWolin,etal.DelaysinNeuroendocrineTumorDiagnosis:USResultsFromtheFirstGlobalNETPaUentSurvey.DigesUveDiseaseweek,2015

TotalUSsample(n=758)

8% 18% 36% 34% 59.0

GINETs 8% 15% 37% 36% 61.4

pNETs 6% 21% 40% 29% 53.4

LungNETs 8% 24% 33% 31% 58.2

<6Months

6Months–5Years

≥5Years

NETDiagnosisintheFollowingTimePeriod

Don’tKnow/NA

Mean(months)

DiagnosedataNETSpecialist

Center

9%

8%

14%a

4%

NumberofHCPs/OfficeVisitsPriortoaNETDiagnosis

9

NumberofHCPsinvolvedinaNETdiagnosis

USPa

Dents,%

USPa

Dents,%

8%

15% 16%

13%

10%

15%

8%

4%

11%

1 3 5 10-19 Don't know/can't remember

Mean,5.7HCPs

13%

18%

13%

6% 6% 6%

16%

20%

1-2 5-6 9-10 16+

Mean,12.7visits

NumberofvisitstoHCPstoreceiveaNETdiagnosis

EdwardWolin,etal.DelaysinNeuroendocrineTumorDiagnosis:USResultsFromtheFirstGlobalNETPatientSurvey.DigestiveDiseaseweek,2015

DiagnosesReceivedPriortoaNETDiagnosis•  49%reportedNETwasnottheiniUaldiagnosis;mostiniUallydiagnosed

withanotherGIcondiUon•  38%werediagnosedwithpsychiatriccondiUons,includinganxietyand

psychosomaUcdisease•  78%didnotsuspecttheirsymptomswerecancerrelated

EdwardWolin,etal.DelaysinNeuroendocrineTumorDiagnosis:USResultsFromtheFirstGlobalNETPatientSurvey.DigestiveDiseaseweek,2015

34%

7%

8%

8%

12%

13%

15%

19%

23%

26%

46%

49%

Other

Diabetes

Rosacea

Pneumonia

Psychiatricdisorder

Ulcer

Menopause

Asthma

IBDs(Crohndisease,ulceraUvecoliUs)

Anxiety/psychosomaUc-typecondiUon

GastriUs/otherdigesUvedisorder

IBS

IBSdiagnosis―GINETs(61%)vspNET(40%),lungNETs(18%)(P<0.05)

Asthma/pneumoniadiagnosis―lungNETs(56%/35%)vspNETs(11%/2%),GINETs(11%/2%)(P<0.05)

USPaDents,%

John Godfrey Saxe One of the most famous versions of the 19th century was the poem "The Blind Men and the Elephant" by John Godfrey Saxe (1816–1887).

And so these men of Hindustan Disputed loud and long, Each in his own opinion Exceeding stiff and strong, Though each was partly in the right And all were in the wrong.

"The Blind Men and the ElephantJohn Godfrey Saxe (1816–1887).

Carcinoid–NeuroendocrineTumorProgramMulUdisciplinaryManagementTeam

MedicalOncology

Endocrinology

RadiaDonOncology

Cardiology

Gastro-enterology

Pathology

IntervenDonalRadiology

DiagnosDcRadiology

NuclearMedicine

Surgery

NETPATIENT

TherapyforNETofProvenEffecUveness

MoertelCGetal.NEnglJMed1980;Moerteletal.NEnglJMed1992;RinkeAetalJCO2009;YaoJCetalNEJM2011;RaymondEetalNEJM2011;CaplanMetalNEJM2014;

YaoJCLancet2016;NETTER-1ESMO2015

SuniUnibinprogressive

PNETSU011248

2011Streptozocin-basedchemoprogressive

PNET1980,1992

OctreoUdeLARinmidgutNET(Ki67<2%)PROMID2009

Everolimusinprogressive

PNETRADIANT-3

2011

LanreoUdeDepotinGEP-andCUP-NET

(Ki67<10%)CLARINET2014

PRRTinprogressivemidgutNETNETTER-12015

Everolimusin

progressivemidgut&lungNETRADIANT-4

2015

1980s 2010s 2015-2016

What is Somatostatin?

•  Somatostatin (SST) is a peptide hormone.

•  It stops NET hormone production and cell division of NET cells.

•  The action of somatostatin occurs after it adheres to the somatostatin receptors (SSTR) on the cell membrane.

•  Very short-acting, with a 2-3 minute half-life.

SomatostaUnAnalogs

•  ala gly cys lys asn phe phe

cys ser thr phe thr

lys

trp

Dphe cys phe

cys thr

thr

lys

Dtrp

Human somatostatin

Octreotide

Lanreotide AminoacidsessenDalforreceptorbinding

Halflife:3minutes Halflife:90minutes

Dβnal cys tyr

cys val

lys

Dtrp

Derived from Pavel, ESMO 2014

AE PercentageDiarrhea 37.3%

Steatorrhoea 39.3%

Flatulence 28.1%PainatinjecDon

site 28.1%

Gallstones 17.9%

Emesis 11.5%

Hyperglycaemia 10.8%

Bradycardia 4.3%

CholangiDs 4.3%

SepDcemia <1%

TolerabilityofSomatostaUnAnalogs

§  Mostsideeffectsaretransient§  30yearsofexperience§  Verygoodlong-termtolerability

PROMID:PhaseIIIStudyofOctreoUdeLARinAdvancedMidgutNeuroendocrineTumors

R

OctreoDdeLAR30mgIMQ4weeks

PlaceboIMQ4weeks

Rinkeetal,JCO,27:4656-3663,2009

N=85

WelldifferenUatedmidgutNETs

PROMID: PFS Treatment Naïve Midgut NETs

0"

0.25"

0.5"

0.75"

1"

0" 6" 12" 18" 24" 30" 36" 42" 48" 54" 60" 66" 72" 78" 84" 90"

HR="0.33"[95%"CI:"0.19–0.55]"P=0.000017"

Prop

or;o

n"with

out"p

rogressio

n"

Time"(months)"

Octreo;de"LAR:"42"pa;ents"/"27"events""Median"15.6"months"[95%"CI:"11.0–29.4]""

"Placebo:"43""pa;ents"/"41"events""Median"5.9"months"[95%"CI:"5.5–9.1]"

Rinke et al, JCO 2009

Placebo-ControlledstudyofLanreoDdeAnDproliferaDveResponseInpaDentswithenteropancreaDcNeuroEndocrineTumors

GEP-NETs,gastroenteropancreaDcneuroendocrinetumors;SC,subcutaneous.CaplinME,etal.NEnglJMed.2014;371(3):224-233.

1:112-24weeks

1 12 24 36 48 72 96(baseline) Studyvisits

(weeks)

Scan1 Scan2

LanreoUdeDepotSC120mgq28days

PlaceboSCq28days

Studydesign: Phase3,96-week,randomized,double-blind,placebo-controlled,mulUcenterstudy(14countries:theUS,India,and12Europeancountries)

PopulaDon: N=204adultswithwell-ormoderatelydifferenUated,metastaUc,and/orlocallyadvancedunresectableGEP-NETs,andKi-67<10%

Treatments: LanreoUdeDepot120mg(fixeddose)vsplaceboevery28days

CLARINET:PrimaryEfficacyEndpoint(PFS)

DataarefromtheITTpopulaUon.P-valuederivedfromstraUfiedlog-ranktest;HRderivedfromCoxproporUonalhazardsmodel.HR,hazardraUo;ITT,intenUontotreat;PBO,placebo;PD,progressivedisease;PFS,progression-freesurvival.CaplinME,etal.NEnglJMed.2014;371(3):224-233.

LanreoDde32events,101paDentsMedianPFSnotreached

Placebo60events,103paDentsMedianPFS=18.0months[95%CI:12.1,24.0]

0 3 6 9 12 18 24 270

10

20

30

40

50

60

70

80

90

100Pa

Dentsa

livean

dwith

noprogression(%

)

Time(months)

62%

22%

LanreoDde120mgvs.PBOP<0.001HR=0.47[95%CI:0.30,0.73]

Progression-freesurvival(ITTpopulaDon*)

101 94 84 78 71 61

103 101 87 76 59 43

40

NumbersofpaDentsatriskofdeathorPD

26 0

0

SummaryofCLARINET

GEP-NETs,gastroenteropancreaUcneuroendocrinetumors;NETs,neuroendocrinetumors;PFS,progression-freesurvival;SSA,somatostaUnanalog.CaplinME,etal.NEnglJMed.2014;371(3):224-233.

u  CLARINETisthefirstPhase3tumorcontroltrialofasomatostaUnanalogwhichincludedalltypesofGEP-NET

u  ProlongaDonofPFSwassignificant,whetherGEP-NETwerewell-ormoderatelydifferenUated,whethermetastaUcorlocallyadvanced,andwhetherhighorlowlivertumorburden

u  LanreoDdereducedriskoftumorprogressionordeathby53%.

u  PFSwas>96-weeksforlanreoUdevs18monthsforplacebou  HazardraUofavoredlanreoUdeinmidgutandpancreaUcNETu  Qualityoflifenotsignificantlydifferentorimpairedby

lanreoUde.u  Overallsurvivalnotdifferentbetweengroups

ELECTPhase3TrialMetPrimaryEndpoint

•  ELECT®metitsprimaryendpoint

•  AgreaterproporUonofpaUentsinthelanreoUde®armexperiencedacompleteresponse(40.7%vs.23.2%,respecUvely)

•  Resultslargelyconsistentacrosssubgroups

ELECT:AphaseIIIrandomizeddouble-blindplacebo-controlledmulUnaUonalstudyofefficacyandsafetyoflanreoUdetreatmentforcarcinoidsyndromein115paUentswithneuroendocrinetumors(NETs)

SYMNET:PrimaryEndpoint(SaUsfacUonwithDiarrheaControl)

RuszniewskiP,etal.PosterpresentedatENETS.March5-7,2014;Barcelona,Spain.

76%“Completely”or“Rather”SaDsfied

PaDents’SaDsfacDonwithControlofDiarrheaDuringLanreoDdeDepot

Treatment(N=268)

SYMNET:OtherEndpoints(GISymptoms)

RuszniewskiP,etal.PosterpresentedatENETS.March5-7,2014;Barcelona,Spain.

4.4 3.92.3

38.8

15.3

25.2

0

5

10

15

20

25

30

35

40

45

50

Stool urgency (n=227) Stool leakage (n=255) Associated pain (n=258)

Perc

enta

ge o

f patie

nts

Absent before treatment but present afterPresent before treatment but absent afterP<0.001

P<0.001

P<0.001

ChangesinStoolUrgency,StoolLeakage,andDiarrhea-AssociatedPainPost-LanreoDde

Treatment

LanreoDdeinLungNET:SPINETStudyDesign

•  ObjecDve:DetermineeffecUvenessoflanreoUdeincontrollingNETarisinginlung.

•  Studydesign:Phase3TrialoflanreoUde120mgSQevery28daysvsplacebo*2:1randomizaUoninfavoroflanreoUde.

•  *Cross-overforplaceboarmifprogressionoccurs.•  PopulaDon:N=216adultswithlocallyadvancedormetastaUc

lungcarcinoid(typicaloratypicalcarcinoid)•  Keyeligibilitycriteria:

–  MusthavemeasurabletumoronCTorMRI–  MusthaveposiUveoctreoscanorGa-68PET–  MustnothavebeenpreviouslytreatedwithOctreoUdeorlanteoUde

SOM230–C2303 Pasireotide vs. Octreotide

0 3 6 9 12 Time, months

15 21 27

Sur

viva

l Pro

babi

lity

0.0

0.2

0.4

0.6

0.8

1.0

Octreotide n/N = 20/56 Pasireotide n/N = 18/52 Censored

Kaplan-Meier median PFS Pasireotide: 11.8 months, 95% CI [11.0–not reached] Octreotide: 6.8 months, 95% CI [5.6–not reached] Hazard ratio = 0.46, 95% CI [0.20–0.98]

Total events = 38

26

P = 0.045 (log-rank test)

Wolin et. al., A multicenter, randomized, blinded, phase III study of pasireotide LAR versus octreotide LAR in patients with metastatic neuroendocrine tumors (NET) with disease-relatedsymptoms inadequately controlled by somatostatin analogs. J Clin Oncol 31, 2013 (suppl; abstr 4031)

Schematic Representation of a Drug for Imaging and Targeted Therapy

Molecular Address •  Antibodies, minibodies,

Affibodies, SHALs, Aptamers

• Regulatory peptides and analogs thereof

•  Amino Acids

Target •  Antigens

(e.g. CD20, HER2)

•  GPCRs •  Transporters

Reporting Unit •  99mTc, 111In, 67Ga

•  64Cu, 68Ga •  Gd3+

Cytotoxic Unit •  90Y, 177Lu, 213Bi •  105Rh, 67Cu, 186,188Re

Courtesy Helmut Mäcke (modified)

Targeted Molecular Imaging and Therapy The Key-Lock Principle

Lock Key 68Ga, 90Y, 177Lu

pharmacokineDc/biodistribuDonmodifier

ChelatorLinkerLigandTarget

A brief overview of 177Lu-DOTATATE

•  177Lu-DOTATATE belongs to an innovative drug category called PRRT (Peptide Receptor Radionuclide Therapy). PRRT involves the systemic administration of a specific radiopharmaceutical to deliver cytotoxic radiation to a tumor.

•  177Lu-DOTATATE is composed of a lutetium radionuclide chelated to a peptide. Lutetium emits high energy electrons (therapy) and gamma rays (imaging).

•  The peptide is designed to target somatostatin receptors with a high binding affinity.

The affinity for SSTRs and the specificity of binding enables a high level of specificity in the delivery of radiation to the tumor

29

Lutathera®Mechanism of Action

30

Intravenous injection

Concentration into neuroendocrine tumor (NET) sites

Lutathera binds to somatostatin receptors type 2 (sstr2) overexpressed by NETs

Lutathera is internalized in the NET cell

Lutathera delivers radiation within the cancer cell

Radiation induces DNA strand breaks causing tumor cell death

31PresentaUonPresidenUalSessionIIofthe18thECCO–40thESMO–EuropeanCancerCongress2015,27September2015,abstract6LBA,Vienna

Aim

Design InternaUonal,mulUcenter,randomized,comparator-controlled,parallel-group

Evaluatetheefficacyandsafetyof177Lu-Dotatate+SSAs(symptomscontrol)comparedtoOctreoUdeLAR60mg(off-labeluse)1inpaUentswithinoperable,somatostaUnreceptorposiUve,midgutNET,progressiveunderOctreoUdeLAR30mg(labeluse)

Baselineand

RandomizaUon

n=115

Dose1

n=115

TreatmentandAssessmentsProgressionfreesurvival(Recistcriteria)every12weeks

5Yearsfollowup

Dose2Dose3Dose4

NETTER-1StudyObjecDvesandDesign

4administraUonsof7.4GBqof177Lu-Dotatateevery8weeks+SSAs(symptomscontrol)

OctreoUdeLAR(highdose-60mgevery4weeks1)

Progression-Free Survival

32 Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna

Hazard Ratio [95% CI] 0.209 [0.129 – 0.338] p < 0.0001

N = 229 (ITT) Number of events: 90

•  177Lu-Dotatate: 23 •  Oct 60 mg LAR:

67

All progressions centrally confirmed and independently reviewed for eligibility (SAP)

Octreotide LAR 60 mg Median PFS: 8.4 months

177Lu-Dotatate Median PFS: Not reached

Overall Survival (interim analysis)

33 Presentation Presidential Session II of the 18th ECCO – 40th ESMO – European Cancer Congress 2015, 27 September 2015, abstract 6LBA, Vienna

N = 229 (ITT) Number of deaths: 35

•  177Lu-Dotatate: 13 •  Octreotide 60 mg LAR: 22

P < 0.0186

0.5

Inclusion Criteria Expanded Access

1. Presence of metastatic or locally advanced, inoperable (curative intent) midgut carcinoid tumor. 2. Ki-67 index < 20%. 3. Patients progressive on SSA (any dose) at the time of enrollment Recist NOT required) 4. Patients > 18 years of age. 5. Target lesions overexpressing somatostatin receptors according to an appropriate imaging method (e.g. 111In-pentetreotide (Octreoscan) imaging or 68Ga-DOTA0-Tyr3-Octreotate imaging) (Bodei et al., 2014).

PepUdesandReceptorsinImage-GuidedTherapy:TheranosUcsofNeuroendocrineNeoplasms

R.Baumetal.SeminNucl.Med42:190-207(2012)

Importance of 18F-FDG PET/CTThe role of 18F-FDG PET/CT in the assessment of response totherapy is limited, primarily because NENs are slow-growingtumors and glucose metabolism does not necessarily increasein slow-growing, well-differentiated tumors. In addition, nodefinitive therapy exists that influences the metabolism di-rectly enough to be assessed by 18F-FDG. It has been postu-lated that18F-FDG PET should be performed only if SSTRimaging is negative.56 The main use of 18F-FDG PET in diag-nosis of NEN depends on the grade of differentiation and/oraggressiveness of NEN and has been proposed for compre-hensive tumor assessment in intermediate- and high-gradetumors (Fig. 8).45,57 Intense metabolic activity, reflected on18F-FDG PET scans, can still be an important prognostic in-dicator, being related to an outgrowth of aggressive tumorclones, suggesting a poor prognosis. However, functional im-aging with both 68Ga-DOTATATE and 18F-FDG has shown toaddress different biological properties of the neuroendocrinetumor lesions in patients planned for PRRNT.57

In a preliminary study at Zentralklinik Bad Berka, we se-lected 25 subjects at random from a group of 505 patientswith metastasized NEN who were scheduled for treatmentwith PRRNT (138 lesions) and compared pre- and posttreat-ment images acquired using 68Ga-DOTANOC PET/CT (mo-lecular response), 18F-FDG PET/CT (metabolic response),

and contrast-enhanced CT (morphological response).58 A re-sponse index was calculated for each lesion from PET imagesbased on the pre- and posttreatment SUVmax. RECIST criteriawere applied to the contrast-enhanced CT data. All lesionswere categorized as partial responders, stable disease, or PD.No correlation was observed between any of the 3 modalities;for example, 68Ga-DOTANOC PET classified 70.6% of thelesions as partial responders, whereas FDG-PET put 43.8%into this category, and CT, just 17.6%. The sensitivity andspecificity of 68Ga-DOTANOC PET to predict response toradiopeptide therapy were calculated as 89% and 71%, re-spectively. 68Ga-DOTANOC PET/CT was found to be supe-rior to 18F-FDG PET/CT and morphological imaging for earlyand better prediction of response to PRRNT. Furthermore, amatching pattern between receptor expression and glucosemetabolism was observed to increase with the grade of NEN;therefore, in high-grade NENs, a concurrence between thechanges in glucose metabolism and SSTR expression, ie, on18F-FDG PET/CT and 68Ga-DOTANOC PET/CT, respec-tively, after PRRNT was noticed. Also, higher tumor remis-sion rate was correlated with a high baseline SUVmax on SSTRPET/CT. This finding is consistent with previous studies, andPRRNT was confirmed to be an effective therapy option forNEN patients expressing adequate densities of SSTRs on thetumors.21 In another recent study, 68Ga-DOTATATE PET/CT

Figure 7 Molecular response as demonstrated by receptor PET/CT using the SMS analog 68Ga-DOTANOC in a patientwith liver metastases of a NEN before and after the first and second cycle of peptide receptor radionuclide therapy(PRRNT); relapse in the liver (after complete remission as shown by CT and PET) is first detected by SMS-receptorimaging (molecular response precedes morphology).

Peptides and receptors in image-guided therapy 199

AddedValueof68Ga-DOTATATEPET/CT

Mojtahedi A, Am J Nucl Med Mol Imaging 2014;4(5):426-434

Impactof68Ga-DOTATATEPET/CT

•  100consecuUveptsscanned,andreferringphysicianscompleted88pre-andpost-scanquesUonnaires(88%).

•  Intendedmanagementchangedin53of88(60%)ofpts.•  23%scheduledtoundergochemotherapyswitchedtotreatmentswithoutchemotherapy.

•  7%switchedfromwatch-and-waittoothertreatment.•  6%switchedfromtreatmentstrategytowatch-and-wait.

KenHerrmann,JohannesCzernin,EdwardM.Wolin,etal.Impactof68Ga-DOTATATEPET/CTontheManagementofNeuroendocrineTumors:TheReferringPhysician’sPerspecUve.JNuclMed2015;56:70–75.

RADIANT-3StudyDesign

Everolimus 10 mg/d + best supportive care*

n = 207

Placebo + best supportive care*

n = 203

Multi-phasic CT or MRI performed every 12 weeks

Treatment until disease progression

Patients with advanced pNET, N = 410 Stratified by: •  WHO PS •  Prior

Chemotherapy

Crossover

1:1

Concurrent somatostatin analogs allowed

RANDOMI ZE

Primary endpoint: •  PFS (RECIST)

Secondary endpoints: •  Response, OS, biomarkers, safety, and PK

Randomization August 2007 - May 2009

Phase III Double Blind Placebo Controlled Trial

RADIANT-3PFSbyCentralReview*

* Independent adjudicated central review committee •  P-value obtained from stratified one-sided log rank test •  Hazard ratio is obtained from stratified unadjusted Cox model

Kaplan-Meier medians PFS Everolimus: 11.4 months Placebo: 5.4 months

Hazard ratio = 0.34; 95% CI [0.26-0.44] P-value: <0.0001

No. of patients still at risk Everolimus Placebo

207 203

187 180

152 99

126 60

117 52

81 22

49 12

36 5

27 3

22 1

10 1

6 1

2 0

0 0

Time (months)

100

80

Per

cent

age

even

t-fre

e

Censoring Times Everolimus (n/N = 95/207) Placebo (n/N = 142/203)

60

40

20

0 0 2 4 6 8 10 12 14 16 18 20 22 24 26

RADIANT-4 Study Design

*Based on prognostic level, grouped as: Stratum A (better prognosis) - appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worst prognosis) - lung, stomach, rectum, and colon except caecum. 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=205

Treated until PD, intolerable AE, or

consent withdrawal

Patients with well-differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N=302) • Absence of active or any

history of carcinoid syndrome

• Pathologically confirmed advanced disease

• Radiologic disease progression in ≤ 6 months

2:1

RANDOMI ZE

Placebo N=97

Stratified by: •  Prior SSA treatment (yes vs. no) •  Tumor origin (stratum A vs. B)* •  WHO PS (0 vs. 1)

RADIANT-4 Primary Endpoint: PFS by Central Radiology Review

52% reduction in the relative risk of progression or death with everolimus vs placebo

HR = 0.48 (95% CI, 0.35-0.67); P < 0.00001

P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model. CI, confidence interval; HR, hazard ratio.

205 168 145 124 101 81 65 52 26 1 0 3 0 0 97 65 39 30 24 21 17 15 11 6 5 1 0 Placebo

Everolimus

No.of patients still at risk

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

Prob

abili

ty o

f Pro

gres

sion

-free

Sur

viva

l (%

)

Kaplan–Meier medians Everolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43)

Censoring Times Everolimus (n/N = 113/205) Placebo (n/N = 65/97)

DualKinasemTORInhibiDoninCarcinoid

•  CC-223inhibits2enzymes–TORC-1andTORC-2(Everolimus,isaTORC1-selecUveinhibitor.)

Phase1btrialofCC-223in40ptswithwell-differenUatedNET•  SymptomaUcimprovementin92%occurredquicklyandpersisted

duringthetrial.•  Carcinoidsyndromemarkedlyimproved:reducUonofflushing(80%)

andreducUonofbowelmovements(57%).•  ReducUoninFDG-PETglucoseuptake(≥25%SUV)atday15was

observed(57%).•  Longprogression-freesurvivalobserved.

(Wolin,E.etal.Phase1expansionstudyofanoralTORC1/TORC2inhibitor(CC-223)innon-pancreaDcneuroendocrinetumors(NET).NANETS.Oct.4,2013)

RaDonaleforAlpelisib(BYL719)+EverolimusinpNET

•  EverolimusisacUveagainstmTORC1only.•  Lowresponseratetoeverolimusmayreflectthedrug’sinabilitytopreventmTORC2-mediatedacUvaUonofAkt.

•  PI3K/Akt/mTORacUvaUonandreacUvaUoncouldpotenUallybeavoidedthroughtheconcomitantuseofPI3KandmTORinhibitors.

•  Alpelisibandeverolimuseachadministereddailyatthedosefrompreviouslycompleted1atrialinnewtrialopeningatMontefiore.

Wolin,E.PI3K/Akt/mTORPathwayInhibitorsintheTherapyofPancreaUcNeuroendocrineTumors.CancerLev.2013Jul10;335(1):1-8.

Pazopanib (CALGB 81103) study Design Randomized phase II trial in CARCINOID

RANDOMIZE

Pazopanib 800 mg PO qD

No breaks

N≈150 • Progressive, advanced carcinoid tumor

• Functional or non-functional •  Concurrent octreotide OK if PD documented

1°EPPFS

(Centralreview)

Placebo

Option for cross-over at progression

1 cycle=28 days CT scan q 12 wk

Study design

Presented By James Yao at 2015 ASCO Annual Meeting

Conclusion

Presented By James Yao at 2015 ASCO Annual Meeting

CALGB 80701 (Alliance): Schema<br />N=148

Presented By Diane Reidy at 2015 ASCO Annual Meeting

CALGB 80701: Efficacy

Presented By Diane Reidy at 2015 ASCO Annual Meeting

CombinaUon:Biologic+BiologicPhIITemsirolimus+Bevacizumab

Hobdayetal,JCO,33:1551-1556,2015

Advanced,progressiveG1/G2pancreaUc

NETs(n=55)

Temsirolimus25mgIVdays1,8,15,22

Bevacizumab10mg/kgdays1,15

RepeatQ28days

ConfirmedPR

23(41%)

6-monthPFS 79%MedPFS 11.7

mo12-monthPFS

48%

PrimaryEP:RRand6-monthPFS

ChemotherapyOpUonsforGEP-NETs

Regimen TumorType n

TTPorPFS(mo)

OS(mo)

RR(%) Reference

Cytotoxics

Streptozocin/5-FUvs.CarcinoidandpNET

42Not

reportedNot

reported

33

Moertel,1979.Streptozocin/Cyclophosphamide* 47 26

Streptozocin/Doxorubicinvs.

pNET

38 20 26.4 69

Moertel,1992.Streptozocin/5-FUvs. 34 6.9 16.8 45

Chlorozotocin 33 6.9 16.8 30

Temozolomide/Capecitabine pNET 30 18 na 70 Strosberg,

2011.

*RegistraUontrialleadingtoFDAapproval

ArmA: Everolimus Everolimus(10mg,daily) (10mg,daily)ArmB: STZ-5FU STZ-5FU

SequencemTORStudy(SEQTOR)Everolimus-STZ5-FUinProgressivepNET

•  Accrualgoal=180pts•  StudypopulaUon:progressive,metastaUcpNET,1stlineaxerSSA,G1/G2•  PrimaryEP:PFS2;SecondaryEP:OS,RR,biochemicalresponse•  Studyisongoing

Course1 Progression Course2

SlidecourtesyofR.Salazar,,BarcelonaNCT02246127

CytotoxicCombinaUonVersusSingleAgent

AdvancedpancreaUcNETs,

G1/G2n=145

R

Temozolomide+Capecitabine

Temozolomide

ECOG/ACRIN2211(PI:Kunz):randomizedPhaseII

PrimaryendpointPFS

TargetedAgentsinEarlyClinicalTrialsinNETs

Drug Target(s)

BEZ235 Dual PI3K/mTOR

Axitinib Multiple kinases including VEGFR2

Ibrutinib BTK

MK2206 Akt

LEE011 CDK 4/6

Dovitinib FGFR

Pembrolizumab PD-1

Ziv-aflibercept VEGF, PLGF

Entcretinib TRK, ROS1, ALK

Nintadanib VEGFR, FGFR, PDGFR

Cerfilzomib 20S proteosome

TPHCatalyzestheFirstStepofSerotoninSynthesis

5-HIAA(5-HydroxyindoleaceDcacid)

Tryptophan Hydroxylase (TPH)

Tryptophan

Serotonin(5-Hydroxytryptamine,5-HT)

5-Hydroxytryptophan

TelotristatEDprate

TelestarStudyofTelotristat

R

TelotristateDprate500

mgTID*(n=45)

TelotristateDprate250mgTID(n=45)

PlaceboTID(n=45)

3-to4-weekrun-in(n=135)

TelotristateDprate

500mgTID

All patients required to be on SSA at enrollment and continue SSA therapy throughout study period

Evaluation of primary endpoint: Reduction in number of daily BMs from baseline (averaged over 12-

week double-blind treatment phase)

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

57 5-HIAA, 5-hydroxyindoleacetic acid; SSA, somatostatin analog.

11.47

-40.13

-57.73 -60

-50

-40

-30

-20

-10

0

10

20

Placebo Telotristat etiprate 250 mg

Telotristat etiprate 500 mg

Mea

n U

rinar

y 5-

HIA

A C

hang

e fr

om

Bas

elin

e (m

g/24

h)

n=29 n=32 n=31

TelotristatResultsofPhase3Study

•  TelotristatsignificantlyreducedBMfrequencybyanaddiUonal35%inpaUentsalreadytakingsomatostaUnanalogs,from6BM/dayto3.8BM/day.

•  Durableresponseinover40%ofpaUents(definedas>30%reducUoninBMfrequencyfor>50%ofthedouble-blindstudy)

•  UrinaryexcreUonof5-HIAAwasreducedby58%comparingbaselinewithweek12.

Netest.pptx

§ Multi Gene expression assay performed on peripheral blood (liquid biopsy)

§ Developed specifically for neuroendocrine tumors

§ Provides a quantitative score that reflects disease activity

§ Verified and validated across 3,000 clinical samples

The NETest from Wren Laboratories

NETest Accuracy – Limit of Detection Comparison with imaging

Modlinetal.PlosOne2013e63364

LimitofDetecDon=1NETcell/ml

CTScan

10mm3=1,000,000,000cells

NETest

5.5litersofblood

(70kgmale)

NETest = ~125,000 x more sensitive than imagery

StableDisease ProgressiveDisease

p<0.001,HR31.8p<0.01,HR14.6

95% predictive accuracy 92%

NETest and Somatostatin Analog Efficacy

CwiklaJetal.JCEM2015;100:E1437-45

NETest correlates with SSA efficacy