Neuroendocrine TumorsRocío García CarboneroHospital 12 de Octubre, Madrid

Outline1. Epidemiology and prognosis

2. Singularities of NETs

3. Therapeutic aims in advanced disease (G1-G2 tumors)

4. Available treatment options (G1-G2 tumors)

Targeting somatostatin receptors

Targeting angiogenesis

Targeting mTOR

5. Therapeutic algorythms & clinical guidelines

Epidemiology of GEP-NENs

Incidence of NETs continues to grow: 6.98/105h/year(SEER 2012)

64,971 patients diagnosed with NETs from 1973 to 2012 (USA)

Age-adjusted incidence by site

Lung

Pancreas

Small IntestineRectum

Dasari et al, JAMA Oncol 2017

Prognosis by stage, grade and primary tumor site

Median OS for all patients: 112 months Local stage: from > 360 m for appendix to 168 m for small intestine Regional stage: from > 360 m for appendix to 33 m for unknown primary Distant stage: from 70 m for small intestine to 4 m for colon

Dasari et al, JAMA Oncol 2017

RectumAppendixStomachColonSmall intestineLungCecumPancreasLiver

A: Survival by stage B: Survival by grade C: Survival by tumor site

• Overall survival has improved over time, particularly for NETs ofpancreatic or GI origin with advanced disease

Dasari et al, JAMA Oncol 2017

2005-2008

2000-2004

2009-2012

Year of Dx

Prognosis by year of diagnosis

Prevalence of GEP-NETs

2x more prevalent than pancreatic cancer

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

2. Modlin IM, Lye KD, Kidd M. Cancer. 2003;97:934–959.

1,200,000

1,100,000

100,000

0Colorectal1 GEP-NET2 Stomach1 Pancreas1 Oesophagus1 Hepatobiliary1

Prevalence in SEER Database

TAXONOMY OF NENs

1. Oberndorfer (1907)

- Carcinoid vs Carcinoma

2. William & Sandler (1963)

- Embriologic origin: foregut, midgut, hindgut

3. WHO classification (2000/2010/2015)

4. TNM staging- ENETS 2006/2007- AJCC 2007

William & Sandler (1963)

FOREGUT

MIDGUT

HINDGUT

Tumor GradeKi67/MIB-1

WELL DIFFERENTIATED

NEUROENDOCRINE TUMOR

POORLY DIFFERENTIATED

NEUROENDOCRINE CARCINOMA

Clinical Presentation• Median age: 55-60 years• Primary tumor site: 25% lung 50% GI (small intestine, rectum) 6-7% pancreatic 10-15% UK primary

• Tumor grade: ≈ 40% G1 / 20% G3• 30-50% Stage IV at diagnosis (> for pancreatic or G3)• 20-25% Hormonal syndrome• 20% Incidental diagnosis• 5% MEN syndrome

Tumor Hormone SymtomsCarcinoid

Insulinoma

Gastrinoma

Glucagonoma

VIPoma

Somatostatinoma

Serotonin

Insulin

Gastrin

Glucagon

Vasoactive Int. Peptide

Somatostatina

Flushes, diarrea. bronchospasm, carcinoid right heart disease

Hypoglicemia: dizziness, fatigue, confusion, sweats, tremor

Zollinger-Ellison Sd: severe pepticulcer, diarrea

Diabetes, necrolytic migratoryerithema, glositis, thromboembolic disease

Verner-Morrison Sd (WDHA) : watery diarrea, hipokalemia, achloridria

Diabetes, esteatorrea, colelitiasis

Hormone Syndromes of Functional NETs

Localized disease: Surgery

Endoscopic resection (small rectal or gastricNETs)

Advanced disease: Hormonal syndrome control (G1-2 NETs)

Control of tumor proliferation

o G1-2: focus of this presentation

o G3: treat like SCLC

Antiproliferative Therapeutic Options

G1-G2 NETs - Available evidence from RCT:

Somatostatin analogues: “cold” (Octreotide, Lanreotide); “hot” (PRRT)

Targeted therapies: Sunitinib, Everolimus

Chemotherapy: STZ, 5FU, ADR, other..

G3 P-NECs - Available evidence from case series & non-controlled or retrospective studies:

Chemotherapy: CDDP/CBDCA-VP16, TEM-CAP, OX-FP, IRI-FP, IRI-Platinum,…

Singularities of NETs: SSTR• 80-90% of well diff. NETs express Somatostatin Receptors

relevant diagnostic and therapeutic implications

• Their natural ligand is Somatostatin, a physiological neuropeptide involved in the regulation of neurotransmission, GI motility, nutrient and ion

absorption, exocrine and endocrine secretion.

• Somatostatin analogs were developed with a longer half-life to enable clinical use

Modlin et al, Aliment Pharmacol Ther 2010; 31:169

Inhibition of angiogenesis

Modulation of immune system

SMS Mechanism of Action

Antisecretory action Antiproliferative action

Guillermet-Guibert et al, Best Pract Res Clin Gastroenterol 2005.

OCTREOSCAN

• Scintigraphy with radiolabeled somatostatin analogs (SRS) 111In-DTPA-D-Phe1-octreotide (In-111 Pentreotide)

• Imaging technique to detect tumors expressing STS-R

Limitations of Octreoscan

Evaluation of organs with high physiological uptake (liver and gut)

Poor spatial resolution (partially improved with the addition of

SPECT/CT to SRS planar views)

Not all NETs express STS-R (i.e. Insulinomas 50-60%)

Time consuming / irradiation

Benefits of 68Ga-based NET tracers over OctreoScan

Decreased radiation dose (shorter half-life)

Improved image quality (PET vs SPECT)

Decreased biliary excretion

Improved lesion detection

Improved patient convenience

Availability of quantitation

Based on the ITT analysis

67% reduction in the risk of tumour progression HR=0.33; 95% CI: 0.19–0.55; P=0.000017

Time (months)

0

0.25

0.5

0.75

1

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

Prop

ortio

n w

ithou

t pro

gres

sion

Time (months)

Octreotide LAR: 42 pts / 27 eventsMedian 15.6 months [95% CI: 11.0–29.4]

Placebo: 43 patients / 41 eventsMedian 5.9 months [95% CI: 5.5–9.1]

Rinke A et al. J Clin Oncol 2009;27:4656

PROMIDOctreotide LAR vs Placebo in G1 Midgut NETs

Antiproliferative Effect of “cold” SSA in GEP-NETs

CLARINETLanreotide Autogel vs Placebo in GEP-NETs (ki67

22

Pasireotide LAREverolimusPasireotide LAR and everolimus

0.7

1.0

0.9

0.8

0.6

0.2

0.4

KM P

roba

bilit

y of E

vent

0.5

0.3

0.0

0.1

Time (months)6 12 1590 3

No. of patients still at riskPasireotide LAREverolimusCombination

221927

574

000

161725

414241

293030

LUNA TRIAL: PROGRESSION-FREE SURVIVAL

124 pts with advanced WD typical and atypical carcinoids of the LUNG or THYMUS

%PFS at 9 monthsPASIREOTIDE + EVE: 79.2%EVEROLIMUS: 56.9%PASIREOTIDE: 49.6%

Median PFS • 177-Lu: NOT REACHED• Control: 8.4 months

HR=0.21P

In mean, during the study, DIARRHOEA: LUTATHERA: 39% improved / 19% worsened Octreotide LAR: 23% improved / 23% worsened

QOL: Global Health Status/DiarrheaPercentage of patients with at least 10 point changes compared to baseline

In mean, during the study, GLOBAL HEALTH STATUS : LUTATHERA: 28% improved / 18% worsened Octreotide LAR: 15% improved / 26% worsened

EORTC QLQ-G.I.NET21 questionnaire

Other Targeted Agents

Approved by FDA (2017) for use with SSA in patients with

carcinoid syndrome diarrhea not controlled by SSA:

TELOTRISTAT

Approved by FDA/EMA (2016) in GI and Lung NETs:

EVEROLIMUS

Approved by FDA/EMA (2011) for the treatment of PNETs:

SUNITINIB

EVEROLIMUS

Telotristat Etiprate A Tryptophan Hydroxylase (TPH) Inhibitor

• Telotristat etiprate is a novel oral inhibitor of TPH, the rate-limiting enzyme in serotonin biosynthesis1

• Two early-stage clinical studies of telotristat etiprate demonstrated a favorable safety profile and evidence of clinical activity in carcinoid syndrome2,3

• Both preclinical and clinical studies suggested that telotristat etiprate is associated with minimal CNS activity1-3

• Granted Fast Track Status and Orphan Drug Designation4

31

5-HT secretion

Tryptophan

5-HTP

5-HT

5-HT in blood

5-HIAA

5-HIAA filtered by kidney

5-HIAA in urine

Monoamine oxidaseAldehyde dehydrogenase

TPH TelotristatEtiprate

5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, serotonin; 5-HTP, hydroxytryptophan; CNS, central nervous system; TPH, tryptophan hydroxylase.1. Liu Q, Yang Q, Sun W, et al. J Pharmacol Exp Ther 2008; 325:47–55. 2. Kulke MH, O'Dorisio T, Phan A, et al. Endocr Relat Cancer2014;21:705–714. 3. Pavel M, Horsch D, Caplin M, et al. J Clin Endocrinol Metab 2015;100:1511–1519. 4. FDA Orphan Drug Designations. Available at: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index. Accessed September 2015. 5. Kronenberg HM, Melmed S, Polonsky KS, et al. Williams Textbook of Endocrinology, 11th edn. 2008:1823–1824.

Serotonin Synthesis in Carcinoid Tumor Cells

http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index

TELESTARPhase 3 Study Design

32

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

BM, bowel movement; SSA, somatostatin analog; TID, three times daily.ClinicalTrials.gov. NCT01677910 TELESTAR. Available at: https://clinicaltrials.gov/ct2/show/NCT01677910. Accessed September 2015.

Telotristat etiprate 500 mg TID* (n=45)

Telotristat etiprate 250 mg TID (n=45)

Placebo TID (n=45)

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

1:1:13- to 4-

week run-in (n=135)

R

Telotristat etiprate

500 mg TID

Evaluation of primary endpoint:Reduction in number of daily BMs from baseline

(averaged over 12-week double-blind treatment phase)

Run in: Evaluation of

bowel movement

(BM) frequency

https://clinicaltrials.gov/ct2/show/NCT01677910

33

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

BM, bowel movement; SSA, somatostatin analog.

All patients continue SSA therapy throughout study period

Placebo n=45Telotristat etiprate 250 mg n=45Telotristat etiprate 500 mg n=45

• Hodges–Lehmann estimator of treatment differences estimated a reduction versus placebo of • –0.81 BMs daily for telotristat etiprate 250 mg dose (P

• Wilcoxon rank-sum test showed significant differences for each telotristat etiprate dose vs. placebo (p

VEGF WHO I VEGF WHO III High MVD Low MVD

A rich vascular network is a distinctive feature of NETs

A negative correlation of microvascular density (MVD) and VEGF expression with tumor progression has been documented

Low MVD is an unfavorable prognostic factor in PNETs

British Journal of Cancer 2005;92:94-101.; Gastroenterology 2003;125:1094-1104.

Raymond, NEJM 2011

Sunitinib: 11,5 monthsPlacebo: 5,5 months

HR 0.42P

Sunitinib vs Placebo in PNETs 2016 – Final OS analysis 5y after study closure

Raymond, ASCO GI 2016

69% crossoverΔ 9,5 months

Median OSSunitinib: 38,6 monthsPlacebo: 29,1 months

HR 0.73P=0.094

19/06/2017 38

mTOR activation in tumors Occurs in ~ 50% of human cancers

Pathway activation occurs through: Excess of ligand Receptor overexpression (EGFR, Her2,..) Gain of function mutations (PI3K, AKT,..) Inactivation of PTEN, TSC1/TSC2, LKB1,.. Other (bcr-abl traslocation, ras-raf mutations..)

Pathogenesis of NETs: Familial syndromes: NF1, TSC1/TSC2, menin? Sporadic PNETs: 15% mutations PI3K-mTOR

pathway (WES) Sporadic Si-NETs: 29% PI3K-mTOR genetic

alterations(amplifications/mutations AKT/mTOR/PI3K)

Altered expression of mTOR pathway componentsassociated with proliferative index, metastaticpotential and survival

Chan et al, Curr Treat Options Oncol. 2014

Yao et al, NEJM 2011

Everolimus (n=191) Placebo (n=189)

Tumor Shrinkage: 64% Tumor Shrinkage: 21%

ORR= 4.8% ORR= 2.0%

RADIANT-3: Everolimus vs Placebo in Pancreatic NETs(N=410)

Crossover: 73%

Yao et al, NEJM 2011

RADIANT-2 Study DesignInternational, Multicenter, Double-Blind, Placebo-Controlled, Phase III Trial

Treatment until disease progression

Adult patients with advanced NET and a history of secretory symptoms (N = 429)

• Advanced low- or intermediate-grade NET

• Radiologic progression in the past 12 months

• History of secretory symptoms (flushing or diarrhea)

• Previous antitumor therapy allowed

• WHO Performance Status d2

1:1

Multi-phasic CT or MRI performed every 12 weeks

Crossover at time of disease progression

Enrollment January 2007 to May 2008.

Everolimus 10 mg/d + Octreotide LAR 30 mg q28d

n = 216

Placebo + Octreotide LAR 30 mg q28d

n = 213

RANDOMIZE

PFS by Central Review*

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

216213

202202

167155

129117

120106

10284

8172

6965

6357

5650

5042

4235

3324

2218

1711

119

43

11

10

00

*Independent adjudicated central review committee. The prespecified boundary for significance was P ≤ 0.0246.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

enta

ge E

vent

-Fre

e

Kaplan-Meier median PFSEverolimus + octreotide LAR: 16.4 monthsPlacebo + octreotide LAR: 11.3 months

Hazard ratio, 0.77; 95% CI, 0.59-1.00P = 0.026

Total events = 223Censoring timesE + O (n/N = 103/216)P + O (n/N = 120/213)

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 (worse 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.

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 • Enrolled within 6 months from

radiologic progression

Everolimus 10 mg/day N = 205

Treated until PD, intolerable AE, or

consent withdrawal

2:1

Placebo N = 97

RANDOMIZE

Endpoints: • Primary: PFS (central)• Key Secondary: OS• Secondary: ORR, DCR, safety, HRQoL (FACT-G),

WHO PS, NSE/CgA, PK

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

Yao JC et al. Lancet 2015; Published Online December 15, 2015.

Baseline and Disease Characteristics (2/2)

†Organs as per target and non-target lesion locations observed at baseline by central radiology review.‡Patients were expected to have disease progression in ≤ 6 months prior to enrolment as per inclusion criteria. Protocol deviation was reported in 7 patients.

Characteristic EverolimusN = 205PlaceboN = 97

Tumor gradeGrade 1 / grade 2 63% / 37% 67% / 33%

Metastatic extent of disease†Liver 80% 78%Lymph node or lymphatic system 42% 46%Lung 22% 21%Bone 21% 16%

Median time from initial diagnosis to randomization, months (range) 29.9 (0.7-258.4) 28.9 (1.1-303.3)

Median time from most recent progression until enrolment, months (range)‡ 1.68 (0.0-7.8) 1.45 (0.2-11.8)

Prior treatmentsSomatostatin analogues 53% 56%Surgery 59% 72%Chemotherapy 26% 24%Radiotherapy including PRRT 22% 20%Locoregional and ablative therapies 11% 10%

Yao JC et al. Lancet 2015; Published Online December 15, 2015.

Primary Endpoint: PFS by Central Review

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

52% reduction in the relative risk of progression or death with everolimus vs placeboHR = 0.48 (95% CI, 0.35-0.67); P < 0.00001

205 168 145 124 101 81 65 52 26 10 3 0 097 65 39 30 24 21 17 15 11 6 5 1 0Placebo

Everolimus

No.of patients still at risk

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

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 mediansEverolimus: 11.0 months (95% CI, 9.23-13.31) Placebo: 3.9 months (95% CI, 3.58-7.43)

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

Yao JC et al. Lancet 2015; Published Online December 15, 2015.

PFS HR by Primary Tumor Origin –Retrospective Analysis, Central Review

*One patient with thymus as primary tumor origin was not included.†Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI.Hazard ratio obtained from unstratified Cox model.GI, gastrointestinal; NET, neuroendocrine tumors

Lung

GI†

NET of unknown primary

Hazard Ratio (95% CI)Subgroups*

90

175

36

No.

0.1 0.4 1 10

0.50 (0.28-0.88)

0.56 (0.37-0.84)

0.60 (0.24-1.51)

Everolimus Better Placebo Better

Yao JC et al. Lancet 2015; Published Online December 15, 2015.

PFS midgut vs non-midgut

Stomach, colon, rectumDuodenum, jejunum, ileum, caecum, appendix, small intestine

Interim Overall Survival Analysis

*Boundary for significance = 0.0002.P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.NS, not significant.

First interim OS analysis performed with 37% of information fraction favored the everolimus arm

205 195 184 179 172 170 158 143 100 59 31 5 097 94 86 80 75 70 67 61 42 21 13 5 0Placebo

Everolimus

No. of patients still at risk

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

0

10

20

30

40

50

60

70

80

90

100

Prob

abili

ty o

f Ove

rall

Surv

ival

(%)

Censoring TimesEverolimus (n/N = 42/205)Placebo (n/N = 28/97)

Everolimus vs PlaceboHR = 0.64 (95% CI, 0.40-1.05); P = 0.037 (NS)*

Next interim analysis is expected in 2016

Yao JC et al. Lancet 2015; Published Online December 15, 2015.

Moertel et al, NEJM 1980

STREPTOZOTOCIN

1950’s – 1st isolated 1968 – 1st case report 1982 – FDA approval for PNETs

Cytotoxic chemotherapy

Cytotoxic Chemotherapy: Randomized Trials

N Tx arms RR OS

PANCREATIC NETS

Moertel - ECOG 1972 84 STZ + FU 63%* 26 m(NEJM 1980) STZ 36% 16 m

Moertel - ECOG 1978 105 STZ + DOX 69%* 26 m*

(NEJM 1992) STZ + FU 45% 17 m

Chlorozotocin 30% 18 m

RR includes clinical, biochemical and radiological responses * p < .05

Moertel et al, NEJM 1980 Moertel et al, NEJM 1992

Cytotoxic Chemotherapy: Randomized Trials

• No proper assessment of STZ vs placebo or BSC

• Adding 5FU to STZ improves response rate and survival

• Doxo is better than 5FU in combination with STZ (↑ RR and OS)

Temozolomide-based chemotherapy

Type of study Treatment Regimen # Pts Grade RR PFS OS

All (PNET) PNET

Retrospective1 TMZ 200 mg/m2 d1-5 q4w 36 (12) Any 8% NR NR

Phase II2 TMZ 150 mg/m2 d1-7 q2w 29 (11) WD 45% NR NR

Thalidomide 50-400 mg/d

Retrospective3 Capecitabine 750 mg/m2 bid d1-14 q4w 30 (30) WD 70% NR NR

TMZ 200 mg/m2 d10-14 q4w

Phase II4 Capecitabine 750 mg/m2 bid d1-14 q4w 28 (11) WD 45% NR NR

TMZ 200 mg/m2 d10-14 q4w

Retrospective5 Capecitabine 750-1000 mg/m2 bid d1-14 q4w 65 (46) G1-G2 52% 18.4 38.3

TMZ 150-200 mg/m2 d10-14 q4w

Encouraging data from small non-controlled studies or retrospective series Convenient and well tolerated Role of MGMT?

1Ekeblad et al, Clin Cancer Res 2007; 2Kulke et al, JCO 2006; 3Strosberg et al, Cancer2011; 4Fine et al, ASCO GI 2014; 5Crespo et al, Future Oncol 2016

19/06/2017 53

Chemotherapy vs Targeted agents

Chemotherapy:

poorer available evidence: few RCT, many small prospective or retrospective cohorts

limited availability of some agents (STZ)higher tumor response? less convenient (iv) but cheaper

Targeted agents:

high level of evidence (placebo-controlled trials) no tumor shrinkage (RR < 10%) improved PFS but no evidence of improved survival more convenient (oral) but greater cost

19/06/2017 54

When would we favor chemotherapy?

High tumor burden

control symptoms related to tumor bulk

neoadjuvant setting: induce tumor shrinkage to facilitate surgery

High mitotic or proliferative index (ki-67 cut-off?)

Poorly differentiated tumors

Pancreatic primary

Biomarkers? (MGMT deficient -> temozolomide?)

Optimal Sequence?

PD

Pancreatic NEN: ENETS Guidelines for advanced disease

Pavel M et al, Neuroendocrinology 2016

PD

Pancreatic NEN: ENETS Guidelines for advanced disease

Pavel M et al, Neuroendocrinology 2016

SI-NEN: ENETS Guidelines for advanced disease

Pavel et al, Neuroendocrinology 2016

19/06/2017 59

Conclusions Medical and non-medical therapeutic options are increasing:

PNETs: Lanreotide, Sunitinib, Everolimus, Chemotherapy GI NETs: SSA, PRRT, Everolimus Lung NETs: Everolimus

New challenges arise: What to use and when? For how long? Optimal sequence and combination? Integration with other non medical therapies?

Pending issues: What is the best option for each individual pt? – Biomarkers!! Improve safety and efficacy!! Novel targets

Número de diapositiva 1Número de diapositiva 2Epidemiology of GEP-NENsPrognosis by stage, grade and primary tumor siteNúmero de diapositiva 5Prevalence of GEP-NETsTAXONOMY OF NENsWilliam & Sandler (1963)�Número de diapositiva 9Tumor GradeNúmero de diapositiva 11Clinical PresentationNúmero de diapositiva 13Número de diapositiva 14Antiproliferative Therapeutic OptionsNúmero de diapositiva 16SMS Mechanism of ActionNúmero de diapositiva 18Número de diapositiva 19Número de diapositiva 20PROMID�Octreotide LAR vs Placebo in G1 Midgut NETsNúmero de diapositiva 22Número de diapositiva 23Número de diapositiva 24Número de diapositiva 25Número de diapositiva 26Número de diapositiva 27Número de diapositiva 28Número de diapositiva 29Other Targeted AgentsTelotristat Etiprate �A Tryptophan Hydroxylase (TPH) Inhibitor TELESTAR �Phase 3 Study DesignTELESTAR: Reduction in Daily Bowel Movement Frequency Averaged Over Double-Blind Treatment PhaseTELESTAR: Mean Absolute Change in Urinary 5-HIAA (mg/24 h) from Baseline to Week 12Número de diapositiva 35Número de diapositiva 36Sunitinib vs Placebo in PNETs �2016 – Final OS analysis 5y after study closuremTOR activation in tumorsNúmero de diapositiva 39Número de diapositiva 40RADIANT-2 Study DesignPFS by Central Review*RADIANT-4 Study DesignBaseline and Disease Characteristics (2/2)Primary Endpoint: PFS by Central Review PFS HR by Primary Tumor Origin – �Retrospective Analysis, Central Review PFS midgut vs non-midgutInterim Overall Survival AnalysisNúmero de diapositiva 49Número de diapositiva 50Número de diapositiva 51Número de diapositiva 52Chemotherapy vs Targeted agentsWhen would we favor chemotherapy?Número de diapositiva 55Número de diapositiva 56Número de diapositiva 57Número de diapositiva 58Conclusions