avances en el tratamiento sistémico de los tumores ......sistémico de los tumores neuroendocrinos...

Avances en el tratamiento sistémico de los tumores

neuroendocrinos

Emma Dotor19.3.2013

Características de los TNE

Localización: 70% de los casos en la región Gastro-Entero Pancreática

Infrecuentes

Funcionantes / No funcionantes

Asociación con riesgo genético (MEN)

Heterogeneidad

Parameters With an Impacton Therapeutic Decision Making

Histology

– Grading G1/G2 (NET) vs G3 (NEC) (WHO 2010)

– Well/moderately or poorly differentiated NET/NEC (US)

Functionality– Carcinoid syndrome, insulinoma, gastrinoma, VIPoma

Primary tumor site – Pancreatic vs intestinal

‐ 5‐year overall survival 40‐50% vs 70‐90% in metastatic disease

Somatostatin receptor imaging

Tumor burden/extrahepatic disease

Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; WHO, World Health Organization.

Tratamiento quirúrgico en los TNE metastásicos

• Objetivo: tratamiento curativo o reducir masa tumoral(garantizar mínimo resección 90% masa tumoral)

• Chen H / J Am Coll Surg 1998;187:88-93:38 pacientes con metástasis hepáticas como localización única.15 pacientes con resección quirúrgica y 23 sin cirugía.OS 5a : 73% vs 29%

• Chamberlain RS / J Am Coll Surg 2000;190:432-445:85 pacientes con metastasis hepáticas por TNE. 34 pacientes conintervención quirúrgica (15 con cirugía potencialmente curativa y 19con resección paliativa).OS 5a: 85% cirugía completa vs 63% cirugía incompleta

Current Antiproliferative Therapyin G1/G2 Gastroenteropancreatic NET

Somatostatin analogues– PROMID: octreotide LAR vs placebo1

TTP 14.3 mo vs 6 mo

– CLARINET: lanreotide vs placebo (ongoing trial)2

Interferon alphaPPRTEverolimus?– RADIANT‐2: everolimus + octreotide LAR

vs placebo + octreotide LAR3

– RADIANT‐4: everolimus vs placebo (ongoing trial)4

Chemotherapy– Streptozotocin + 5‐FU: RR ~40%5

– Temozolomide + capecitabine: RR up to 70% (retrospective trial)5

Everolimus, sunitinib– RADIANT‐3: everolimus vs placebo6

– Sunitinib trial: sunitinib vs placebo7

Somatostatin analogues?– Octreotide/ lanreotide

– CLARINET: lanreotide vs placebo(ongoing trial)2

PRRTInterferon alpha

Intestinal (Midgut)a NET G1/G2 Pancreatic NET G1/G2

Abbreviations: LAR, long‐acting release; PPRT, peptide receptor radionuclide therapy; RR, response rate; TTP, time to progression.a Includes carcinoid tumors and tumors at other sites.1. Rinke A, et al. J Clin Oncol. 2009;27:4656‐63. 2. ClinicalTrials.gov NCT00353496. 3. Pavel M, et al. Lancet. 2011;378:2005‐12. 4. ClinicalTrials.gov NCT01524783 6. 5. Frilling A, et al. Endocrine‐Related Cancer. 2012;19:R163‐85 7. 6. Yao J, et al. N Engl J Med. 2011;364:514‐523. 7. Raymond E, et al. N Engl J Med. 2011;364:501‐13.

QT en TNE bien diferenciados de páncreas/duodeno

Régimen N RO(%) SG (m)STZ-DOX (Eriksson 1990)

CLZ-5FU (Bukowski 1992)

STZ-DOX-5FU (Rivera 1998)

5FU-DTIC-EPI (Bajetta 2002)

STZ-DOX-5FU (Kouvaraki 2004)

STZ-DOX (Delaunoit 2004)

TMZ-TAL (Kulke 2006)

TMZ-CAP (Isacoff 2006)

TMZ-BVZ (Kulke 2006)

84

44

12

82

84

45

11

17

17

36

36

55

27,8

39

36

45

59

24

-

-

21

38

36

24

-

-

Fase III aleatorizado STZ-ADR vs STZ-5FU vs CLZMoertel, NEJM 1992

Esquema(n:105)

0R (%)

OS (a.) TTP (m.) RESP (m.)

STZ-ADR 69 2,2 18

STZ-FU 45 1,4 14

CLZ 30 1,4 17

20

6,9

6,9

Quimioterapia en TNE indiferenciadosRégimen N % RR SG

CDDP-VP16(Seitz 1995)

11 54

CDDP-VP16(Moertel 1991)

18 67 19

CDDP-VP16(Mitry1999)

41 42 15

CDDP-VP16(Fjallskog2001)

36 55 19

TAX-CBDCA-VP16 (Miranda 2005)

66 55 14,8

TAX-CDDP-VP16(Hainsworth 2006)

78 53 14,8

Estudios fase II: IFN y análogos-SST

Estudio N DosisIFN SST

Resp-Biol (%)

Resp-Tum (%)

Janson (1991) 24 9 MU/s 300 mcg/d 77 0

Frank (1999) 21 15 MU/s 600 mcg/d 69 5

Fjallskog (2003) 16 9 MU/s 450 mcg/d 63 18

Pavel (2006) 17 50-100 mcg/s 20-30 mg 40 12

IFN y análogos SST. Fases III

Estudio N Esquema Resultdos P

Kölby (2003) 68 IFNOCT-IFN

Superv 5 a30,656,8

P=0.132

Faiss (2003) 80 IFNLANLAN-IFN

SLP 1 a44,44050

P=0,69

Arnold (2005) 109 IFNOCT_IFN

OS3551

P=0.55

90 pts 1/2001-1/2008: 85 pts aleatorizados. Midgut welldifferentiated tumors

43 pts octeotride LAR im 30 mg/28 d42 pts placebo im c/28 d hasta progresión o muerte

Primary end point: Time to tumor progression

Secondary end points: survival time, quality of life and clinicaland biochemical response

-Pacientes diagnosticados, sin tratamiento previo-Confirmación histológica, TNE intestino medio

inoperables o metastáticos

-TNE de intestino medio funcionantes y no funcionantes

- No opciones terapéuticas curativas

-Tumor medible por TAC o RNM

Criterios de Inclusión

Patient DemographicsOctreotide LAR

(n=42)Placebo

(n=43)Total(n=85)

Median age, years (range) 63.5 (38–79) 61.0 (39–82) 62.0 (38–82)

Sex male (%)female (%)

47.6% 52.4%

53.5%46.5%

50.6%49.4%

Time since diagnosis, months (range) 7.5 (0.8–271.2) 3.3 (0.8–109.4) 4.3 (0.8–271.2)

Karnofsky Score ≤80>80

16.7%83.3%

11.6%88.4%

14.1%85.9%

Carcinoid syndrome* 40.5% 37.2% 38.8%

Resection of primary 69.1% 62.8% 65.9%

Hepatic tumor load0%0–10%10–25%25–50%50%

16.7%59.5%7.1%11.9%4.8%

11.6%62.8%4.7%9.3%11.6%

14.1%61.2%5.9%

10.6%8.2%

Octreoscan positive 76.2% 72.1% 74.1%

Ki-67 up to 2% 97.6% 93.0% 95.3%

CgA elevated 61.9% 69.8% 65.9%

* not requiring octreotide for symptom control

0

0.25

0.5

0.75

1

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

Octreotide LAR 30mg Significantly Increases Time to Tumor Progression (TTP)

Octreotide LAR vs placebo P=0.000017HR= 0.33 [95% CI: 0.19–0.55]

Based on Intention to treat analysis

Prop

ortio

n w

ithou

t pro

gres

sion

Time (months)

Octreotide LAR: 42 patients / 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]

Octreotide LAR (n=42)

Placebo(n=43)

Complete response (n) 0 0

Partial response (n) 1 1

Stable disease (n) 28 (64%) 16 (37 %)

Progressive disease (n) 10 23

Unknown (n) 3 3

Wilcoxon-Mann-Whitney: P=0.0079

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

0

0.25

0.5

0.75

1

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 900

0.25

0.5

0.75

1

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

Based on the per protocol analysis

P=0.0008; HR=0.27 [95% CI: 0.12–0.61]

Prop

ortio

n w

ithou

t pro

gres

sion

P=0.0007; HR=0.23 [95% CI: 0.09–0.57]

Prop

ortio

n w

ithou

t pro

gres

sion

Octreotide LAR Lengthens TTP in Patients with Functioning and Non-Functioning Midgut NETs

Patients with non-functioning tumors Patients with functioning tumors

Time (months)Time (months)

Octreotide LAR: 17 patients / 11 eventsMedian TTP 10.35 months

Placebo: 16 patients / 14 eventsMedian TTP 5.45 months



0

0.25

0.5

0.75

1

0 3 6 9 12 15



Patients with tumor load ≤10%

Based on the per protocol analysis

Octreotide LAR Increases TTP Predominantly in Patients with Hepatic Tumor Load≤10%



0

0.25

0.5

0.75

1

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

Patients with tumor load >10%

P<0.0001; HR=0.21 [95% CI: 0.10–0.44] P=0.1381; HR=0.45 [95% CI: 0.15–1.35]

Prop

ortio

n w

ithou

t pro

gres

sion

Prop

ortio

n w

ithou

t pro

gres

sion

Overall survivalOctreotide LAR median survival duration not yet reached (>77.4 months)Placebo: 73.7 months

Octreotide LAR: 42 patients / 7 eventsMedian >77.4 months (not reached)

Placebo: 43 patients / 9 eventsMedian 73.7 months

0

0.25

0.5

0.75

1

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

Pro

porti

on w

ithou

t pro

gres

sion

Time (months)

Es probable que no se observen diferencias en SG debido a que

son pacientes con TNE bien diferenciados, que son tumores de

crecimiento lento

El tto recibido tras la progresión en ambos grupos fue a criterio del

clinico y no formó parte del protocolo del estudio.

Safety Consistent with Established Octreotide LAR Profile

• No treatment-related deaths

• Treatment was discontinued because of AEs in 5 of 42 octreotide LARrecipients and 0 of 43 placebo recipients

• Most frequent serious AEs affected:– GI tract (octreotide LAR n=6; placebo n=8)– Hematopoietic system (octreotide LAR n=5; placebo n=1)– General health status, e.g. fatigue, fever (octreotide LAR n=8; placebo

n=2)

• Serious AEs in 11 octreotide LAR and 10 placebo recipients

• Octreotide LAR 30mg significantly prolongs TTP in all patients andpatients with low tumor load (≤10%) show an even more impressiveresponse

–Thus, initiating octreotide LAR early may improve patient outcomes,even following cytoreductive surgery

• Octreotide LAR should be considered the standard of care in patientswith well-differentiated midgut neuroendocrine tumors

Conclusions

Randomized, Phase III Trial of Everolimus + Octreotide LAR vs Placebo + Octreotide LAR in

Patients with Advanced Neuroendocrine Tumours (NET) (RADIANT-2)

Marianne Pavel1, John Hainsworth2,Eric Baudin3, Marc Peeters4, Dieter Hoersch5,

Lowell Anthony6, Sakina Hoosen7, Jessica St Peter7, Valentine Jehl8, and James Yao9

for the RADIANT-2 Study Group

1Charité-Universitätsmedizin Berlin/Campus Virchow Klinikum, Berlin, Germany; 2Sarah Cannon Cancer Center, Nashville, TN, USA; 3Oncologie Endocrinienne et Médecine Nucléaire, Institut Gustave Roussy,

Villejuif, France; 4Department of Oncology, Antwerp University Hospital, Edegem, Belgium; 5Klinik für Innere Medizin, Gastroenterologie und Endokrinologie, Zentralklinik Bad Berka GmbH, Bad Berka,

Germany; 6Ochsner Kenner Medical Center, Kenner, LA, USA; 7Novartis Oncology, Florham Park, NJ, USA; 8Novartis Pharma, Basel, Switzerland ; 9M. D. Anderson Cancer Center, Houston, TX, USA

RADIANT-2 Study Design

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

RANDOMIZE

Enrollment January 2007 ‐March 2008

1:1

Multi-phasic CT or MRI performed every 12 weeks

Crossover allowed at time of PD (n=123)

Phase III Double Blind Placebo Controlled Trial

Pavel M, Hainsworth J, Baudin E, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA8

• Primary endpoint: PFS (RECIST 1,0)

• Secondary end points: Tumour response, OS, biomarkers, safety, PK

• Advanced low- orintermediate-grade NET•Radiologicprogression ≤ 12 months• History of secretorysymptoms (flushing, diarrhea)• Prior antitumortherapy allowed• WHO PS ≤ 2

Everolimus + Oct LARN = 216, %

Placebo + Oct LARN = 213, %

Median age, years (range) 60 (22-83) 60 (27-81)Male 45 58Female 55 42WHO Performance Status

0 55 661 / 2* 39 / 6 29 / 5

Primary siteSmall intestine 51 53Lung* 15 5Colon 7 7Pancreas 5 7Liver 3 5

Baseline Characteristics

*One missing PS in placebo armOct LAR= Octreotide LAR

*Statistically significant for imbalance, P < 0.05


Prior Therapies

Everolimus + Oct LARN = 216n (%)

Placebo + Oct LARN = 213n (%)

Prior long-acting SSA 173 (80.1) 166 (77.9)Other systemic anti-tumour therapies 99 (45.8) 82 (38.5)

Chemotherapy* 75 (34.7) 55 (25.8)Immunotherapy 27 (12.5) 20 (9.4)Targeted therapy 15 (6.9) 16 (7.5)Other 21 (9.7) 28 (13.1)

24

*Statistically significant, p < 0.05

Oct LAR = Octreotide LAR


PFS by Central Review*

Time (months)No. 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• P-value is obtained from the one-sided log rank test• Hazard ratio is obtained from unadjusted Cox model

E + O = Everolimus + Octreotide LARP + 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

Per

cent

age

even

t-fre

eKaplan-Meier median PFSEverolimus + Octreotide LAR: 16.4 monthsPlacebo + Octreotide LAR: 11.3 months

Hazard ratio = 0.77; 95% CI [0.59 -1.00]P-value = 0.026

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


PFS by Local Investigator Review

• P-value is obtained from the one-sided log rank test• Hazard ratio is obtained from unadjusted Cox model

No. of patients still at riskE + OP + O

216213

199201

167159

129121

119114

10092

8175

7472

6864

6256

5150

4041

3227

2421

1811

1110

44

21

10

00

E + O = Everolimus + Octreotide LARP + O = Placebo + Octreotide LAR

Per

cent

age

even

t-fre

e

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 38Time (months)

Kaplan-Meier median PFSEverolimus + Octreotide LAR: 12.0 monthsPlacebo + Octreotide LAR: 8.6 months

Hazard ratio = 0.78; 95% CI [0.62-0.98]P-value = 0.018

Total events = 284Censoring timesE + O (n/N = 128/216)P + O (n/N = 156/213)


Everolimus plus octreotide LAR (E+O) versus placebo plus octreotide LAR (P+O) in patients with advanced neuroendocrine tumors (NET): Updated

results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-2).

N HR CI P-valuePFS

Ever + LAR Plac + LARCentral review 429 0.77 0.59-1.00 0.026 16.4 11.3Prior SSA 339 0.81 0.60-1.09 0.077 14.3 11.1No prior SSA 90 0.63 0.35-1.11 0.054 25.2 13.6

HR P-valueMedian PFS (95% CI)

Ever + LAR Plac + LARLocal review(284 events)

0.78(0.62; 0.98) 0.018 12.0 (10.6; 16.1) 8.6 (8.1; 11.1)

Central review(223 events)

0.77(0.59; 1.00) 0.026 16.4 (13.7; 21.2) 11.3 (8.4; 14.6)

Ever + LAR Plac + LARDisease progression, N (%) 95 (44) 146 (68.5%)AEs, N (%) 57 (26.4) 14 (6.6)Duration of exposure, weeks median (range) 37 (1-163) 37 (0-152)

Occurring in >10%Everolimus + Octreotide LAR

n = 215+ Octreotide Placebo LAR

n = 211All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%)

Stomatitis* 62 7 14 0Rash 37 1 12 0Fatigue 31 7 23 3Diarrhea 27 6 16 2Nausea 20 1 16 1Infections* 20 5 6 1Dysgeusia 17 1 3 0Anemia 15 1 5 0Weight decreased 15 1 3 0Thrombocytopenia 14 5 0 0Decreased appetite 14 0 6 0Peripheral edema 13 0 3 0Hyperglycemia 12 5 2 1Dyspnea 12 2 1 0Pulmonary events* 12 2 0 0Vomiting 11 1 5 1Pruritus 11 0 4 0Asthenia 10 1 7 1

*Related toxicities grouped for calculations

Treatment Related Adverse Events


Summary• Everolimus + octreotide LAR demonstrates a 5.1 month

prolongation of median PFS (HR = 0.77; P = 0.026); did not reach statistical significance (pre-specified P = 0.0246)

• Local assessment supports activity of everolimus + octreotide LAR with a similar HR of 0.78 (P = 0.018)

• Pre-specified statistical analysis (IPCW) adjusting for different censoring patterns, loss of power and baseline imbalances demonstrates a consistent benefit (HR = 0.60)

• Everolimus + octreotide LAR demonstrates benefit across all subgroups

• Everolimus + octreotide LAR has an acceptable safety profile

RADIANT-3: Phase III Randomized Trial of Everolimus vs. Placebo in Advanced

Pancreatic NET(RADIANT-3)

RADIANT-3 Study Design

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

Crossover

1:1

* Concurrent somatostatin analogs allowed

RANDOMIZE

Primary endpoint:• PFS (RECIST)

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

Randomization August 2007 ‐May 2009

Phase III Double Blind Placebo Controlled Trial

Yao JC, Shah M, Ito T, et al. N Engl J Med 2011 Feb 10;364(6):514-23

• Disease progression within 12 months

• Prior antitumor therapy allowed

• WHO PS ≤ 2

Stratified by• WHO PS• Prior chemotherapy

RADIANT-3: Baseline Characteristics Everolimus 10mg

(N = 207)Placebo(N = 203)

Median age, years (range) 58 (23-87) 57 (20-82)Male (%) 53 58Female (%) 47 42WHO Performance Status (%)

0 67 661 30 322 3 3

Number of organs involved (%)1 25 312 41 32≥3 34 38

Histologic Grade (%)Well differentiated 82 84Moderately differentiated 17 15Unknown 1 1


RADIANT-3: Prior Therapies

Everolimus 10mg N = 207, %

Placebo N = 203, %

Somatostatin analogs 49 50

Systemic anti-tumour therapy 58 58

Chemotherapy 50 50

Targeted therapy 5 7

Immunotherapy 3 4

Hormonal therapy 1 1

Other 10 13


RADIANT-3: PFS by Investigator Review

• P-value obtained from stratified one-sided log rank test• Hazard ratio is obtained from stratified unadjusted Cox model

No. of patients still at riskEverolimusPlacebo

207203

189177

15398

12659

11452

8024

4916

367

284

213

102

61

21

01

Kaplan-Meier medians PFSEverolimus: 11.0 monthsPlacebo: 4.6 months

Hazard ratio = 0.35; 95% CI [0.27-0.45]P-value: <0.0001

01

00

Time (months)

100

80

Per

cent

age

even

t-fre

e

Censoring TimesEverolimus (n/N = 109/207)Placebo (n/N = 165/203)

60

40

20

0

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


RADIANT-3: PFS by Central Review*

* 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 PFSEverolimus: 11.4 monthsPlacebo: 5.4 months

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

No. of patients still at riskEverolimusPlacebo

207203

187180

15299

12660

11752

8122

4912

365

273

221

101

61

20

00

Time (months)

100

80

Percentage event‐free

Censoring TimesEverolimus (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-3: Response to Everolimus was Significantly Superior to Placebo

Everolimus 10mg N = 207 n (%)

PlaceboN = 203n (%)

Complete response (CR) 0 0Partial response (PR) 10 (4.8) 4 (2.0)Stable disease (SD) 151 (72.9) 103 (50.7)Progressive disease (PD) 29 (14.0) 85 (41.9)Unknown 17 (8.2) 11 (5.4)Two-sided P-value for treatment difference* P < 0.0001

Disease control rate (CR + PR +SD) 161 (77.7) 107 (52.7)

*Wilcoxon two‐sample test

Per investigator reviewRECIST 1.0


RADIANT-3: Overall Survival

Everolimus 10mg

N = 207

Placebo N = 203

Kaplan-Meier estimates [95% CI] at:2

3 months 97.1 [93.6-98.7]

98.5 [95.5-99.5]

6 months 93.1 [88.7-95.9]

91.6 [86.8-94.7]

12 months

82.3 [76.0-87.0]

82.6 [76.5-87.3]

18 months

73.1 [65.1-79.6]

73.9 [66.1-80.2]

24 months

57.3 [43.0-69.2]

62.8 [51.1-72.4]

148 placebo patients crossed over to receive everolimus

100

80

60

40

20

0

Perc

enta

ge o

f eve

nt-fr

ee

No. of patients still at risk

Censoring Times1

Everolimus (n/N = 51/207)Placebo (n/N = 50/203)

EverolimusPlacebo

207203

Kaplan Meier mediansEverolimus: NA monthsPlacebo : NA months

Hazard Ratio: 1.0595% CI [0.71,1.55]

Log-rank p-value = 0.594

0 2 4 6 8 10 12 14 16 18 20 22 24 26Time (months)

203199

195195

188183

181174

162160

122129

97109

7487

5363

3842

2623

916

57

28 30

03

01

32

00


Occurring in >10% Everolimus n = 204 Placebo n = 203All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%)

Stomatitis* 64 7 17 0Rash 49 <1 10 0Diarrhea 34 3 10 0Fatigue 31 2 14 <1Nausea 20 2 18 0Infections* 23 3 6 1Peripheral Edema 20 <1 3 0Decreased appetite 20 0 7 1Headache 19 0 6 0Dysgeusia 17 0 4 0Anemia 17 6 3 0Epistaxis 17 0 0 0Weight decreased 16 0 4 0Vomiting 15 0 6 0Pruritus 15 0 9 0Hyperglycemia 13 5 4 2Thrombocytopenia 13 4 <1 0Asthenia 13 1 8 1Pulmonary Events* 17 3 0 0Nail disorder 12 <1 1 0Cough 11 0 2 0Pyrexia 11 0 0 0

RADIANT‐3: Treatment Related Adverse Events

RADIANT 3: Conclusion

• RADIANT 3 evaluated the efficacy and safety of everolimus in advanced pNET, enrolling 410 patients in the largest-ever placebo-controlled phase III clinical trial in this patient population

• Everolimus provided a 65% reduction in risk for progression compared to placebo in patients with pancreatic NET (HR = 0.35, P < 0.0001)

• Everolimus 10mg daily provided a 6.4 month improvement in median progression free survival compared to placebo demonstrating a 2.4 fold increase– 11.0 months with everolimus compared to 4.6 months with placebo

RADIANT 3: Conclusion

• 18 months PFS rate of 34% vs. 9% placebo demonstrates a durable benefit with everolimus

• Disease control rate (CR+PR+SD) was 77.7% with a significant response difference, P < 0.0001

• Everolimus showed a consistent benefit in all subgroups

• Everolimus has an acceptable safety profile

• Everolimus should be considered a standard of care for patients with advanced pancreatic NET

Updated Results of the Phase III Trial

of Sunitinib vs. Placebo for Treatment of Advanced Pancreatic

Neuroendocrine Tumors

Eric Raymond,1 Patricia Niccoli,2 Yung-Jue Bang,3 Ivan Borbath,4Catherine Lombard-Bohas,5 Juan Valle,6 Shem Patyna,7Dongrui-Ray Lu,7 Richard Chao,7 Jean-Luc Raoul8

Phase III, Randomized, Double-Blind Study of Sunitinib vs. Placebo in Patients with Advanced, Progressive,

Well-Differentiated Pancreatic Endocrine Tumors

RANDOMIZATION

N=340

Study A6181111

Eligibility criteria•Well‐differentiated, malignant pancreatic endocrine tumor

• Disease progression in past 12 months

• Not amenable to treatment with curative intent

Balanced by region• Europe, Asia, Americas/Australia

Sunitinib 37.5 mg/day orally, continuous daily dosing (CDD)*

Arm A

Placebo*

Arm B

1:1

*With best supportive care

Somatostatin analogs were permitted

Primary endpoint: PFS

Secondary endpoints: OS, ORR, TTR, duration of response, safety, patient‐reported outcomes

1. Escudier B, et al. J Clin Oncol 2009;27:4068–75; 2. George S, et al. Eur J Cancer 2009;45:1959–683. Barrios CH, et al. Eur J Cancer Suppl 2009;7:429

Previous experience with sunitinib daily dosing:

Demographic and Baseline Characteristics

● Patients were enrolled between June 2007 and April 2009 Sunitinib

(n=86)Placebo(n=85)

Median (range) age, years 56 (25–84) 57 (26–78)Gender, n (%)

MaleFemale

42 (48.8)44 (51.2)

40 (47.1)45 (52.9)

ECOG performance status, n (%)012

53 (61.6)33 (38.4)

0

41 (48.2)43 (50.6)1 (1.2)*

Race, n (%)WhiteAsianOther/unspecified†

48 (55.8)13 (15.1)25 (29.1)

53 (62.4)10 (11.8)22 (25.9)

*Protocol violation†Per local regulations, race was not routinely reported in one participating country

Tumor Characteristics at Baseline Sunitinib

(n=86)Placebo (n=85)

Tumor functionality, n (%)*Non-functioningFunctioning

GastrinomaGlucagonomaInsulinomaVIPomaOther/multiple neuropeptide(s)

Not specified

42 (48.8)

9 (10.5)3 (3.5)2 (2.3)

011 (12.8)19 (22.1)

44 (51.8)

10 (11.8)2 (2.4)2 (2.4)2 (2.4)5 (5.9)

20 (23.5)Ki-67 index

Patients with Ki-67 index reported, n≤2%>2–5% >5–10%>10%

367

1658

366

14106

*Tumor functionality was as reported by investigators

Prior Treatments and Concomitant Somatostatin Analog (SSA) Use

Sunitinib (n=86)

Placebo (n=85)

Prior treatments, n (%) of patientsSurgeryRadiation therapyChemoembolizationRadiofrequency ablationPercutaneous ethanol injectionSSA

76 (88.4)9 (10.5)7 (8.1)3 (3.5)1 (1.2)

21 (24.4)

77 (90.6)12 (14.1)14 (16.5)6 (7.1)2 (2.4)

19 (22.4)Prior systemic treatment, n (%) of patients

AnyStreptozocinAnthracyclinesFluoropyrimidines

57 (66.3)24 (27.9)27 (31.4)20 (23.3)

61 (71.8)28 (32.9)35 (41.2)25 (29.4)

Concomitant SSA treatment, n (%) of patientsStarted prior to study and continuedStarted during study

17 (20.5)15 (18.1)2 (2.4)

18 (22.0)12 (14.6)6 (7.3)

Progression-Free Survival (Primary Endpoint)

1.0

0.8

0.6

0.4

0.2

0

Prop

ortio

n of patients

0 5 10 15 20 25

86 39 19 4 0 085 28 7 2 1 0

Number at risk

SunitinibPlacebo

Time (months)

Median PFSSunitinib 11.4 months (95% CI 7.4, 19.8)Placebo 5.5 months (95% CI 3.6, 7.4)

HR 0.418 (95% CI 0.263, 0.662)p=0.0001

Study stoppedearly

– Many events censored

– Number at risk low from month 15

Overall Survival1.0

0.8

0.6

0.4

0.2

0

Prop

ortio

n of patients

0 5 10 15 20 25

86 60 38 16 3 085 61 33 12 3 0

Number at risk

SunitinibPlacebo

Time (months)

Sunitinib

Placebo

HR 0.409 (95% CI 0.187, 0.894)

p=0.0204

RECIST-Defined Objective Tumor Responses

Sunitinib (n=86)

Placebo(n=85)

Best confirmed tumor response, n (%)Complete responsePartial responseStable disease/no responseObjective progressionNot evaluable

2 (2.3)6 (7.0)

54 (62.8)12 (14.0)12 (14.0)

00

51 (60.0)23 (27.1)11 (12.9)

Objective response rate (95% CI) Two-sided p value for treatment difference

9.3% (3.2%, 15.4%) 0.0066

0

Median (range) duration of response, months 8.1 (1.0–15.0) –

Stable disease >6 months, n (%) 30 (34.9) 21 (24.7)

Tumor responses were assessed using RECIST 1.1Objective response rate = patients with complete or partial tumor response

Most Frequent Grade 3+ Adverse Events with Sunitinib 37.5 mg/day CDD

All-causality grade 3/4 adverse events in ≥4 patients in either arm, n (%)

Sunitinib (n=83)

Placebo (n=82)

Neutropenia 10 (12.0) 0

Hypertension 8 (9.6) 1 (1.2)Hand–foot syndrome 5 (6.0) 0Leukopenia 5 (6.0) 0Diarrhea 4 (4.8) 2 (2.4)Asthenia 4 (4.8) 3 (3.7)Fatigue 4 (4.8) 7 (8.5)Abdominal pain 4 (4.8) 8 (9.8)Hypoglycemia 4 (4.8) 1 (1.2)

Back pain 0 4 (4.9)

Grade 5 adverse events

Patients experiencing grade 5 events, n (%) 4 (4.8) 6 (7.3)Treatment-related events, n (%) 1 (1.2) 1 (1.2)Nature of treatment-related event Cardiac failure Dehydration

Summary• In patients with progressive, well-differentiated pancreatic endocrine tumors,

sunitinib 37.5 mg/day continuous daily dosing resulted in:– Clinically significant improvement in median PFS vs. placebo

• 11.4 months vs. 5.5 with placebo, HR 0.418, p=0.0001– Improvement in overall survival vs. placebo

• HR 0.409, p=0.0204– Clinically significant increase in ORR vs. placebo

• 9.3% vs 0%, p=0.0066

• Adverse events observed with sunitinib continuous daily dosing weregenerally tolerable, and manageable by dosing interruption, dose reductionand/or standard medical therapy

– The most frequent events were consistent with previous trials of sunitinib1,2

– Rates of asthenia, vomiting and fatigue were similar in both arms

• These data support the clinical safety and efficacy of sunitinib inpatients with advanced pancreatic NET

1. Faivre S, et al. J Clin Oncol 2006;24:25–35; 2. Kulke MH, et al. J Clin Oncol 2008;26:3403–10

Conclusiones

Parameters With an Impacton Therapeutic Decision Making

Histology

– Grading G1/G2 (NET) vs G3 (NEC) (WHO 2010)

– Well/moderately or poorly differentiated NET/NEC (US)

Functionality– Carcinoid syndrome, insulinoma, gastrinoma, VIPoma

Primary tumor site – Pancreatic vs intestinal

‐ 5‐year overall survival 40‐50% vs 70‐90% in metastatic disease

Somatostatin receptor imaging

Tumor burden/extrahepatic disease

Abbreviations: NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; WHO, World Health Organization.

Conclusiones

ENETS Consensus Guidelines

Gracias

avances en el tratamiento sistémico de los tumores ......sistémico de los tumores neuroendocrinos...

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