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Avances en el tratamiento del Cáncer Gástrico y Esofágico
Fernando Rivera HerreroHospital Universitario Marqués de Valdecilla, Santander
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del Cáncer Gástrico y Esofágico
Cáncer Esófago-Gástrico Grupo heterogéneo de enfermedades
Cáncer de esófago
- Ca. Epidermoide- Adenocarcinoma
Adenocarcinoma de la UEG
Adenoca. Gástrico
Gastric Cancer: Comprehensive Molecular Characterization
Esophageal Cancer Gastric CancerPts 5y OS* Pts 5y OS*
Early disease 10% 70% 10% 70%(T1-2 N0 M0)
Locally advanced 50% 30% 40% 30%resectable (T3-4, N+, M0)
Locally advanced 25% <5% 20% <5%unresectable Metastatic 15% <5% 30% <5%
(M1)*5y OS with Surgery alone
Esophago-Gastric Cancer Resectability at Diagnosis
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del cáncer Gástrico y Esofágico
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
- Definitive chemoradiotherapy- Preoperative Chemotherapy- Preoperative Chemo-RadiotherapyEsophageal
Cancer
Gastric Cancer
- Perioperative Chemotherapy- Postoperative Chemo-Radiotherapy- Postoperative Chemotherapy ??
- Preoperative Chemo-Radiotherapy- Perioperative Chemotherapy
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
- Definitive chemoradiotherapy- Preoperative Chemotherapy- Preoperative Chemo-RadiotherapyEsophageal
Cancer
Definitive Chemo-Radiotherapy
F III RTOG 85-01: QT/RT vs RT(Herskowic, N Engl J Med, 1992)
123 pts(87% Squamous)
RT (64 Gy)
LR control (5y) 34% 53%P<0.05
PF, PF, PF,PFRT (50Gy)
Systemic control (1y) 71% 84%P<0.05
Survival (5y) 0% 28%P<0.05
If no resection, CT/RT is the gold standard
QT/RT definitiva en C. Esófago
267 PTSCa esófago (Epid/Aden)Est I-IVA
CF/RT4 ciclos, 2 concomitantes
con 50Gy de RT
FOLFOX /RT6 ciclos, 3 concomitantes
con 50Gy de RT
F. III PRODIGE 5/ACCORD 17 1
Objetivo 1º: SLP (mediana) 9,7 m HR 0,93; p 0,64 9,4 mFOLFOX/RT menos tóxico
102 PTSCa esófago (Epid/Aden)Est I-IVA
CF/RTCarbo-Pacli /RT
E. Retrospectivo holandés (no randomizado) 2
Sv (mediana) 13,8 m HR 0,97; p 0,87 16,1 mSLP (mediana) 9,7 m HR 0,93; p 0,76 11,1 m
Carbo-Pacli/RT menos tóxico
1.- Conroy T et al. Lancet Oncology 2014; 2.- Honing J et al. Ann Oncol 2014
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
- Definitive chemoradiotherapy- Preoperative Chemotherapy- Preoperative Chemo-RadiotherapyEsophageal
Cancer
Preoperative ChemotherapyPhase III studies
Phase III Preop.CT N Pts Histol. Sv (3y,median) Preop CT vs Surg.
pRC
Hatlevoll Cis/Bleo 97 Squam. 3% vs 9%
Roth Cis/Vds/Bleo 39 Squam. 25% vs 5%
Schlag Cis/5-FU 75 Squam. 10m vs 10m
Kok Cis/Etop 171 Squam. 18,5m vs 15m *
INT 113 Cis/5-FU x 3 440 51%Aden. 23% vs 26% 2,5%
MRC OE-02 Cis/5-FU x 2 802 66%Aden 34% vs 26% * 3%
* P<0.05
Preoperative Chemo-RadiotherapyPhase III studies
Phase III
Preop CT-RT
N
Histol.
3y Sv CT/RT/S vs Surg
Postoper. Mortality CT/RT/S vs Surg
pRC
Nygaard Cis-Bleo 35Gy 88 Squam 21% vs 9% 13% vs 24%
Le Prise Cis-5FU 20Gy 86 Squam 19% vs 14% 8% vs 7%
Walsh Cis-5FU / 40Gy 113 Adenoc 32% vs 6% * 12% vs 4% 25%
EORTC Cis / 37Gy(3,7x10) 282 Squam 34% vs 36% 16% vs 5%* 26%
Urba Cis-5FU-Vbl/ 45Gy 100 75%Ade 30% vs 16% 2% vs 4% 28%
Lee Cis/5FU/45Gy(28d) 101 Squam 45% vs 40% 30%
Burmeister Cis-5FU / 35Gy 256 63%Ade 35% vs 31% 16%
CALGB-9781 Cis-5FU / 50Gy 56 75%Ade (5a)39% vs 16%* 0% vs 8% 40%
CROSS ASCO-10 #4004
Pacli-Carbo/ 41Gy 363 75% Ade 59% vs 48%* 3,8% vs 3,7% 33%
QT vs QT/RT Preoperatoria en Ca Esófago
Estudios / pts10 1209
SupervivenciaHR 0,81(0,7-0,93) p 0,002
Dif absoluta Sv 2a13 %
Meta-análisis Gebski et al, Lancet Oncology 07
Estudios / pts8 1724
SupervivenciaHR 0,9(0,81-1) p 0,05
Dif absoluta Sv 2a7 %
QT/RT preCx
QT preCx
Is it possible to avoid Surgeryafter CT/RT?
- In all patients?
QT/RT Surgery vs QT/RT
Phase III Stahl (Stahl, J Clin Oncol 2005)(only Squamous) 172 pts
Loco-Regional Control Survival
Is it possible to avoid Surgeryafter CT/RT?
- Only in initially responding patients?
Phase III FFCD 9102 (Bedenne et al, J Clin Oncol, 2007)
Phase III: FFCD 9102(Bedenne, J Clin Oncol, 2007)
Resectable Stage II-IV (M0)Squamous 90% 455 pts received CFx2 / 46Gy
PR: 259 pts
Sv (2y) 34% p NS 40%LRC(2y) 66,4 p NS 57%Treat.Mortality 9% 1%Q of L better
Surgery CT/RTCFx1 / 20Gy
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del Cáncer Gástrico y Esofágico
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
Gastric Cancer
- Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
Gastric Cancer
- Postoperative Chemotherapy ??-Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy
GASTRIC “GLOBAL ADVANCED/ADJUVANT STOMACH TUMOR RESEARCH THROUGH INTERNATIONAL COLLABORATION”
JAMA. 201 0 MAY 5;303(1 7): 1 729- 37
Meta-Analysis 17 phase III trials 3 838 ptsIndividual data
HR: 0,82 (0,76-0,90)
5y OS: 55% vs 49%
Sakuramoto S et al, NEJM-07
1059 PTSR0 Resected Gastric adenocarc.St II-IV, D2+ nodal dissection No Postop
treatmentPostoperative S-1(S1 80mg/m2/d,
d 1-28 each 42d, 1 year)
Postoperative Chemotherapy: S-1Phase III ACTS-GC (Japan)
Primary endpoint: Sv
S1 No CT HR p Sv (3y) 80% vs 70% 0.68 0.003
Postoperative Chemotherapy
1035 PTSR0 resected Gastric cancer, D2St II-IIIB SurgerySurgery XELOX
Primary endpoint: SLP
Phase III CLASSIC (Asia)
HR p . SLP (3y) 74% 0.58 <0.001 60%
Obj 2º OSMedian follow-up 34 m
Bang et al. Lancet. 2012 (Preplanned interim analysis)
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
Gastric Cancer
- Postoperative Chemotherapy ??-Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy
Postoperative Chemo-RadiotherapySWOG 9008/INT 0116
Macdonald et al, N Engl J Med 2001
566 PTSR0, St.IB-IV (M0)
Gastric 80% E-G Junction 20% No Postop
treatmentCT/RTFU-Lv x5 / (45 Gy)
Sv (3 y) 50% p=0.005 41%Loc.Relap(3y) 19% p=0.005 29% Dist.Relap(3y) 33% 18%
Survival
(MacDonald JS et al. ASCO-04)
INT 0116Survival according to Histology
Intestinal (61% of pts) Diffuse (39% of pts)
Postoperative Chemo-Radiotherapy
546 PTS R0 resected Gastric C.
Surgery ECFx2F/RTECFx2
Surgery FLx2F/RTFLx2
Primary endpoint: OS
P. III CALGB 80101(US-Intergroup)
- Survival (median/3y) 37m /50% HR 1,03 p 0,8 38m/52%- DFS (median/3y) 30m /46% HR 1,03 p 0,8 28m/47%- G 4 Tox 40% p<0,001 26%
(Fuchs, ASCO 2011#4003)
Postoperative Chemo-Radiotherapy
- DFS (3y) 74% HR 0,74 p 0,09 78%intestinal 83% p 0,01 94% pN+ 72% p 0,04 76%
- LR relapse 13% p 0,03 7%- OS (3y) 87% HR 1,13 p 0,52 84%
Lee J et al. ASCO 2014- #4008
OSDFS
458 PTS R0 resected Gastric cancer, D2St II-IV
SurgeryXP/RTSurgery XP
P. III ARTIST (Korea)
1º endpoint: DFS
POSTOPERATIVE CHEMO-RADIOTHERAPYP. III ARTIST (Korea)
Lee J et al. ASCO 2014- #4008
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
Gastric Cancer
- Postoperative Chemotherapy ??-Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy
Perioperative Chemotherapy MAGIC-1
Cunningham et al, N Engl J Med 2006
503 PTSResectable St. II-IV (M0)Gastric 74% E-G Junction 26%
SurgeryPerioperative CTECFx3Surg.ECFx3
(44% of pts)
Sv (3y) 43% p<0.05 32%Loc Rel (3y): 29% p<0.05 44%Dist Rel (3y): 31% p<0.05 45%
Survival
Boige V et al, ASCO-07 # 4510
224 PTSResectable adenocarcinoma -Gastric (no EGJ) 25 % -EGJ 64 %-distal esophagous 11 %
PS 0 / 1 (75% / 25%)
SurgeryPerioperative CTCFx2-3Surgery(CF x4 postSx if OR or SD with pN+: 50% pts)
CFSur Sur HR p Sv (5y) 38% vs 24% 0,66 0,01DFS (5y) 34% vs 21% 0,65 0,003
Perioperative ChemotherapyPhase III FNLCC-ACCORD07-FFCD 9703
Primary endpoint: Sv
Perioperative CT vs Postoperative CT/RTMAGIC-1: 503 PTS
ECFx3CxECFx3 vs Cx
Sv
Cunningham et al, N Engl J Med 2006
FIII 9703: 224 PTSCFx2-3CxCFx4 vs Cx
Boige V et al, ASCO-07 # 4510
Sv
Sv
INT 0116: 566 PTSCx FU-LV/RT vs Cx
Macdonald et al, N Engl J Med 2001
Should RT be added to perioperative CT?
- Perioperative Chemotherapy does not include RT- The addition of RT to Perioperat CT is “investigational”
788 PTSResectable Gastric Cancer St.
II-IV (M0)Primary end point: Survival
Perioperative CTECX x3Surg. ECX x3
Preop CT + Postop CT/RTECX x3Surg. RT/Xeloda
F. III CRITICS (Dutch)
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del Cáncer Gástrico y Esofágico
Treatment options in Resectable -Esophageal Cancer
- EGJ Adenocarcinoma- Gastric Adenocarcinoma
- Preoperative Chemo-Radiotherapy- Perioperative Chemotherapy
Stahl et al. J Clin Oncol 2009; 27: 851-856
119 Pts in 5 y (planned 177)Siewert I / II-III 55%/45%ECOG 0/1 60%/40%Weight loss >10% 16%
Preop CT/RT PFLx2PE/RTCx
OS (3y) 27% HR 0.67 (0.41-1.07) p 0.07 47%Local Control (3y) 59% HR 0,45 (0,19-1,05) p 0.06 76%R0 69% p NS 72%pCR 2% p 0.03 16%Perioperative Mort. 4% p 0.26 10%
Resectable EGJ adenocarcinomaF. III POET (Preop CT vs Preop CT-RT)
Primary endpoint: OS
Preop. CTPFLx3Cx
Resectable EGJ AdenocaPhase III POET
Sv
Control Local27.7%
36%
Perioperative Chemotherapy in EGJ Adenoca
1.- Cunningham et al, N Engl J Med 20062.- Boige et al, ASCO 2007 # 4510
131 pts included with - Distal esophageal adenoca (73 pts) - EGJ adenoca (58 pts)
MAGIC 1
FNLCC 2 64% o pts (143 pts) included with - EGJ adenoca
EGJ AdenocarcinomaSiewert Clasification
«Esophageal» options? Preop CT/RT
«Gastric» options? Perioperative CT
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del Cáncer Gástrico y Esofágico
Cetuximab-QT/RT: Ca esófago no metastásico…dos Fases III negativos
258 PTS (no se paso a F.III por análisis de futilidad)
Ca esófago (Epid/Aden)Est I-III
Cis-Cape/RT4 ciclos, 3º-4ºcon 50Gy
Cetuxi+Cis-Cape/RT4 ciclos, 3º-4º con 50Gy
F. II-III SCOPE 1 1
Objetivo 1º F II: TTF (24 sem) 66% 77% Sv (mediana) 22,1m HR 1,53; p 0,03 25,4m
Más Toxicidad en brazo con Cetuximab
1.- Crosby T el al. Lancet Oncology 2013 ; 2.- Suntharalingam et al, ASCO-GI 2014
328 PTS Ca esófago (Adenoc 62%)Est I-IVA
Cis-Paclitaxel/RT50Gy
Cetuxi+Cis-Pacli/RT50Gy
F.III RTOG 0436 2
Objetivo 1º Sv (12 m) 64% p 0,7 65% Sv (24 m) 44% p 0,7 42%
No diferencias en Ca epiderm y Adenoca
MAGIC-B, MRC-ST03 (ECX ± Bevacizumab)
– Phase III (N=950) - Primary Objetive: Overall Survival
UK MRC ST03 (MAGIC-B) Phase III trial:ECX ± Beva (perioperative) in early stage GC
Gastric or GEJ Cancertype III resectable
N=950
ECX3 cycles
ECX + Avastin3 cycles
ECX3 cycles
ECX + Avastin3 cycles
SurgeryAvastin
6 cycles
ECX (q3w)Epirubicina 50mg/m2 d1Cisplatin 60mg/m2 d1Capecitabine 1250mg/m2 d1-21
Bevacizumab 7.5mg/kg d1q3w
5w (ECX)8w (ECX-B)
6-10w
Studies with trastuzumab in resectable Her2+ esophago-gastric adenocarcinoma
36 PtsResectable Her2 +,Gastric-EGJ Cancer
Primary endpoint: DFS
Perioperative Xelox-Trastuz.Xelox-T x3Surg. Xelox-T x3Tx12
P. II NEOXH (Spain)
53 Pts Resectable Her 2+, Gastric-EGJ Cancer
Primary endpoint: pCR
Perioperative FLOT-Trastuz.FLOT-T x4Surg. FLOT-T x4Tx9
P II AIO-STO 0310 (Germany)
(Hofheinz R et al, ASCO 2014, #4073) R0: 93% , pCR: 22%
(Rivera F et al, ASCO-GI 2015 #107) R0: 78% (MAGIC: 69%)pCR: 8% (MAGIC: 0%)
24 m PFS: 60% (MAGIC: 45%)24 m OS: 75% (MAGIC: 50)
USO EXPERIMENTAL/FUERA DE INDICACIÓN
Studies with trastuzumab in resectable Her2+ esophago-gastric adenocarcinoma
160 PtsResectable Her2+ Esoph-EGJ Adenoca
Primary endpoint: DFS
Preop.CarbTax-RT CarbTax/RT 50Gy Surg. P III RTOG 1010 (USA)
Preop.CarbTax-RT+ Periop.Trastuz.T-CarbTax/RT 50Gy Surg. Tx13
USO EXPERIMENTAL/FUERA DE INDICACIÓN
USO EXPERIMENTAL/FUERA DE INDICACIÓN
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del Cáncer Gástrico y Esofágico
Cisplatino-Fluoropirimidina…..¿Carboplatino?…..¿Taxanos?… antiEGFR MoAb en investigación
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del Cáncer Gástrico y Esofágico
Chemotherapy
0 5 10 15
EOX (6)XP (7)
ECX (6)ECF (6)DCF (4)EOF (6)
IF (5)CF (4)
FAMTX (2)BSC (1)
Months
C+S1 (3)
1Murad et al 1993; 2Vanhoefer et al 2000; 3Ajani et al 2009;
4Van Cutsem et al 2006; 5Dank et al 2008; 6Cunningham et al 2008; 7Kang et al 2009;
8Van Cutsem et al 2009
ChemotherapyMedian OS
10-11 m
Introducción Tratamiento de la Enfermedad Resecable
Ca. Esofago Adenoca Gástrico Adenoca de la UEG Nuevas dianas
Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico
Quimioterapia Nuevas dianas
Avances en el tratamiento del Cáncer Gástrico y Esofágico
- Succes: Trastuzumab- Doubts: Lapatinib- Hopes: T-DM1, Pertuzumab
3807 scrined pts 810 (21%) HER2+. 584 pts included
97% M1; 32% EGJ; 10% ECOG 2 CX(87%)-/F(13%)-Trast 86mg/kg/3w
P. III TOGA (C-X/F vs C-X/F-Trastuzumab)
CX(87%)/F(13%)
Bang IJ, Lancet 2010
Primary endpoint OS
OS (median) 11.1 m HR 0.74 p 0.004 13.8 mPFS(median) 5.5 m HR 0.71 p 0.0002 6.7 mRR (CR+PR) 34% p 0.001 47%
Chemotherapy
0 5 10 15
EOX (6)XP (7)
ECX (6)ECF (6)DCF (4)EOF (6)
IF (5)CF (4)
FAMTX (2)BSC (1)
Months
C+S1 (3)
1Murad et al 1993; 2Vanhoefer et al 2000; 3Ajani et al 2009;
4Van Cutsem et al 2006; 5Dank et al 2008; 6Cunningham et al 2008; 7Kang et al 2009;
8Van Cutsem et al 2009
Trastuzumab + X/FC (8) HER2 IHC 2+ / FISH+ and IHC 3+
ChemotherapyMedian OS
10-11 m
P III trials with Lapatinib
Primary endpoint: OS
OS (median) 8.9 m HR 0,84 p 0.20 11 mpts HER-2 IHQ+++ (preplanned analysis)
(median) 7.6 m HR 0,59 p 0.01 14 m
Asia, 2nd line HER2+. 261 pts Taxol-LapatinibTaxol
P. III TYTAN Yung-Jue Bang et al. ASCO-GI 2013
1st líne, HER2+. 540 pts (Asian 40%) CapOx-LapatinibCapOx
P. III LOGIC ASCO 2013
Primary endpoint OS
- OS (median) 10.5 m HR 0,91 p 0.73 12.2 m No better results in en HER-2 IHC+++ OS improvement in asian and <60 y
- PFS (median) 5.4 m HR 0,86 p <0.05 6.8 m
1st líne, HER2+ or EGFR+ 69 pts (planned 350) ECF/X-LapatinibECF/X-Pcb
P. III EORTC 40071 ASCO –GI, 2015
Primary endpoint PFS
- PFS (median) 5.9 m HR 0,94 p NS 7.1 m- OS (median) 10.1 m HR 0,90 p NS 13,8 m
USO EXPERIMENTAL/FUERA DE INDICACIÓN
Gastric Cancer: Other anti HER-2T-DM1
Phase II/III GATSBY Taxane-T-DM12nd line Taxane412 pts, HER2 + Primary endpoint: P.II: efficacy, tox
P.III: OS
Ongoing
Mechanism of action
USO EXPERIMENTAL/FUERA DE INDICACIÓN
Gastric Cancer: Other anti HER-2: Pertuzumab
Fase III JACOB (NCT01774786) QT-Tratuzumab-Pertuzumab1ª línea QT-Trastuzumab-placebo780 pts, HER2 + Objetivo 1º: Sv
En marcha
USO EXPERIMENTAL/FUERA DE INDICACIÓN
-Succes: Ramucirumab, apatinib- Deceptions: Bevacizumab, sorafenib- Hopes: Regorafenib…
Ramucirumab (IgG1 anti VGFR-2)Two positive P III in second line…
1) Fuchs CS et al. Lancet 2014; 383: 31-9
P. III REGARD 1
Advanced Gastric Adenoca. , 2nd line 355 pts (rand 2/1)
PlaceboRamucirumab 8 mg/kg cada 2 sem
OS (median) 5.2 m HR 0,77 p 0,04 3,8 mDFS(median) 2,1 m HR 0,48 p<0,0001 1,3 mPR+SD 49% p<0,0001 23%
Tox (G 3-4) Ramu / Pcb-Hypertension: 8% 3% -Haemorragia 3,4% 2,6%-Arterial TE 1,7% 0-GI Perforation 0,7% 0
Objetivo 1º: SvPrimary endpoint: OS
Months
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Pro
gre
ss
ion
Fre
e S
urv
iva
l
0.0
0.2
0.4
0.6
0.8
1.0
RamucirumabPlaceboCensored
SLPDFS
Ramucirumab (IgG1 anti VGFR-2)Two positive P III in second line …
1) Wilke H et al. Lancet Oncology 2014
P. III RAINBOW 1
Advanced Gastric cancer, 2nd line 665 pts (rand 1/1)
Paclitaxel-placebo
Paclitaxel 80 mg/m2 d 1,8,15
Ramucirumab 8mg/kg d 1, 15 cada 28d
Primary Endpoint:OS
OS (median) 9,6 m HR 0,80 p 0,01 7,3 mDFS(median) 4,4 m HR 0,63 p<0,0001 2,8 mRR 28% p<0,0001 16%PR+SD 80% p<0,0001 64%
CT in advanced Gastric CancerSecond line CT
1.- Thuss-Patience. Eur J Cancer ; 2.- S.H.Park. ASCO-11, # 4004 ; 3.- ASCO 2013, #4023
HR: 0,63
P.III Korean 2: 202 pIrino o Docetaxel vs BSC
1º endpoint: OS
HR 0,63
P. III AIO 1: 40 pIrinotecán vs BSC
1º endpoint: OS
P. III COUGAR-2 3: 168 pDocetaxel vs BSC
1ª endpoint: OS
OS 5,2m vs 3,6 m,HR 0,67, p 0,01
HR: 0,63
Kim H S et al. Ann Oncol 2013;24:2850-2854
CT in advanced Gastric CancerSecond line CT: Meta-analysis
Second line Treatmentin Advanced Gastric Cancer
S Qin et al, ASCO 2014, # 4003
VEGFR TKI: Apatinib
P. III chineseAdvanced Gastric Cancer, 3rd line
273 pts
PlaceboApatinibPrimary endpoint: OSOS (median) 6,5 m HR 0,70 p 0,01 4,7 mDFS(median) 2,6 m HR 0,44 p<0,0001 1,8 mPR+SD 42% p<0,0001 8 %
USO EXPERIMENTAL/FUERA DE INDICACIÓN
774 pts 98% M1; 14% EGJ; 5% ECOG 2intestinal 38%, diffuse 50%, mixt 8%Asia 49%, Europe 32%, America 19% CX-Beva 7,5 mg/kg/3s
P. III AVAGAST (CX vs CX-Bevacizumab)
CX-placebo
Van Cutsem E, ESMO 10 #713P; Kang, ASCO 2010 #LBA4007
OS (median) 10,1 m HR 0,87 p 0.10 12,1mDFS (median) 5.3 m HR 0,80 p 0.003 6,7 m(CR+PR) 37% p 0.03 46%No important differences in G 3-4 Toxicity
1º endpoint: OS
DFS
USO EXPERIMENTAL/FUERA DE INDICACIÓN
195 pts (asian), 1st lineM1; 15% EGJ; ECOG 0-1
CX-Sorafenib
P. III STARGATE (CX vs CX-Sorafenib)
CX
Kang YK et al, ESMO 2014 #LBA4007
1º endpoint: DFS
OS
DFS (median) 5,3 m HR 0,92 p 0.60 5,6 mOS (median ) 10,8 m HR 0,93 p 0.66 11,7 m(CR+PR) 52% p 0.82 54%
USO EXPERIMENTAL/FUERA DE INDICACIÓN
147 pts , 2ª,3ª linea, ECOG 0-1, Rand 2:1Estratificación: Región (37% Asia); líneas previas (1:43%) Placebo
P. II Rand. INTEGRATE (Regorafenib vs placebo)
Regorafenib1600 mg/d, d 1-21 cada 28d
1º endpoint: PFSPFS (median) 2,7 m HR 0,41 p<0.0001 1 mOS (median ) 6,2 m HR 0,68 p 0.06 4,7 m
Pavlakis N et al. ASCO-GI 2015
Prog
OS
USO EXPERIMENTAL/FUERA DE INDICACIÓN
- Deceptions: anti-EGFR, everolimus, ¿anti-MET/HGF?
- Hopes: Inmunoterapy…
Cetuximab and PanitumumabTwo negative P III: EXPAND and REAL-3
USO EXPERIMENTAL/FUERA DE INDICACIÓN
Everolimus
1) Ohtsu A, et al. J Clin Oncol, 2013
mTOR inhibitor
P. III GRANYTE-1 1Advanced Gastric Cancer, 2nd, 3rd line
656 pts
PlaceboEverolimus Primary endpoint: OS
OS (median) 5.4 m p 0,12 4,3 mDFS(median) 1,7 m p<0,0001 1,4 m
USO EXPERIMENTAL/FUERA DE INDICACIÓN
P III RILOMET-1 ECX-Rilotumumab (15 mg/kg)1st line , c-Met +, HER2 - ECX-Placebo609 pts, Primary endpoint: OS Cunningham D, ASCO 2015
Anti HGF/c-Met in Advanced Gastric CancerP III with Rilotumumab and Onartuzumab
P. III METGASTRIC mFOLFOX-Onartuzumab1st line , c-Met +, HER2 - mFOLFOX-placebo560 pts, Primary endpoint: OS Shah MA, ASCO 2015
OS PFS
OS and MetICH
FISH
OS PFS
PFSMet 2+/3+
OSMet 2+/3+
MET
AMG 337)
Anti HGF/c-Met in Advanced Gastric CancerAMG 337 (anti MET TKI)
F I AMG 337 (90 pts)
USO EXPERIMENTAL/FUERA DE INDICACIÓN
Kwak EL et al. ASCO-GI 2015
21 pts con C Esof-Gast Av 13 pts MET amplif
Rta: 8/13: 62%
Immunomodulators
Pembrolizumab
P I Pembrolizumab in refractory Advanced Gastric Cancer
Muro K et al, ASCO- 2015
39 pts, (19 asian)Tumours PD-L1 + (40%)RR 22%, PR+SD: 36% (Central Review)
USO EXPERIMENTAL/FUERA DE INDICACIÓN
Conclusiones: enfermedad Resecable
- Definitive chemoradiotherapy- Preoperative Chemotherapy- Preoperative Chemo-RadiotherapyEsophageal
Cancer
Gastric Cancer
- Perioperative Chemotherapy- Postoperative Chemo-Radiotherapy- Postoperative Chemotherapy ??
- Preoperative Chemo-Radiotherapy- Perioperative Chemotherapy
- Succes: Trastuzumab- Doubts: Lapatinib- Hopes: T-DM1, Pertuzumab
-Succes: Ramucirumab, apatinib- Deceptions: Bevacizumab, sorafenib- Hopes: Regorafenib…
- Deceptions: anti-EGFR, everolimus, ¿anti-MET/HGF?
- Hopes: Inmunoterapia…
Gracias
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