Avances en el tratamiento del Cáncer Gástrico y Esofágico

Transcripción

1 Avances en el tratamiento del Cáncer Gástrico y Esofágico Fernando Rivera Herrero Servicio de Oncología Médica. Hospital Universitario Marqués de Valdecilla. Santander

2 Avances en el tratamiento del Cáncer Gástrico y Esofágico 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

3 Cáncer Esófago-Gástrico Grupo heterogéneo de enfermedades Cáncer de esófago Adenoca. Gástrico - Ca. Epidermoide - Adenocarcinoma Adenocarcinoma de la UEG

4

5 Gastric Cancer: Comprehensive Molecular Characterization

6 Esophago-Gastric Cancer Resectability at Diagnosis Esophageal Cancer Gastric Cancer Pts 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

8 Treatment options in Resectable -Esophageal Cancer - EGJ Adenocarcinoma - Gastric Adenocarcinoma Esophageal Cancer Gastric Cancer - Definitive chemoradiotherapy - Preoperative Chemotherapy - Preoperative Chemo-Radiotherapy - Preoperative Chemo-Radiotherapy - Perioperative Chemotherapy - Perioperative Chemotherapy - Postoperative Chemo-Radiotherapy - Postoperative Chemotherapy??

9 Treatment options in Resectable -Esophageal Cancer - EGJ Adenocarcinoma - Gastric Adenocarcinoma Esophageal Cancer - Definitive chemoradiotherapy - Preoperative Chemotherapy - Preoperative Chemo-Radiotherapy

10 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) PF, PF, PF,PF RT (50Gy) LR control (5y) 34% P< % Systemic control (1y) 71% P< % Survival (5y) 0% P< % If no resection, CT/RT is the gold standard

11 QT/RT definitiva en C. Esófago F. III PRODIGE 5/ACCORD PTS Ca esófago (Epid/Aden) Est I-IVA FOLFOX /RT 6 ciclos, 3 concomitantes con 50Gy de RT CF/RT 4 ciclos, 2 concomitantes con 50Gy de RT Objetivo 1º: SLP (mediana) 9,7 m HR 0,93; p 0,64 9,4 m FOLFOX/RT menos tóxico E. Retrospectivo holandés (no randomizado) PTS Ca esófago (Epid/Aden) Est I-IVA Carbo-Pacli /RT CF/RT Sv (mediana) 13,8 m HR 0,97; p 0,87 16,1 m SLP (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

12 Treatment options in Resectable -Esophageal Cancer - EGJ Adenocarcinoma - Gastric Adenocarcinoma Esophageal Cancer - Definitive chemoradiotherapy - Preoperative Chemotherapy - Preoperative Chemo-Radiotherapy

13 Preoperative Chemotherapy Phase III studies Phase III Preop.CT N Pts Histol. Sv (3y,median) Preop CT vs Surg. Hatlevoll Cis/Bleo 97 Squam. 3% vs 9% prc 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 %Aden. 23% vs 26% 2,5% MRC OE-02 Cis/5-FU x %Aden 34% vs 26% * 3% * P<0.05

14 Preoperative Chemo-Radiotherapy Phase III studies Phase III Preop CT-RT N Histol. 3y Sv CT/RT/S vs Surg Postoper. Mortality CT/RT/S vs Surg Nygaard Cis-Bleo 35Gy 88 Squam 21% vs 9% 13% vs 24% prc 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 %Ade 30% vs 16% 2% vs 4% 28% Lee Cis/5FU/45Gy(28d) 101 Squam 45% vs 40% 30% Burmeister Cis-5FU / 35Gy %Ade 35% vs 31% 16% CALGB-9781 Cis-5FU / 50Gy 56 75%Ade (5a)39% vs 16%* 0% vs 8% 40% CROSS NEJIM 2012 Pacli-Carbo/ 41Gy % Ade 59% vs 48%* 3,8% vs 3,7% 33%

15 QT vs QT/RT Preoperatoria en Ca Esófago Meta-análisis Gebski et al, Lancet Oncology 07 QT/RT precx Estudios / pts QT precx Estudios / pts Supervivencia HR 0,81 (0,7-0,93) p 0,002 Supervivencia HR 0,9 (0,81-1) p 0,05 Dif absoluta Sv 2a 13 % Dif absoluta Sv 2a 7 %

16 Is it possible to avoid Surgery after 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

17 Is it possible to avoid Surgery after CT/RT? - Only in initially responding patients? Phase III FFCD 9102 (Bedenne et al, J Clin Oncol, 2007)

18 Phase III: FFCD 9102 (Bedenne, J Clin Oncol, 2007) Resectable Stage II-IV (M0) Squamous 90% 455 pts received CFx2 / 46Gy PR: 259 pts Surgery CT/RT CFx1 / 20Gy Sv (2y) 34% p NS 40% LRC(2y) 66,4 p NS 57% Treat.Mortality 9% 1% Q of L better

19 MULTIDISCIPLINARY TREATMENT OF LOCALLY ADVANCED ESOPHAGEAL CANCER UNFIT PATIENTS More toxicity and less efficacy I fulfill inclusion criteria Unfit pts: usually excluded in clinical trials

21 Treatment options in Resectable -Esophageal Cancer - EGJ Adenocarcinoma - Gastric Adenocarcinoma Gastric Cancer - Postoperative Chemotherapy -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

22 Treatment options in Resectable -Esophageal Cancer - EGJ Adenocarcinoma - Gastric Adenocarcinoma Gastric Cancer - Postoperative Chemotherapy?? -Postoperative Chemo-Radiotherapy - Perioperative Chemotherapy

23 GASTRIC GLOBAL ADVANCED/ADJUVANT STOMACH TUMOR RESEARCH THROUGH INTERNATIONAL COLLABORATION JAMA MAY 5; 303(1 7): Meta-Analysis 17 phase III trials pts Individual data 5y OS: 55% vs 49% HR: 0,82 (0,76-0,90)

24 Postoperative Chemotherapy: S-1 Phase III ACTS-GC (Japan) 1059 PTS R0 Resected Gastric adenocarc. St II-IV, D2+ nodal dissection Primary endpoint: Sv Postoperative S-1 ( S1 80mg/m2/d, d 1-28 each 42d, 1 year) No Postop treatment S1 No CT HR p Sv (3y) 80% vs 70% Sakuramoto S et al, NEJM-07

25 Postoperative Chemotherapy Phase III CLASSIC (Asia) 1035 PTS Bang et al. Lancet (Preplanned interim analysis) R0 resected Gastric cancer, D2 St II-IIIB Surgery XELOX Surgery Primary endpoint: SLP HR p. SLP (3y) 74% 0.58 < % Obj 2º OS Median follow-up 34 m

27 Postoperative Chemo-Radiotherapy SWOG 9008/INT PTS R0, St.IB-IV (M0) Gastric 80% E-G Junction 20% CT/RT FU-Lv x5 / (45 Gy) No Postop treatment Survival Sv (3 y) 50% p= % Loc.Relap(3y) 19% p= % Dist.Relap(3y) 33% 18% Macdonald et al, N Engl J Med 2001

28 Postoperative Chemo-Radiotherapy P. III CALGB 80101(US-Intergroup) 546 PTS R0 resected Gastric C. Primary endpoint: OS Surgery FLx2 F/RT FLx2 Surgery ECFx2 F/RT ECFx2 - 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)

29 Postoperative Chemo-Radiotherapy P. III ARTIST (Korea) 458 PTS R0 resected Gastric cancer, D2 St II-IV 1º endpoint: DFS Surgery XP Surgery XP/RT - 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% DFS OS Lee J et al. ASCO #4008

30 POSTOPERATIVE CHEMO-RADIOTHERAPY P. III ARTIST (Korea) Lee J et al. ASCO #4008

32 Perioperative Chemotherapy MAGIC PTS Resectable St. II-IV (M0) Gastric 74% E-G Junction 26% Survival Perioperative CT Surgery ECFx3 Surg. ECFx3 (44% of pts) Sv (3y) 43% p< % Loc Rel (3y): 29% p< % Dist Rel (3y): 31% p< % Cunningham et al, N Engl J Med 2006

33 Perioperative Chemotherapy Phase III FNLCC-ACCORD07-FFCD PTS Resectable adenocarcinoma -Gastric (no EGJ) 25 % -EGJ 64 % -distal esophagous 11 % PS 0 / 1 (75% / 25%) Perioperative CT CFx2-3 Surgery ( CF x4 postsx if OR or SD with pn+: 50% pts) Surgery Primary endpoint: Sv CF Sur Sur HR p Sv (5y) 38% vs 24% 0,66 0,01 DFS (5y) 34% vs 21% 0,65 0,003 Boige V et al, ASCO-07 # 4510

34 Should RT be added to perioperative CT? F. III CRITICS (Dutch) 788 PTS Resectable Gastric Cancer St. II-IV (M0) Primary end point: Survival 1º endpoint OS Perioperative CT Preop CT + Postop CT/RT ECX x3 Surg. ECX x3 ECX x3 Surg. RT/Xeloda OS (5 y) 40.8 m p 0, m PFS (5 y) 38.5% p 0, % PFS

35 Should RT be added to perioperative CT? - Perioperative Chemotherapy does not include RT - The addition of RT to Perioperat CT is investigational F. III TOP GEAR (International Intergroup) 752 PTS Resectable Gastric Cancer T3-4 and/or N+ (M0) Primary end point: Survival Perioperative CT ECF x3 Surg. ECF x3 Preop CT/RT + Postop CT ECF x2 RT/Fu Surg. ECFx3

37 Treatment options in Resectable -Esophageal Cancer - EGJ Adenocarcinoma - Gastric Adenocarcinoma - Preoperative Chemo-Radiotherapy - Perioperative Chemotherapy

38 Resectable EGJ adenocarcinoma F. III POET (Preop CT vs Preop CT-RT) 119 Pts in 5 y (planned 177) Siewert I / II-III 55%/45% ECOG 0/1 60%/40% Weight loss >10% 16% Primary endpoint: OS Preop. CT PFLx3 Cx Preop CT/RT PFLx2 PE/RT Cx OS (3y) 27% HR 0.67 ( ) p % Local Control (3y) 59% HR 0,45 (0,19-1,05) p % R0 69% p NS 72% pcr 2% p % Perioperative Mort. 4% p % Stahl et al. J Clin Oncol 2009; 27:

39 Resectable EGJ Adenoca Phase III POET Sv 36% 27.7% Control Local

40 Perioperative Chemotherapy in EGJ Adenoca MAGIC pts included with - Distal esophageal adenoca (73 pts) - EGJ adenoca (58 pts) FNLCC 2 64% o pts (143 pts) included with - EGJ adenoca 1.- Cunningham et al, N Engl J Med Boige et al, ASCO 2007 # 4510

41 EGJ Adenocarcinoma Siewert Clasification «Esophageal» options? Preop CT/RT «Gastric» options? Perioperative CT

43 Cetuximab-CT/RT: No metastatic Esophageal Ca P. II-III SCOPE PTS (P.III no initiated due to futility analysis) Esophageal Ca (Epid/Aden) St I-III Two negative P III Cetuxi+Cis-Cape/RT 4 courses, 3º-4º with 50Gy Cis-Cape/RT 4 courses, 3º-4º with 50Gy 1º Endpoint P II: TTF (24 w) 66% 77% OS (median) 22,1m HR 1,53; p 0,03 25,4m More Toxicity in the Cetuximab arm P.III RTOG PTS Esophageal Ca(Adenoc 62%) St I-IVA Cetuxi+Cis-Pacli/RT 50Gy Cis-Paclitaxel/RT 1º Endpoint OS (12 m) 64% p 0,7 65% OS (24 m) 44% p 0,7 42% No differences between Ca epiderm and Adenoca 50Gy 1.- Crosby T el al. Lancet Oncology 2013 ; 2.- Suntharalingam et al, ASCO-GI 2014

44 UK MRC ST03 (MAGIC-B) Phase III trial: ECX ± Beva (perioperative) in early stage GC Primary Objetive: Overall Survival Gastric or GEJ Cancer type III resectable N=1063 ECX 3 cycles ECX + Avastin 3 cycles Surgery ECX 3 cycles ECX + Avastin 3 cycles Avastin 6 cycles ECX ECX-Avastin Primary objetive: OS (3 y) 48.9% HR 1.06 p< % PFS HR 1,02 p 0.76 Cunningham et al., ECC-ESMO 2015

45 Studies with trastuzumab in resectable Her2+ esophago-gastric adenocarcinoma P. II NEOXH (Spain) 36 Pts Resectable Her2 +,Gastric-EGJ Cancer Primary endpoint: DFS Perioperative Xelox-Trastuz. Xelox-T x3 Surg. Xelox-T x3 Tx12 (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) P II AIO-STO 0310 (Germany) 53 Pts Resectable Her 2+, Gastric-EGJ Cancer Primary endpoint: pcr Perioperative FLOT-Trastuz. FLOT-T x4 Surg. FLOT-T x4 Tx9 (Hofheinz R et al, ASCO 2014, #4073) R0: 93%, pcr: 22% USO EXPERIMENTAL/FUERA DE INDICACIÓN

46 Studies with trastuzumab in resectable Her2+ esophago-gastric adenocarcinoma Preop.CarbTax-RT P III RTOG 1010 (USA) 160 Pts Resectable Her2+ Esoph-EGJ Adenoca Primary endpoint: DFS CarbTax/RT 50Gy Surg. Preop.CarbTax-RT+ Periop.Trastuz. T-CarbTax/RT 50Gy Surg. Tx13 USO EXPERIMENTAL/FUERA DE INDICACIÓN

47 USO EXPERIMENTAL/FUERA DE INDICACIÓN

48 Ongoing trials with Inmunotherapy in GC Slide 30

49 Avances en el tratamiento del Cáncer Gástrico y Esofágico Introducción Cisplatino-Fluoropirimidina Tratamiento de la Enfermedad Resecable.. Carboplatino? Ca. Esofago.. Taxanos? Adenoca F Gástrico III POWER con CF +/- panitumumab Adenoca de la UEG Nuevas dianas (Análisis intermedio de futilidad parada del reclutamiento) En inicio estudios con inmunoterapia Tratamiento de la Enfermedad Avanzada Ca. Epidermoide de esófago Adenoca del esofago distal, la UEG y gástrico Quimioterapia Nuevas dianas

51 Chemotherapy BSC (1) FAMTX (2) C+S1 (3) CF (4) IF (5) EOF (6) DCF (4) ECF (6) ECX (6) XP (7) EOX (6) Chemotherapy Median OS m Murad et al 1993; 2 Vanhoefer et al 2000; 3 Ajani et al 2009; 8 4 Van Cutsem et al 2006; 5 Van Cutsem et al 2009 Dank et al 2008; 6 Cunningham et al 2008; 7 Kang et al 2009; Months

53

54 - Succes: Trastuzumab - Dissapointment: Lapatinib T-DM1 - Hopes: Pertuzumab

55 P. III TOGA (C-X/F vs C-X/F-Trastuzumab) 3807 scrined pts 810 (21%) HER pts included 97% M1; 32% EGJ; 10% ECOG 2 CX(87%)-/F(13%)-Trast CX(87%)/F(13%) 8 6mg/kg/3w Primary endpoint OS OS (median) 11.1 m HR 0.74 p m PFS(median) 5.5 m HR 0.71 p m RR (CR+PR) 34% p % Bang IJ, Lancet 2010

56 P III trials with Lapatinib P. III TYTAN Yung-Jue Bang et al. ASCO-GI 2013 Asia, 2nd line HER pts Primary endpoint: OS P. III LOGIC ASCO 2013 Taxol Taxol-Lapatinib OS (median) 8.9 m HR 0,84 p m pts HER-2 IHQ+++ (preplanned analysis) (median) 7.6 m HR 0,59 p m 1st líne, HER pts (Asian 40%) CapOx CapOx-Lapatinib - OS (median) 10.5 m HR 0,91 p m Primary endpoint No better results in en HER-2 IHC+++ OS OS improvement in asian and <60 y - PFS (median) 5.4 m HR 0,86 p < m P. III EORTC ASCO GI, st líne, HER2+ or EGFR+ 69 pts (planned 350) ECF/X-Pcb ECF/X-Lapatinib Primary endpoint - PFS (median) 5.9 m HR 0,94 p NS 7.1 m PFS - OS (median) 10.1 m HR 0,90 p NS 13,8 m USO EXPERIMENTAL/FUERA DE INDICACIÓN

57 Gastric Cancer: Other anti HER-2 T-DM1 Mechanism of action Phase II/III GATSBY Taxane-T-DM1 2nd line Taxane 412 pts, HER2 + Primary endpoint: P.II: efficacy, tox P.III: OS USO EXPERIMENTAL/FUERA DE INDICACIÓN Kang Y-K et al. ASCO GI San Francisco 2016

58 Gastric Cancer: Other anti HER-2: Pertuzumab En marcha Fase III JACOB (NCT ) QT-Tratuzumab-Pertuzumab 1ª línea QT-Trastuzumab-placebo 780 pts, HER2 + Objetivo 1º: Sv USO EXPERIMENTAL/FUERA DE INDICACIÓN

59 -Succes: Ramucirumab, apatinib - Deceptions: Bevacizumab, sorafenib - Hopes: Regorafenib

60 Ramucirumab (IgG1 anti VGFR-2) Two positive P III in second line P. III REGARD 1 Advanced Gastric Adenoca., 2nd line 355 pts (rand 2/1) Ramucirumab 8 mg/kg cada 2 sem Placebo OS (median) 5.2 m HR 0,77 p 0,04 3,8 m DFS(median) 2,1 m HR 0,48 p<0,0001 1,3 m PR+SD 49% p<0, % Objetivo 1º: Sv Primary endpoint: OS 1) Fuchs CS et al. Lancet 2014; 383: 31-9 Progression Free Survival SLP DFS Ramucirumab Placebo Censored Months Tox (G 3-4) Ramu / Pcb -Hypertension: 8% 3% -Haemorragia 3,4% 2,6% -Arterial TE 1,7% 0 -GI Perforation 0,7% 0

61 Ramucirumab (IgG1 anti VGFR-2) Two positive P III in second line P. III RAINBOW 1 Advanced Gastric cancer, 2nd line 665 pts (rand 1/1) Primary Endpoint:OS Paclitaxel 80 mg/m2 d 1,8,15 Ramucirumab 8mg/kg d 1, 15 cada 28d Paclitaxelplacebo OS (median) 9,6 m HR 0,80 p 0,01 7,3 m DFS(median) 4,4 m HR 0,63 p<0,0001 2,8 m RR 28% p<0, % PR+SD 80% p<0, % 1) Wilke H et al. Lancet Oncology 2014

62 CT in advanced Gastric Cancer Second line CT P. III AIO 1 : 40 p Irinotecán vs BSC 1º endpoint: OS P.III Korean 2 : 202 p Irino o Docetaxel vs BSC 1º endpoint: OS P. III COUGAR-2 3 : 168 p Docetaxel vs BSC 1ª endpoint: OS HR 0,63 HR: 0,63 OS 5,2m vs 3,6 m, HR 0,67, p 0, Thuss-Patience. Eur J Cancer ; 2.- S.H.Park. ASCO-11, # 4004 ; 3.- ASCO 2013, #4023

63 CT in advanced Gastric Cancer Second line CT: Meta-analysis HR: 0,63 Kim H S et al. Ann Oncol 2013;24:

64 Second line Treatment in Advanced Gastric Cancer comorbidities, patient preferences appropiate for combined treatment no appropiate for combined treatment no appropiate for monotherapy

65 VEGFR TKI: Apatinib P. III chinese Advanced Gastric Cancer, 3rd line 273 pts Primary endpoint: OS Apatinib Placebo OS (median) 6,5 m HR 0,70 p 0,01 4,7 m DFS(median) 2,6 m HR 0,44 p<0,0001 1,8 m PR+SD 42% p<0, % S Qin et al, ASCO 2014, # 4003 USO EXPERIMENTAL/FUERA DE INDICACIÓN

66 P. III AVAGAST (CX vs CX-Bevacizumab) 774 pts 98% M1; 14% EGJ; 5% ECOG 2 intestinal 38%, diffuse 50%, mixt 8% Asia 49%, Europe 32%, America 19% CX-placebo CX-Beva 7,5 mg/kg/3s 1º endpoint: OS OS (median) 10,1 m HR 0,87 p ,1m DFS (median) 5.3 m HR 0,80 p ,7 m (CR+PR) 37% p % No important differences in G 3-4 Toxicity DFS USO EXPERIMENTAL/FUERA DE INDICACIÓN Van Cutsem E, ESMO 10 #713P; Kang, ASCO 2010 #LBA4007

67 P. III STARGATE (CX vs CX-Sorafenib) 195 pts (asian), 1st line M1; 15% EGJ; ECOG 0-1 CX CX-Sorafenib 1º endpoint: DFS DFS (median) 5,3 m HR 0,92 p ,6 m OS (median ) 10,8 m HR 0,93 p ,7 m (CR+PR) 52% p % OS USO EXPERIMENTAL/FUERA DE INDICACIÓN Kang YK et al, ESMO 2014 #LBA4007

68 P. II Rand. INTEGRATE (Regorafenib vs placebo) 147 pts, 2ª,3ª linea, ECOG 0-1, Rand 2:1 Estratificación: Región (37% Asia); líneas previas (1:43%) Regorafenib 1600 mg/d, d 1-21 cada 28d Prog Placebo 1º endpoint: PFS PFS (median) 2,7 m HR 0,41 p< m OS (median ) 6,2 m HR 0,68 p ,7 m OS USO EXPERIMENTAL/FUERA DE INDICACIÓN Pavlakis N et al. ASCO-GI 2015

69 - Deceptions: anti-egfr, everolimus, anti-met/hgf - Hopes: Inmunoterapy

70 Cetuximab and Panitumumab Two negative P III: EXPAND and REAL-3 USO EXPERIMENTAL/FUERA DE INDICACIÓN

71 Everolimus mtor inhibitor P. III GRANYTE-1 1 Advanced Gastric Cancer, 2nd, 3rd line 656 pts Primary endpoint: OS Everolimus Placebo OS (median) 5.4 m p 0,12 4,3 m DFS(median) 1,7 m p<0,0001 1,4 m 1) Ohtsu A, et al. J Clin Oncol, 2013 USO EXPERIMENTAL/FUERA DE INDICACIÓN

72 Anti HGF/c-Met in Advanced Gastric Cancer P III with Rilotumumab and Onartuzumab P III RILOMET-1 ECX-Rilotumumab (15 mg/kg) 1st line, c-met +, HER2 - ECX-Placebo 609 pts, Primary endpoint: OS Cunningham D, ASCO 2015 ICH OS and Met OS PFS FISH P. III METGASTRIC mfolfox-onartuzumab 1st line, c-met +, HER2 - mfolfox-placebo 560 pts, Primary endpoint: OS Shah MA, ASCO 2015 PFS Met 2+/3+ OS PFS OS Met 2+/3+

73 Anti HGF/c-Met in Advanced Gastric Cancer AMG 337 (anti MET TKI) AMG 337) F I AMG 337 (90 pts) MET 21 pts con C Esof-Gast Av 13 pts MET amplif Rta: 8/13: 62% Kwak EL et al. ASCO-GI 2015 USO EXPERIMENTAL/FUERA DE INDICACIÓN

74 Inmunocheckpoints Responsables de la tolerancia periférica Pueden ser desregulados por tumores como mecanismo de evasión inmune Manipulación induce respuestas antitumorales

75 P I Pembrolizumab in refractory Advanced Gastric Cancer 39 pts, Tumours PD-L1 + (40%) RR 22%, PR+SD: 36% (Central Review) Muro K et al, ASCO USO EXPERIMENTAL/FUERA DE INDICACIÓN

76 P I JAVELIN 1 : Nivolumab in 1st line manteinement or 2nd line Advanced Gastric Cancer 52 pts Tumours PD-L1 +/- RR (9% 1Lm ; 9,7% 2L) 1/3 were durable No clear predictive value of PD-L1 Rand P I/II CheckMate : Nivo vs Nivo3+Ipi1 vs Nivo1+Ipi3 in 2nd line Gastric Cancer Advanced Gastric Cancer 160 pts Tumours PD-L1 +/- RR : 16% DC: 36% Better PFS Nivo1+Ipi23 P III trial Rand P II 3 : Ipi vs Obs as manteinement after 1st line in Advanced Gastric Cancer 114 pts Negative trial (no dif in irpfs nor OS USO EXPERIMENTAL/FUERA DE INDICACIÓN 1.- Chung HC et al. ASCO 2016 # 4009; 2.- Janjijian YY, et al. ASCO 2016 # Moehler M et al. ASCO 2016 #4011

77 Ongoing trials with Inmunotherapy in GC Slide 30

78 Rand P. II FAST (IMAB 362 in 1st line AGC) 161 pts HER2- and Claudine + (48%) 1st line AGC IMAB + EOF/X EOF/X PFS (median) 7.9 m HR 0,5 p m OS (median ) 13.2 m HR 0,51 p < m OS in High claudina HR 0,44 1º endpoint: PFS OS USO EXPERIMENTAL/FUERA DE INDICACIÓN Al-Batran SE et al. ASCO 2016 #4001

79 Conclusiones: enfermedad Resecable Esophageal Cancer Gastric Cancer - Definitive chemoradiotherapy - Preoperative Chemotherapy - Preoperative Chemo-Radiotherapy - Preoperative Chemo-Radiotherapy - Perioperative Chemotherapy - Perioperative Chemotherapy - Postoperative Chemo-Radiotherapy - Postoperative Chemotherapy??

80 - Succes: Trastuzumab - Deceptions: Lapatinib, T-DM1 - Hopes: Pertuzumab -Succes: Ramucirumab, apatinib - Deceptions: Bevacizumab, sorafenib - Hopes: Regorafenib - Deceptions: anti-egfr, everolimus, anti-met/hgf - Hopes: Immunotherapy, anticlaudine

81 Gracias