Hacia dnde vamos en el tratamiento del cncer

¿Hacia dónde vamos en el tratamiento del cáncer gástrico? Fernando Rivera Herrero Jefe del

¿Hacia dónde vamos en el tratamiento del cáncer gástrico? n n Introduction Anti-HER 2

Gastric Cancer: Comprehensive Molecular Characterization

Gastric adenocarcinoma INTRODUCTION Gastric adenoca n 5 y OS 25% 1 5 y OS

P. III TOGA (C-X/F vs C-X/F-Trastuzumab) 3807 scrined pts 810 HER 2+. 584 pts

P III trials with Lapatinib P. III TYTAN Yung-Jue Bang et al. ASCO-GI 2013

Gastric Cancer: Other anti HER-2 T-DM 1 Mechanism of action Phase II/III GATSBY Taxane-T-DM

Gastric Cancer: Other anti HER-2: Pertuzumab Ongoing P III JACOB (NCT 01774786) CT-Tratuzumab-Pertuzumab 1

Studies with trastuzumab in resectable Her 2+ esophago-gastric adenocarcinoma P. II NEOXH (Spain) 36

Ramucirumab P. III REGARD 1 (Ig. G 1 anti VGFR-2) Two positive P III

Ramucirumab (Ig. G 1 anti VGFR-2) Two positive P III in second line …

Second line Treatment in Advanced Gastric Cancer comorbidities, patient preferences appropiate for combined treatment

VEGFR TKI: Apatinib P. III chinese Advanced Gastric Cancer, 3 rd line 273 pts

P. III AVAGAST (CX vs CX-Bevacizumab) 774 pts 98% M 1; 14% EGJ; 5%

UK MRC ST 03 (MAGIC-B) Phase III trial: ECX ± Beva (perioperative) in early

P. III STARGATE (CX vs CX-Sorafenib) 195 pts (asian), 1 st line M 1;

Rand P. II INTEGRATE (Regorafenib vs placebo) 147 pts , 2 nd, 3 rd

Immunotherapy in Gastric Cancer n Immunomodulation Immune “check points” n Other Immunotherapies

Pembrolizumab: P I KEYNOTE 012. Gastric cancer cohort 39 pts PD-L 1 + RR

Kaplan-Meier Estimates of Survival b ma u z i l o going T+Pembr line

Checkpoint inhibitors in GC: nivolumab, ipilimumab P I JAVELIN 1: Nivolumab in 1 st

Ongoing trials with Inmunotherapy in GC Slide 30

Rand P. II FAST (IMAB 362 in 1 st line AGC) 161 pts HER

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

Everolimus m. TOR inhibitor P. III GRANYTE-1 1 Advanced Gastric Cancer, 2 nd, 3

AZD 4547 Rand P. II SHINE (anti FGFR 2) 1 Advanced Gastric Cancer, 2

Anti HGF/c-Met in Advanced Gastric Cancer P III with Rilotumumab and Onartuzumab P III

Olaparib P. III GOLD (PARP inhibitor) 1 Advanced Gastric Cancer, 2 nd, 3 rd

GENETIC ABNORMALITIES IN GASTRIC CANCER All Gastric cancers

n Anti-HER-2 Conclusions SUCCESS with Trastuzumab, But Negativ results with Lapatinib and T-DM 1

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¿Hacia dónde vamos en el tratamiento del cáncer gástrico? Fernando Rivera Herrero Jefe del Sv Oncología Médica Hospital U. “Marqués de Valdecilla”, Santander

¿Hacia dónde vamos en el tratamiento del cáncer gástrico? n n Introduction Anti-HER 2 n n n n Success: Ramucirumab, Apatinib Disappointment: bevacizumab, sorafenib Developing: regorafenib… Inmunotherapy Other biologics n n n Success: Trastuzumab Disappointment: Lapatinib, T-DM 1 Hopes: Pertuzumab Resectable disease Antiangiogenics n n SUMMARY Negative trials: anti-EGFR, everolimus, anti FGFR 2, anti-MET/HGF, olaparib Genome-guided personalized therapy Conclusions

Gastric Cancer: Comprehensive Molecular Characterization

Gastric adenocarcinoma INTRODUCTION Gastric adenoca n 5 y OS 25% 1 5 y OS n Stage n n Resectable: Early disease (T 1 -2, N 0 M 0) 10% pts 5 y OS: > 80% Resectable: Loc. Advanced (T 3 -4 or N+ M 0) 40% pts 5 y OS: 30% Unresectable Loc. Advanced 15% pts Median OS: 18 m Metastatic 35% pts Median OS: 11 m 1. - De Angelis R et al. EUROCARE-5. Lancet Oncol 2014; 15: 23– 34

ase e s i d nced a v d a y in p a r e h cin) t i o b u m r e i ep d ch r r o a 2008) l , d e 6 n x 0 a a 3 t V cet os o n d P. III : s s i / n / 4 e o + 1 0 -Ther priate opti yrimidine ( Nov-2 ; l a i r p ro o Intg T p r h p o c n u A l e r +f n III F i P t ( a l F p /IL I R I F -FOL Chemotherapy BSC (1) FAMTX (2) C+S 1 (3) CF (4) IF (5) EOF (6) DCF (4) ECF (6) ECX (6) XP (7) EOX (6) 0 1 Murad Chemotherapy Median OS 10 -11 m 5 et al 1993; 2 Vanhoefer et al 2000; 3 Ajani et al 2009; 8 4 Van Cutsem et al 2006; 5 Dank et al 2008; Van Cutsem et al 2009 6 Cunningham et al 2008; 7 Kang et al 2009; 10 15 Months

P. III TOGA (C-X/F vs C-X/F-Trastuzumab) 3807 scrined pts 810 HER 2+. 584 pts included 97% M 1; 32% EGJ; CX(87%)-/F(13%)-Trast 10% ECOG 2 CX(87%)/F(13%) Primary endpoint OS OS (median) 11. 1 m PFS(median) 5. 5 m RR (CR+PR) 34% Bang IJ, Lancet 2010 8 6 mg/kg/3 w HR 0. 74 HR 0. 71 p 0. 004 p 0. 0002 p 0. 001 13. 8 m 6. 7 m 47%

P III trials with Lapatinib P. III TYTAN Yung-Jue Bang et al. ASCO-GI 2013 Asia, 2 nd line HER 2+. 261 pts Taxol Primary endpoint: OS P. III LOGIC OS (median) 8. 9 m Taxol-Lapatinib HR 0, 84 p 0. 20 11 m pts HER-2 IHQ+++ (preplanned analysis) (median) 7. 6 m HR 0, 59 p 0. 01 14 m ASCO 2013 1 st líne, HER 2+. Cap. Ox-Lapatinib 540 pts (Asian 40%) - OS (median) 10. 5 m HR 0, 91 p 0. 73 12. 2 m Primary endpoint No better results in en HER-2 IHC+++ OS improvement in asian and <60 y - PFS (median) P. III EORTC 40071 1 st líne, HER 2+ or EGFR+ 5. 4 m HR 0, 86 p <0. 05 6. 8 m ASCO –GI, 2015 ECF/X-Pcb ECF/X-Lapatinib 69 pts (planned 350) 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

Gastric Cancer: Other anti HER-2 T-DM 1 Mechanism of action Phase II/III GATSBY Taxane-T-DM 1 2 nd line Taxane 345 pts, HER 2 + Primary endpoint: P. II: efficacy, tox P. III: OS USO EXPERIMENTAL/FUERA DE INDICACIÓN Kang Y-K et al. ASCO GI San Francisco 2016

Gastric Cancer: Other anti HER-2: Pertuzumab Ongoing P III JACOB (NCT 01774786) CT-Tratuzumab-Pertuzumab 1 st line CT-Trastuzumab-placebo 780 pts, HER 2 + 1º endpoint: OS USO EXPERIMENTAL/FUERA DE INDICACIÓN

Studies with trastuzumab in resectable Her 2+ esophago-gastric adenocarcinoma P. II NEOXH (Spain) 36 Pts Resectable Her 2 +, Gastric-EGJ Cancer Primary endpoint: 18 m DFS Perioperative Xelox-Trastuz. Xelox-T x 3 Surg. Xelox-T x 3 Tx 12 (Rivera F et al, ASCO-GI 2015 #107) R 0: 78% p. CR: 8% 24 m PFS: 60% 24 m OS: 75% (MAGIC: 69%) (MAGIC: 0%) (MAGIC: 45%) (MAGIC: 50%) P II AIO-STO 0310 (Germany) 53 Pts Resectable Her 2+, Gastric-EGJ Cancer Primary endpoint: p. CR Perioperative FLOT-Trastuz. FLOT-T x 4 Surg. FLOT-T x 4 Tx 9 (Hofheinz R et al, ASCO 2014, #4073) R 0: 93% USO EXPERIMENTAL/FUERA DE INDICACIÓN , p. CR: 22%

USO EXPERIMENTAL/FUERA DE INDICACIÓN

Ramucirumab P. III REGARD 1 (Ig. G 1 anti VGFR-2) Two positive P III in second line… Advanced Gastric Adenoca. , 2 nd line 355 pts (rand 2/1) Ramucirumab OS (median) 5. 2 m DFS(median) 2, 1 m PR+SD 49% Objetivo 1º: Sv. OS Primary endpoint: 1) Fuchs CS et al. Lancet 2014; 383: 31 -9 SLP DFS Placebo 8 mg/kg cada 2 sem HR 0, 77 HR 0, 48 p 0, 04 p<0, 0001 3, 8 m 1, 3 m 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

Ramucirumab (Ig. G 1 anti VGFR-2) Two positive P III in second line … P. III RAINBOW 1 Advanced Gastric cancer, 2 nd line 665 pts (rand 1/1) Primary Endpoint: OS Paclitaxel Ramucirumab 80 mg/m 2 d 1, 8, 15 8 mg/kg d 1, 15 cada 28 d 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, 0001 16% PR+SD 80% p<0, 0001 64% 1) Wilke H et al. Lancet Oncology 2014

n Ficha técnica (AEMPS)

Second line Treatment in Advanced Gastric Cancer comorbidities, patient preferences appropiate for combined treatment ECOG 0 -1 ¿ 2? no appropiate for combined treatment no appropiate for monotherapy

VEGFR TKI: Apatinib P. III chinese Advanced Gastric Cancer, 3 rd line 273 pts Primary endpoint: OS OS (median) Apatinib Placebo 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, 0001 8 % S Qin et al, ASCO 2014, # 4003 USO EXPERIMENTAL/FUERA DE INDICACIÓN

P. III AVAGAST (CX vs CX-Bevacizumab) 774 pts 98% M 1; 14% EGJ; 5% ECOG 2 intestinal 38%, diffuse 50%, mixt 8% Asia 49%, Europe 32%, America 19% 1º endpoint: OS CX-placebo CX-Beva 7, 5 mg/kg/3 s OS (median) 10, 1 m HR 0, 87 p 0. 10 12, 1 m DFS (median) 5. 3 m HR 0, 80 p 0. 003 6, 7 m p 0. 03 46% (CR+PR) 37% No important differences in G 3 -4 Toxicity DFS Van Cutsem E, ESMO 10 #713 P; USO EXPERIMENTAL/FUERA DE INDICACIÓN Kang, ASCO 2010 #LBA 4007

UK MRC ST 03 (MAGIC-B) Phase III trial: ECX ± Beva (perioperative) in early stage GC Primary Objetive: Overall Survival ECX 3 cycles Gastric or GEJ Cancer type III resectable N=1063 ECX 3 cycles Surgery ECX + Avastin 3 cycles ECX Primary objetive: OS (3 y) PFS Cunningham et al. , ECC-ESMO 2015 48. 9% Avastin 6 cycles ECX-Avastin HR 1. 06 p<0. 47 HR 1, 02 p 0. 76 47. 6%

P. III STARGATE (CX vs CX-Sorafenib) 195 pts (asian), 1 st line M 1; 15% EGJ; ECOG 0 -1 CX 1º endpoint: DFS CX-Sorafenib DFS (median) 5, 3 m OS (median ) 10, 8 m (CR+PR) 52% HR 0, 92 HR 0, 93 p 0. 60 p 0. 66 p 0. 82 5, 6 m 11, 7 m 54% OS Kang YK et al, ESMO 2014 #LBA 4007 USO EXPERIMENTAL/FUERA DE INDICACIÓN

Rand P. II INTEGRATE (Regorafenib vs placebo) 147 pts , 2 nd, 3 rd line, ECOG 0 -1, Rand 2: 1 Stratification: Region (37% Asia); previous lines (1: 43%) Placebo Regorafenib Prog 1600 mg/d, d 1 -21 each 28 d 1º endpoint: PFS (median) 2, 7 m HR 0, 41 p<0. 0001 OS (median ) 6, 2 m HR 0, 68 p 0. 06 1 m 4, 7 m OS USO EXPERIMENTAL/FUERA DE INDICACIÓN Pavlakis N et al. ASCO-GI 2015

Immunotherapy in Gastric Cancer n Immunomodulation Immune “check points” n Other Immunotherapies

Pembrolizumab: P I KEYNOTE 012. Gastric cancer cohort 39 pts PD-L 1 + RR 22%, PR+SD: 36% Bang et al, ASCO- 2015 USO EXPERIMENTAL/FUERA DE INDICACIÓN (Central Review)

Kaplan-Meier Estimates of Survival b ma u z i l o going T+Pembr line n o C nd rials t 2 s I I v d I n P a CT in 1 st Presented By Yung-Jue Bang at 2015 ASCO Annual Meeting

Checkpoint inhibitors in GC: nivolumab, ipilimumab P I JAVELIN 1: Nivolumab in 1 st line manteinement or 2 nd line Advanced Gastric Cancer 52 pts Tumours PD-L 1 +/RR (9% 1 Lm ; 9, 7% 2 L) 1/3 were durable No clear predictive value of PD-L 1 Rand P I/II Check. Mate 032 2: Nivo vs Nivo 3+Ipi 1 vs Nivo 1+Ipi 3 in 2 nd line Gastric Cancer Advanced Gastric Cancer 160 pts Tumours PD-L 1 +/RR : 16% DC: 36% Better PFS Nivo 1+Ipi 3 P III trial Rand P II 3: Ipi vs Obs as manteinement after 1 st line in Advanced Gastric Cancer 114 pts Negative trial (no dif in ir. PFS nor OS 1. - Chung HC et al. ASCO 2016 # 4009; 2. - Janjijian YY, et al. ASCO 2016 #4010 3. - Moehler M et al. ASCO 2016 #4011 USO EXPERIMENTAL/FUERA DE INDICACIÓN

Ongoing trials with Inmunotherapy in GC Slide 30

Gastric Cancer: Comprehensive Molecular Characterization

Rand P. II FAST (IMAB 362 in 1 st line AGC) 161 pts HER 2 - and Claudine + (48%) 1 st line AGC IMAB + EOF/X PFS (median) 7. 9 m OS (median ) 13. 2 m OS in High claudina 1º endpoint: PFS USO EXPERIMENTAL/FUERA DE INDICACIÓN HR 0, 51 EOF/X 5. 7 m p 0. 001 p < 0. 05 8. 4 m HR 0, 44 OS Al-Batran SE et al. ASCO 2016 #4001

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

Everolimus m. TOR inhibitor P. III GRANYTE-1 1 Advanced Gastric Cancer, 2 nd, 3 rd 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

AZD 4547 Rand P. II SHINE (anti FGFR 2) 1 Advanced Gastric Cancer, 2 nd, 3 rd line - FGFR 2 polysomy or gene amplification (FISH) 960 pts screened 71 pts included AZD 4547 Paclitaxel Primary endpoint: PFS (median) 1. 5 m 3. 5 m 1) Bang YJ, et al. ASCO 2015 USO EXPERIMENTAL/FUERA DE INDICACIÓN

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

Olaparib P. III GOLD (PARP inhibitor) 1 Advanced Gastric Cancer, 2 nd, 3 rd line 525 pts (Asia) (18% ATM – (IHQ) Co-Primary endpoints: Olaparib (100 mg/12 h) OS (all pts) OS (ATM- pts) + Paclitaxel p < 0, 025 (Hochberg approach) OS (median) All pts 8. 8 m ATM- pts 12 m Placebo + Paclitaxel HR 0. 79 p 0, 026 HR 0. 73 p 0, 24 6. 9 m 10 m 1) Bang et al. ESMO 2016. # LBA 25 USO EXPERIMENTAL/FUERA DE INDICACIÓN

GENETIC ABNORMALITIES IN GASTRIC CANCER All Gastric cancers

n Anti-HER-2 Conclusions SUCCESS with Trastuzumab, But Negativ results with Lapatinib and T-DM 1 WAITING for the P III with Pertuzumab n Slow development in RESECTABLE DISEASE Antiangiogenics SUCCESS with Ramucirumab and Apatinib DISAPPOINTMENT: Bevacizumab (advanced / periop. ) , Sorafenib WAITING for Regorafenib n n Inmunotherapy: Other Biologics Negative trials: Waiting for Phase III. combinations Selection of pts anti-EGFR, everolimus, anti FGFR 2, anti-MET/HGF, olaparib Genome-guided personalized therapy

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