What’s New In UGI Tract Cancers? David H. Ilson, M.D., Ph.D. Attending Physician Memorial Sloan-Kettering Cancer Center New York

Disclosure Research Support Genentech Bristol Myers Squibb / Imclone Sanofi-Aventis Bayer

Esophageal and Gastric Carcinoma US Incidence in 2013 39,590 new cases Gastric: 21,600 (54%) Esophagus: 17,900 (46%) Decline in Gastric Cancer Incidence Increase in Esophageal , GE JX, cardia adeno OS improvement, 1975-77, 1984-86, 1999-2006 Gastric: 16%  18%  27% Esophageal: 5%  10%  19% Siegel et al, CA 63: 11-30; 2013

Gastric and Esophageal Cancer RNA expression signatures Intestinal Cancer Diffuse Cancer GEJ Cancer Shah M A et al. Clin Cancer Res 2011;17:2693-2701 ©2011 by American Association for Cancer Research

GEJ Cancer Diffuse Cancer Intestinal Cancer

Esoph and GEJ: Preop therapy for T2-3 or N+ EMR for T1a Surgery for T1b

Esophageal and GEJ Adenoca: Consensus on Adjuvant Therapy T2-3 or N+: Something more than surgery alone should be done Preop chemo ECF, CF improves overall survival in some but not all trials MAGIC (ECF): 13% ↑ OS at 5 yr (esophageal and GEJ 25% pts) FFCD / FNLC (CF): 14% ↑ OS at 5 yr (esophageal and GEJ cancer, 180 pts)  same as MAGIC, no epirubicin Cunningham NEJM 355: 11; 2006 ,Ychou J Clin Oncol 29: 1715; 2011,

Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy Trials focusing purely on esophageal and GE junction cancers Preop chemo CF failed: MRC 0E0-2 (CF): 800 pts, adeno and squam 5 year update: 6% ↑OS Impacted only on rate of R0 resection U.S. INT 113 (CF): 450 pts, adeno and squam No impact on OS or rate of R0 resection EORTC 40954 (CF): 70 pts, adeno No impact on OS Allum J Clin Oncol 2009, Kelsen NEJM 1998, Schuhmacher J Clin Oncol 28: 5210; 2010

Preop Chemo vs Surgery Alone: 2062 patients, 10 Trials HR favoring Chemo 0.87 (p = 0.005) Squamous: HR 0.92 (p = 0.18) Adeno: HR 0.83 (p = 0.01) Sjoquist Lancet Oncol 12: 681; 2011

Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29 Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE) Van Hagen et al NEJM 366: 2074; 2012

CROSS: Major Results EUS staged patients T3N0-1 75%, median age 60 74% Adenocarcinoma 93% received all courses chemotherapy 23% had > = grade 3 toxicity from pre-op therapy Post-operative morbidity and mortality almost identical (mortality 3.7-3.8%)

Resection rate and resection margins Resection rate of all randomized patients Surgery alone CRT + surgery 186/188 (99%) 168/178 (95%) Resection margins R0 111/161 (69%) 148/161 (92%) p<0.002 R0 = no tumor within 1 mm of the resection margins CROSS study

Overall Survival Improved with Chemo RT + Surgery 5-year survival 47% versus 34% Median survival 49.4 versus 24 months, HR 0.66, p = 0.003) Squamous HR 0.453 Adeno HR 0.732 Squamous path CR 49%, Adeno 23% (p = 0.008)

Preop Chemo RT vs Surgery Alone: 1932 patients, 13 trials HR favoring Chemo RT 0.78 (p < 0.0001) Squamous HR 0.8 (p = 0.004) Adeno HR 0.75 ( p = 0.02) Sjoquist Lancet Oncol 12: 681; 2011

Esophageal Cancer: Preop Chemo, RT, or Both? Conclusions Esophageal, GEJ Adeno Preop ECF Chemo improves survival and is feasible Preop RT + Chemo: superior OS, more path CR’s Esophageal Squamous RT + Chemo: As primary therapy without surgery is preferred Surgery after chemo RT: in selected patients Improved local control  no improvement in survival

PET Scan Directed Therapy Trial Design: CALGB 80803 PET-responders: ≥ 35% SUV decrease: continue same chemo + concurrent RT (5040cGy in 180cGy fx) T3/4 or N1 Esophageal Adenoca PET/CT: Induction Chemo: FOLFOX6 or Carbo/Pacliotaxel Surgical resection 6 weeks post-RT PET Scan day 29-35 PET- nonresponders: < 35% SUV decrease: Cross over to alternate chemo + RT (5040cGy in 180cGy fx) Hypothesis: changing chemo in PET non responding patients will improve pCR during chemo + RT

Optimal Surgery for Gastric Cancer? D2 resection is the standard of care in Asia Increasingly in the West D2 resection is considered the standard Update of Dutch D1 vs D2 resection at 15 years supports D2: Songun I et al Lancet Oncol 11: 439; 2010

Adjuvant Therapy in Gastric Cancer Improves OS Post op RT + chemo (U.S.), less than a D1-2 resection 5FU-LV + RT, INT 116: 10% 5 yr OS, HR 0.65 Pre and post op chemo (U.K.) without RT ECF, MAGIC: 13% 5 yr OS, HR 0.75 Post op chemo (Asia): 2 trials, 2000 pts, D2 resection, no RT S-1 (Oral 5-FU), ACTS-GC: 13% 5 yr OS, HR 0.67 (2011 update) Post op Cape-Oxali , CLASSIC Trial: 14% 3 yr DFS, HR 0.56 Survival improvements with all approaches similar, modest Cunningham NEJM 355: 11; 2006 Sasako JCO 29: 4387; 2011 Bang Lancet 379: 315-321; 2012 Macdonald NEJM 345:725; 2001

CLASSIC study design 8 cycles of XELOX (6 months) R A N D O M I Z A T I O N Surgically (D2) resected Stage II, IIIA, or IIIB GC, 6 weeks prior to randomization No prior chemotherapy or radiotherapy n=1035 n=520 8 cycles of XELOX (6 months) Capecitabine: 1,000mg/m2 bid, d1–14, q3w Oxaliplatin: 130mg/m2, d1, q3w 1:1† Observation: No adjuvant therapy n=515 Primary endpoint: 3-year DFS‡ Secondary endpoints: overall survival and safety profile †Stratified by stage and country with age, sex, and nodal status as covariates ‡GASTRIC project: 3-year DFS and 5-year overall survival are strongly associated, Burzykowski et al. ASCO 2009 Bang Lancet 379: 315-321; 2012 19

Primary endpoint (3-year DFS) met at interim analysis 1.0 0.8 74% XELOX, n=520 0.6 60% Observation, n=515 0.4 0.2 HR=0.56 (95% CI 0.44–0.72) P<0.0001 0.0 6 12 18 24 30 36 42 48 Time (months) No. left XELOX 520 443 410 333 246 166 74 30 10 Observation 515 414 352 286 209 147 58 22 6 ITT population; DFS = disease-free survival Median follow-up 34.4 months (range 16–51) Bang Lancet 379: 3150321; 2012

3-year DFS by stratification factors Category Subgroup HR (95% CI) n HR estimate All 1,035 0.58 Stage of disease Stage II Stage IIIA Stage IIIB 515 377 143 0.55 0.56 0.57 Age group, years <65 ≥65 766 269 0.63 0.46 Sex Female Male 304 731 0.81 0.49 Nodal status N0 N1/2 103 932 0.83 0.56 2 1 0.6 0.4 0.2 ITT population

European / Asian Gastric Adjuvant Trials: Is RT required post op? CRITICS Trial (NL): randomization + / - RT Preop ECX D1 resection Post op chemo + / - RT Korea ARTIST trial: chemo + / - RT (JCO 2011) D2 resection Post op Cape/Cis x 6 mos + / - Post op RT 5% increase in 3 yr DFS, N+ Repeat trial planned targeting N+ pts TROG (Australia): Preop ECF + / - Preop RT Esophageal and gastric, 750 pts

Advanced Gastric Cancer Chemotherapy: What regimen to use? Oxali: EOX or EOF Cape: ECX or EOX XP FLO FUFIRI S-1 Cis DCF ECF Pts 489 513 160 109 170 305 221 126 %RR 44% 45% 41% 34% 32% 54% 36% TTP, mos 6.7 6.5 5.6 5.5 5.0 6.0 7.4 OS, mos 10.9 10.4 10.5 10.7 9.0 13.0 9.2 8.9

Second Line Chemo: Gastric Cancer AGC refractory to prior FP confirmed by imaging Age 20-75, PS 0-2, No history of CPT-11 or Taxane RANDOMIZATION Stratified by Institution, PS 0-1/2, target lesion -/+ weekly Paclitaxel 80 mg/m2 d1, 8, 15 q4w IRI 150 mg/m2 d1, 15 q4w Ueda et al Proc ASCO 2012

Overall Survival IRI wPTX n 111 108 Median 8.4M 9.5M P 0.38 HR (95% CI) 1.13 (0.86-1.49) Log-rank test Probability (%) (Months) Number at risk wPTX IRI 108 111 80 75 36 29 10 2 3 1 1 FAS

Progression Free Survival IRI wPTX n 111 108 Median 2.3M 3.6M P 0.33 HR (95% CI) 1.14 (0.88-1.49) 3.6 Probability (%) 2.3 Log-rank test (Months) Number at risk wPTX IRI 108 111 66 46 16 18 9 8 3 6 2 2 1 FAS

Response Rate n CR PR SD PD NE CR+PR P wPTX 91 19 38 32 2 21% 0.24 IRI 19 38 32 2 21% 0.24 IRI 88 1 11 28 45 3 14% RECIST 1.0 Fisher’s exact test

Ford et al GI Symposium 2013 Kang JCO 30: 1513-1518/ 2012 Second Line Chemotherapy post Platin + 5-FU: Further support for Taxanes Cougar Trial-02 (U.K.) (GI Symposium 2013) 168 pts with gastric and GEJ cancer BSC vs docetaxel 75 mg/m2 every 3 weeks OS improved from 3.6  5.2 months (HR 0.67, p = 0.01) Responses in 7% of patients Kang (JCO): 202 pts with gastric cancer Docetaxel 60 mg/m2 or irinotecan 150 mg/m2 every 3 weeks vs BSC OS improved from 3.8  5.3 months (HR 0.657, p = 0.007) RR 10% irinotecan, 17% for docetaxel Ford et al GI Symposium 2013 Kang JCO 30: 1513-1518/ 2012

Kaplan-Meier estimates for overall survival in randomly assigned patients. Kang J H et al. JCO 2012;30:1513-1518 ©2012 by American Society of Clinical Oncology

Molecular Targets: Gastric Cancer KRAS mutation: < 5-10% BRAF mutation: < 5% EGFr over expression: 50-80% EGFr mutation: < 5% CMET: < 10%, IHC + 40% HER2 over expression: 10-25% TOGA: Trastuzumab + chemo improves OS in HER2+ Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006 Gold GI CA Symp 2008 Abs 96

ToGA trial design Phase III, randomized, open-label, international, multicenter study 5-FU or capecitabinea + cisplatin (n=290) 3807 patients screened1 810 HER2-positive (22.1%) HER2-positive advanced GC (n=584) R 5-FU or capecitabinea + cisplatin + trastuzumab (n=294) Stratification factors advanced vs metastatic GC vs GEJ measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU aChosen at investigator’s discretion GEJ, gastroesophageal junction 1Bang et al; Abstract 4556, ASCO 2009

Primary end point: OS Event 1.0 Median OS 13.8 11.1 0.9 Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 11.1 13.8 0.1 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 1 T, trastuzumab

OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) Event 1.0 Median OS 16.0 11.8 Events 120 136 HR 0.65 95% CI 0.51, 0.83 0.9 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 0.1 11.8 16.0 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 228 218 218 198 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 1

Secondary end point: tumor response rate Intent to treat Patients (%) p=0.0017 F+C + trastuzumab p=0.0145 F+C 47.3% 41.8% 34.5% 32.1% p=0.0599 5.4% 2.4% CR PR ORR ORR= CR + PR CR, complete response; PR, partial response

Secondary end point: PFS Event 1.0 Median PFS 6.7 5.5 Events 226 235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 0.9 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 0.1 5.5 6.7 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (months) No. at risk 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 2

Targeted Agents Phase III: HER2: Met Disease LOGIC: Cape-Ox + / - Lapatinib (HER2+) TYTAN: Paclitaxel + / - Lapatinib (HER2+) Second Line PFS and Survival Benefit in subset of patients IHC 3+ for lapatinib OS 7.6  14.0 months, HR 0.59, p = 0.0176 Bang et al GI Cancers Symposium 2013 Abstract 11

HER 2 Directed Therapy Trials in development First Line: Capecitabine-Cisplatin -Trastuzumab + / - Pertuzumab Second line: Paclitaxel vs TDM-1 Second line MSKCC: Afatinib single agent

RTOG 1010: Phase II Study of Neoadjuvant Trastuzumab and Chemoradiation for Esophageal Adenocarcinoma (Siewert I, II) ‘ CHEMORADIATION SURGERY HER-2 (+) (FISH) TRASTUZUMAB + CHEMORADIATION SURGERY + TRASTUZUMAB (1 YR) HER-2 (-) (FISH) ALTERNATIVE STUDIES Chemoradiation: 5-FU + Oxaliplatin, RT 5040 cGy  Surgery Maintenance trastuzumab post op Sample Size = 130 Her-2 (+) Pts, Increase 3-Yr Survival from 30% to 50%. 520+ pts to be screened

Targeted Agents Phase III: Met Disease Granite: BSC vs Everolimus Negative for OS, but improved PFS Second Line: Paclitaxel + / - Everolimus REAL 3: ECX + / - Panitumumab (U.K.) Negative: Panitumumab had inferior outcomes EXPAND: Cape-Cis + / Cetuximab (E.U.) Negative: Cetuximab trended inferior SCOPE-1: Cape-Cis-RT + / - Cetuximab as definitive chemo + RT, esophageal and GEJ (U.K.) Negative trial, inferior outcomes with cetuximab COG: BSC vs Gefitinib (U.K.): Negative trial for OS

R REAL3 Trial Design Arm A: EOC Arm B: mEOC-P EOC (Arm A): Untreated advanced adenocarcinoma or undifferentiated carcinoma of the oesophagus, OGJ or stomach EOC (Arm A): Epirubicin 50mg/m2 IV D1 Oxaliplatin 130mg/m2 IV D1 Capecitabine 1250mg/m2/day PO in two divided doses D1-21 mEOC-P (Arm B)1: Epirubicin 50mg/m2 IV D1 Oxaliplatin 100mg/m2 IV D1 Capecitabine 1000mg/m2/day PO in two divided doses D1-21 Panitumumab 9mg/kg IV D1 1. Okines et al, JCO 2010

Primary Endpoint – OS Based on 251 OS events 100 Median OS (95% CI) % alive at 1 year 11.3m (9.6 – 13.0) 46% (38% - 54%) 8.8m (7.7 – 9.8) 33% (26% - 41%) HR 1.37, p = 0.013 80 60 Probability of Survival (%) 40 EOC HR 1.37 (95% CI: 1.07 – 1.76) 20 EOC-P 6 12 18 24 30 36 Months from Randomisation Number at risk EOC 275 49 3 EOC-P 278 38 2 Based on 251 OS events

Trial Results - PFS Based on 333 PFS events 100 Median PFS (95% CI) % alive and progression-free at 1 year 7.4m (6.3 – 8.5) 21% (14% - 27%) 6.0m (5.5 – 6.5) 20% (14% - 26%) HR 1.22, p = 0.068 80 60 Probability of Survival (%) 40 EOC 20 EOC-P HR 1.22 (95% CI: 0.98 – 1.52) 6 12 18 24 30 Months from Randomisation Number at risk EOC 275 25 2 EOC-P 278 24 Based on 333 PFS events

Trial Results - RR Best Response EOC (n=238) mEOC-P (n=254) CR 5 (2%) 8 (3%) PR 95 (40%) 108 (43%) SD 51 (21%) 46 (18%) PD 19 (8%) 30 (12%) Not evaluable 68 (29%) 62 (24%) ORR 42% 46% Odds Ratio for Response 1.16 (95% CI: 0.81-1.57) p-value 0.467 Patients who had not reached 1st response assessment at time of data censoring are excluded (n=61)

Death due to “homelessness” (anokis)

Doshi et al Proc ASCO 2012

ECX + / - Rilotumumab in CMET High: RILOMET Trial

Fuchs et al GI Symposium 2013 VEGF Revisited? AVAGAST: Cape or 5-FU + cisplatin + / - bevacizumab PFS and RR improved Non significant increase in OS Ramucirumab (Fuchs, GI Symposium 2013) Humanized antibody blocking VEGFR2 355 patients post 5-FU and platin based chemo BSC vs Ramucirumab 8 mg/kg IV every 3 weeks PFS improved 2.1  3.8 months (HR 0.483, p < 0.0001) OS improved 3.8  5.2 months (HR 0.776, p = 0.0473) Disease control improved from 23% to 49% (p < 0.0001) Essentially no toxicity (rare grade 3/4 hypertension 7.2%) Fuchs et al GI Symposium 2013

Pancreatic Cancer and HCC US Incidence in 2013 45,220 cases, 38,460 deaths (85%) FOLFIRINOX new standard chemotherapy for good PS pts Gemcitabine combination therapy for good PS Adjuvant gemcitabine + / - RT after resection HCC and bile duct 30,640 cases, 21,670 deaths (71%) HCC: sorafenib for metastatic disease Cholangiocarcinoma: gemcitabine/cisplatin for metastatic disease Siegel et al, CA 63: 11-30; 2013

CONKO-001: Efficacy Results Gemcitabine (N= 179) Observation (N= 175) P-value Median DFS 13.4 mths 6.9 mths < 0.001 Median OS 22.8 mths 20.2 mths 0.005 1-Year OS 72% 72.5% - 3-year OS 36.5% 19.5% 5-Year OS 21% 9% Median f/up 53 months Neuhaus, et al. ASCO, 2008 (LBA #4504)

Results ESPAC-3(v2) 1,088 pts, 17 countries 1/00- 1/07 35% R1; 72% node positive; 25% grade III Median follow up 34.2 months 5-FU-LV N= 551 Gemcitabine N= 537 Log-rank Med OS 23 mths 23.6 mths HR= 0.94 (0.81-1.08) p= 0.39 Neoptolemos, et al. JAMA, 2010

Resected Pancreas Cancer US Intergroup/RTOG 0848 R A N D O M I Z E Gemcitabine x 4 cycles Resected Pancreas Cancer N= 952 2nd Randomization +/- ChemoRT Gemcitabine + Erlotinib x 4 Stratification R0 vs R1 resection; T stage; N(+) vs N(-) Primary Endpoint: Overall Survival +/- Erlotinib, +/- RT Secondary Endpoints: DFS +/- Erlotinib, +/- RT, toxicity Tissue acquistion/ correlative science

FOLFIRINOX vs Gemcitabine Prodige 4- ACCORD 11 R A N D O M I Z E FOLFIRINOX (N = 167) Untreated Metastatic Panc Adenocarcinoma ECOG 0-1 Gemcitabine (N = 169) Randomization 1: 1 Stratification PS: 0-1 vs 2; Primary tumor location, Center Primary Endpoint: Overall Survival Conroy, et al. NEJM, 2011

FOLFIRINOX vs Gemcitabine Overall Survival FOLFIRINOX Number at risk Gemcitabine FOLFIRINOX 171 134 89 48 28 14 7 6 3 3 2 2 2 171 146 116 81 62 34 20 13 9 5 3 2 2 1 . 7 5 2 P r o b a i l t y M n h s 3 6 9 8 4 Median 11.1 mo Median 6.8 mo HR = 0.57 P < 0.0001 Gemcitabine Conroy, T. NEJM, 2011

FOLFIRINOX vs Gemcitabine Secondary Endpoints Gemcitabine (N = 169) P-Value Febrile neutropenia 5.4% 0.6% 0.009 Thrombocytopenia 9.1% 2.4% 0.008 Peripheral neuropathy 9% — 0.001 Vomiting 14.5% 4.7% 0.002 Diarrhea 12.7% 1.2% 0.0001 Filgrastim support 42.5% 5% Overall response rate 31.6% 9.4% Median PFS 6.4 m 3.3 m HR = 0.47 Conroy T, et al. NEJM, 2011

Phase III Nab-Paclitaxel + Gemcitabine vs Gemcitabine (MPACT) Median Overall Survival 8.5 mths 6.7 mths HR 0.72, p= 0.000015 1-Year Survival 35% 22% Progression-Free Survival 5.5 mths 3.7 mths Response Rate 23% 7% Neutropenia (Gd 3-4) 38% 27% Fatigue (Gd 3-4) 17% Neuropathy (Gd 3-4) <1% Von Hoff, D. LBA #148. Gastrointestinal Cancers Symposium, 2013

SCALOP Trial: Unresectable Pancreatic Cancer 114 pts with locally advanced pancreatic cancer 3 months of weekly gemcitabine  5040 cGy RT + Gemcitabine 300 mg/m2 weekly vs Capecitabine 830 mg/m2 bid Monday through Friday during RT More heme (18.4% vs 0%) and non heme toxicity (26.3% vv 11.1%) for gemcitabine OS superior with capecitabine (13.4  15.2 months (HR 0.50, p = 0.025) Mukherjee et al GI Cancers Symposium 2013

CMET Targeted Therapy in HCC Tivantinib vs Placebo in HCC (4006) CMET TKI 107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib 160 mg tivantinib vs placebo Cross over permitted at POD TTP 6.0 to 6.9 weeks (HR 0.64, p = 0.04) Effect greatest beyond 8 weeks OS not different, given cross over (6.2-6.6 months) CMET IHC low, better prognosis, no benefit from tivantinib CMET IHC high, OS 3.8 to 7.2 months (HR 0.38, p = 0.01) with tivantinib Phase III Trial planned in CMET high pts

CMET Targeted Therapy in HCC Cabozantinib vs Placebo in HCC (4007) CMET and VEGR2 TKI, most patients failed sorafenib 107 pts, Child’s Pugh A, PS 0-1, most failed sorafenib 100 mg cabozantinib, stable disease randomized to placebo or continuation Cross over permitted at POD 41 treated, 22 randomized to discontinuation PFS 4.4 mos, OS 15 mos in all pts RR 5%, Stable disease 78% Larger phase II trial planned

Continue until withdrawal, PD, or death CALGB 80802 Eligibility Child-Pugh A ECOG PS: 0, 1, 2 (1:1) Randomization (N~480-680) Period 1 Period 2 Continue until withdrawal, PD, or death 6 cycles of: Doxorubicin 60 mg/m2 IV* Day 1 in 21-day cycles Sorafenib 400 mg po bid Sorafenib 400 mg po bid Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent Approved circumstances: benefit from therapy and continues to have normal EF on MUGA