Gastric: 16% 18% 27% Esophageal: 5% 10% 19%

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Barbara Melton
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1 2.5% of all cancers Median age 68 years Decline in gastric cancer incidence Increase in esophageal, GEJ, cardia adenocarcinoma OS improvement, , , Gastric: 16% 18% 27% Esophageal: 5% 10% 19%

2 Localised disease

3 Case study-1 WG 71 yrs male. HT, gout, Impaired Glucose tolerance Reflux- 8 cm ulcer on greater curvature- gastric adenoca (>T2, Nx, Mx) CT- GOJ thickening Laparoscopy- no peritoneal/ liver mets ECHO and PFT- normal PET

5 (Neo)Adjuvant Therapy in Gastric Cancer ( T2) Improves OS Postoperative RT + chemotherapy (US) [1] Treatment: 5-FU/LV + RT (INT-0116 study) 10% 5-yr OS; HR: 0.76 Postop chemo (Asia): 2 trials, 2000 pts, D2 resection, no RT Treatment: S-1 (oral 5-FU) (ACTS-GC study) [3] 10% 5-yr OS; HR: 0.67 Treatment: postop capecitabine/oxaliplatin (CLASSIC trial) [4] 9% 5-yr OS; HR: 0.66 Preop and postop chemo (UK and French) without RT [2] Treatment: ECF (MAGIC study) or CF 13% 5-yr OS; HR: 0.75 Survival improvements with all approaches similar, modest 1. Smalley SR, et al. J Clin Oncol. 2012;30: Cunningham D, et al. N Engl J Med. 2006;355: Sasako M, et al. J Clin Oncol. 2011;29: Noh SH, et al. Lancet Oncol. 2014;15:

6 Current standard of care

7 36 23

8 Randomised 250 Started 237 Completed 3 cycles 215 Surgery 209/ 83% Post- op 137

9 Surgery Post-op complications similar Evidence of down staging

15 MAGIC vs Macdonald (CRT) vs Chemo Atlantic divide Advantages of post-op- accurate pathological staging and offering definitive treatment first Advantage of neoadjuvant chemo- testing the biology of tumor and avoiding unnecessary surgery

16 Case-2 AP 70 yrs- 5 cm tumor in gastric cardia- type III Laparoscopy and PET- normal ECHO and PFT- normal Hematemesis Total gastrectomy- T3, N2 adenoca Offered post op Macdonald approach? Chemo alone (XELOX)

17 GE junction tumors

18 Esophageal and GEJ Adenocarcinoma: Neoadjuvant chemotherapy alone Preop and postop chemo (UK and French) without RT MAGIC (perioperative ECF): 13% OS at 5 yrs; HR: 0.75 (esophageal, 120 pts), no increase in R0 resection [1] FFCD/FNLC (preop CF): 14% OS at 5 yrs; HR: 0.69 (esophageal cancer, 180 pts) same as MAGIC, no epirubicin, increase in R0 resection [2] 1. Cunningham D, et al. N Engl J Med. 2006;355: Ychou M, et al. J Clin Oncol. 2011;29:

19 Esophageal Adenoca: Neoadjuvant chemo Preop chemotherapy MRC OEO-2 (CF): N = 802 [1] 5-yr update: 6% OS increase vs resection alone US INT-113 (CF): N = 440 [2] No impact on OS or any endpoint, including R0 rate MRC OEO5 (CF vs ECX): N = 900, EUS staged [3] CF x 2 vs ECX x 4: equivalent No survival benefit with additional cycles of ECX Poor rates of R0 resection: 60% to 66% Demonstrates no role for anthracyclines in this setting 1. Allum WH, et al. J Clin Oncol. 2009;27: Kelsen DP, et al. N Engl J Med. 1998;339: Cunningham D, et al. ASCO Abstract 4002.

20 Standard of care- Neoadjuvant CRT

22 Preop CRT + Surgery vs Surgery Alone for Esophageal or Junctional Cancer Chemoradiotherapy followed by surgery compared with surgery alone (N = 368) M T W T F S S M T W T F S S M T W T F S S M T W T F S S M T W T F S S Wk 1 Wk 2 Wk 3 Wk 4 Wk 5 XRT CTX Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Paclitaxel 50 mg/m 2 + carboplatin AUC 2 on Days 1, 8, 15, 22, and 29 Concurrent radiotherapy: 41.4 Gy in 23 fractions of 1.8 Gy Surgery within 6 wks after completion of chemoradiotherapy van Hagen P, et al. N Engl J Med. 2012;366:

23 Proportion Surviving Proportion Surviving Preop CRT + Surgery vs Surgery Alone for Esophageal or Junctional Cancer: OS P =.003 OS by Treatment CRT + surgery Surgery alone Mos OS by Tumor Type and Treatment SCC, CRT + surgery AC, CRT + surgery AC, surgery alone SCC, surgery alone 0.2 AC, P =.049 SCC, P = Mos van Hagen P, et al. N Engl J Med. 2012;366: R0 resection increased from 69% w/surgery alone to 92% 5-yr OS: 47% vs 34% with surgery alone Squamous HR: Adeno HR: Pathologic CR with CRT + surgery Squamous: 49% Adenocarcinoma: 23% Considered a new standard of care

24 Case-3 63 yrs with long term reflux Endoscopy- lesion at cm, GOJ at 40 cm CT- distal esophageal tumor, enlarged nodes, liver cyst PET-

26 Pre-op chemo vs chemo RT Chemo RT is standard of care Chemo alone approach only when contraindication to RT or hiatus hernia

27 Carbo Paclitaxel (CROSS) vs Cis-FU RT dose different 41.4 vs Gy Toxicity profile

28 DOCTOR trial AdenoCa oesophagus or OG junction Based on PET response i.e. >35% using standard CF chemo Non-responders CF plus Docetaxel OR CF plus Docetaxel plus 45Gy in 25Fr

29 Localised disease but not surgical candidate: Case-4 JW 81 yrs- geriatric assessment- FIT THR, APR for colorectal tumor, HT, AF, T2DM, CAD Endoscopy- lesion at 30 cm- adenoca CT- distal esophageal tumor PET

33 Case-4 JW 81 yrs- geriatric assessment- FIT THR, APR for colorectal tumor, HT, AF, T2DM, CAD Endoscopy- lesion at 30 cm- adenoca CT/ PET- distal esophageal tumor Good lung functions and ECHO treated with definitive Chemo (carbo taxol) RT

34 Role of post op (adjuvant) treatment in Esophageal or GE cancers None Trials with post op chemo or immune therapies

35 Advanced stage disease

36 First-line Therapy Recommendations Preferred regimens* Fluoropyrimidine + cisplatin (category 1) or oxaliplatin (2A) ECF (category 1) Fluorouracil + irinotecan (category 1) HER2-positive disease Trastuzumab + cisplatin/ fluoropyrimidine (category 1) Trastuzumab + other agents (2B) 1. NCCN. Guidelines: gastric cancer. v Other regimens Paclitaxel + cis- or carboplatin (category 2A) Docetaxel with cisplatin (category 2A) Docetaxel + irinotecan (category 2B) Fluoropyrimidine Docetaxel Paclitaxel *2-drug regimens preferred due to lower toxicity, reserving triplet therapy for younger, medically fit pts. Trastuzumab should not be combined with anthracyclines.

37 Advanced Esophagogastric Cancer Chemotherapy: Which Regimen to Use? Oxali: EOX or EOF [1] 3-Drug Regimens Cape: 2-Drug Regimens EOX [1] DCF [2] FOLFIRI [6] [3] XP [4] FLO [5] [7] S-1 ECX or ECF Cis N ORR, % TTP, mo OS, mo Cunningham D, et al. N Engl J Med. 2008;358: Van Cutsem E, et al. J Clin Oncol. 2006;24: Webb A, et al. J Clin Oncol. 1997;15: Kang YK, et al. Ann Oncol. 2009;20: Al-Batran SE, et al. J Clin Oncol. 2008;26: Guimbaud R, et al. J Clin Oncol. 2014;32: Koizumi W, et al. Lancet Oncol. 2008;9:

39 REAL-2 Trial: Capecitabine vs 5-FU, Oxaliplatin vs Cisplatin ECF (n = 249) Epirubicin Cisplatin 5-FU EOF (n = 235) Epirubicin Oxaliplatin 5-FU 50 mg/m 2 IV q3w 60 mg/m 2 IV q3w 200 mg/m 2 /d IV given continuously 50 mg/m 2 IV q3w 130 mg/m 2 IV q3w 200 mg/m 2 /d IV given continuously ECX (n = 241) Epirubicin Cisplatin Capecitabine EOX (n = 239) Epirubicin Oxaliplatin Capecitabine 50 mg/m 2 IV q3w 60 mg/m 2 IV q3w 625 mg/m 2 PO BID continuously 50 mg/m 2 IV q3w 130 mg/m 2 IV q3w 625 mg/m 2 PO BID continuously 2 x 2 randomization, 8 cycles Noninferiority of X over F and O over C with 1-yr survival of 35% (1-side α of 5%) Cunningham D, et al. N Engl J Med. 2008;358:36-46.

43 Does Epirubicin Add Anything in Advanced GE Cancer? FOLFIRI vs ECX 1.0 Time to Treatment Failure N = 416 1/3 GEJ, 2/3 gastric TTF (Proportion) Pts at Risk, n ECX FOLFIRI Mos ECX FOLFIRI HR: 0.77 (95% CI: ; P =.008) ORR: 39% vs 38% Median PFS: 5.3 vs 5.8 mos Median OS: 9.5 vs 9.7 mos TTF, toxicity favored first-line FOLFIRI over ECX Guimbaud R, et al. J Clin Oncol. 2014;32:

44 Second-line Therapy Recommendations Depends on prior therapy and PS Preferred regimens (all category 1) Ramucirumab + paclitaxel Docetaxel Paclitaxel Irinotecan Ramucirumab Other regimens Irinotecan and cisplatin (category 2A) Irinotecan and fluoropyrimidine (category 2B) Docetaxel and irinotecan (category 2B) Alternative regimens (category 2B) Mitomycin and irinotecan Mitomycin and fluorouracil NCCN Guidelines: gastric cancer. v

45 Improved OS in Phase III Trials of Second-line Chemo for Gastric Cancer Survival Probability SLC BSC OS (%) Docetaxel Active symptom control HR: 0.67 (95% CI: ; P =.01) Mos Mos From Randomization Docetaxel or Irinotecan vs BSC [1] Docetaxel vs BSC [2] 1. Kang JH, et al. J Clin Oncol. 2012;30: Ford HE, et al. Lancet Oncol. 2014;15:78-86.

46 Genome Atlas Project: Gene Amplification in Esophagogastric Cancer 296 Esophageal/Gastric Cancers; 190 CRCs Focal Events per Sample (n) Number of Focal Events per Sample Amplified genes in 37% of gastroesophageal tumors EGFR MET FGFR1-2 KRAS Targetable receptors and receptor tyrosine kinases Dulak AM, et al. Can Res. 2012;72: *** *** n.s. *** *** Colorectal Gastric Esophageal Multilevel Events per Sample (n) HER2 80 *** 0 3 Amplifications Deletions Multicopy Alterations *** *** * n.s. ** 2 ** 1 0 Multicopy Amplifications Multicopy Deletions

47 Gastric Adenocarcinoma: 4 Genomic Subsets Genomically unstable (50%) Intestinal, present in most GEJ tumors High rate of p53 mutation, amplification of RTKs MSI-high (22%): High rate of microsatellite instability, gene mutation, and promoter hypermethylation Genomically stable (20%) Associated with diffuse histology, CHD-1 and RHOA mutation High Epstein-Barr virus burden (9%) High rate of PIK3CA mutation, PD-L1 and PD-L2 amplification, strong IL-12 signaling indicating an immune presence The Cancer Genome Atlas Research Network. Nature. 2014;513:

48 Phase III ToGA: Trastuzumab + Chemo in Advanced HER2+ Gastric Cancer Rationale: a subpopulation of gastric cancers overexpress HER2 Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU Pts with advanced gastric cancer screened for HER2 status (N = 3803) Pts with HER2+ advanced gastric cancer (n = 810; 22% of successful screenings) R (n = 584) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose) (n = 294) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 (n = 290) Primary endpoint: OS *Selected at investigator s discretion: 5-FU 800 mg/m 2 /day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m 2 BID on Days 1-14 q3w x 6. Bang YJ, et al. Lancet. 2010;376:

49 Phase III ToGA: OS Survival Probability Pts at Risk, n FC + T FC Mos Median Events, OS, n mos HR % CI P Value.0046 Bang YJ, et al. Lancet. 2010;376:

50 Phase III ToGA: OS in Pts With IHC 3+ or FISH+ and IHC 2+ Survival Probability Pts at Risk, n Exploratory analysis Mos FC + T FC Median Events, OS, n mos HR % CI Bang YJ, et al. Lancet. 2010;376:

51 Phase III LOGiC: CapeOx ± Lapatinib in HER2+ Advanced Gastric Cancer Stratified by prior neo/adjuvant therapy, region (Asia vs North America vs rest of the world) Pts with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or GEJ cancer (N = 545) CapeOx* + Lapatinib 1250 mg QD 21-day cycles CapeOx* + Placebo *Day 1: oxaliplatin 130 mg/m 2, Days 2-14: capecitabine 850 mg/m 2 BID. Primary endpoint: OS Secondary endpoints: PFS, ORR, DoR, CBR, safety/toxicity, QoL, molecular and pharmacogenetics analyses Hecht J, et al. J Clin Oncol. 2015;[Epub ahead of print].

52 CapeOx ± Lapatinib in HER2+ Advanced Gastric Cancer (LOGiC): OS Cumulative Survival Probability Pts at Risk, n CapeOx + L CapeOx + P CapeOx + L CapeOx + P Mos Since Randomization CapeOx + L (n = 249) CapeOx + P (n = 238) Median OS, Mos (95% CI) 12.2 ( ) 10.5 ( ) HR (95% CI) 0.91 ( ) P = ITT analysis HR: Hecht J, et al. J Clin Oncol. 2015;[Epub ahead of print].

53 Phase III Clinical Trials of HER2-Directed Therapy in Gastric Cancer First line JACOB: capecitabine/cisplatin/trastuzumab ± pertuzumab (planned N = 780) [1] HELOISE: capecitabine/cisplatin + 2 dose levels of trastuzumab (planned N = 400) [2] Second line GATSBY: paclitaxel vs T-DM1 (planned N = 412) [3] T-DM1 was no better than paclitaxel 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

54 VEGF Revisited?: Second and Later Line of Therapy AVAGAST: capecitabine/cisplatin ± bevacizumab [1] No OS benefit for addition of bevacizumab in first-line setting Small-molecule multitargeted TKI with activity against VEGFR Apatinib- Phase III trial at ASCO 2014: median OS significantly longer with 850 mg QD vs placebo (195 vs 140 days, respectively; HR: 0.71) [2] Regorafenib- Ph II Integrate Study- single agent activity 1. Ohtsu A, et al. J Clin Oncol. 2011;29: Qin S, et al. ASCO Abstract 4003.

55 Phase III REGARD Trial: BSC ± Ramucirumab in Met Gastric or GEJ Cancer Stratified by geographic region, weight loss (> vs < 10% over 3 mos), location of primary tumor (gastric vs GEJ) Pts with metastatic gastric or GEJ adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidinecontaining combination therapy, ECOG PS 0-1 (N = 355) Primary objective: OS Ramucirumab 8 mg/kg IV q2w + BSC (n = 238) BSC + Placebo (n = 117) Treatment until PD, unacceptable toxicity, or death Secondary endpoints: PFS, 12-wk PFS, ORR, DoR, QoL, safety Fuchs CS, et al. Lancet. 2014;383:31-39.

56 BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): PFS, Response Proportion Without Progression Pts at Risk, n Ramucirumab Placebo Ramucirumab Placebo Censored Ramucirumab Placebo Pts/events 238/ /108 Median, mos 2.1 ( ) 1.3 ( ) (95% CI) 12-wk PFS, % ORR, % 3 3 DCR, % HR: (95% CI: ; P <.0001) Mos Fuchs CS, et al. Lancet. 2014;383:31-39.

57 BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): OS Proportion Remaining Alive Pts at Risk, n Ramucirumab Placebo Ramucirumab Placebo Pts/events 238/ /99 Median, mos 5.2 ( ) 3.8 ( ) (95% CI) 6-mo OS, % mo OS, % HR: (95% CI: ; P =.0473) Ramucirumab Placebo Censored Mos Fuchs CS, et al. Lancet. 2014;383:31-39.

58 BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): AEs of Interest AE, % Ramucirumab (n = 236) Placebo (n = 115) Any Grade Grade 3 Any Grade Grade 3 Hypertension* Bleeding/hemorrhage Arteriothromboembolic Venous thromboembolic Proteinuria 3 < 1 < 3 < 0 GI perforation < 1 < 1 < 1 < 1 Fistula (GI and non-gi) < 1 < 1 < 1 < 1 Infusion-related reaction < Cardiac failure < *Includes increased blood pressure. No grade 4 hypertension observed among ramucirumab-treated pts. Fuchs CS, et al. Lancet. 2014;383:31-39.

59 Randomized Second-line Gastric Cancer Studies ( ): Median OS Median OS by Study Arm, Mos Ramucirumab vs BSC [1] (n = 355) Docetaxel vs ASC [2] (n = 131) Chemo (docetaxel or irinotecan) vs BSC [3] (n = 202) Irinotecan vs BSC [4] (n = 40) Fuchs CS, et al. Lancet. 2014;383: Ford H, et al. ASCO GI Abstract LBA4. 3. Kang JH, et al. J Clin Oncol. 2012;30: Thuss-Patience PC, et al. Eur J Cancer. 2011;47: Active treatment BSC/ASC

60 RAINBOW: Second-line Paclitaxel ± Ramucirumab in Advanced Gastric Cancer Randomized, double-blind phase III trial Stratified by geographic region, measurable vs nonmeasurable disease, TTP on first-line therapy (< 6 vs 6 mos) 4-wk cycle Pts with metastatic or locally adv unresectable gastric or GEJ cancer and progression on first-line chemo* (N = 665) *Platinum agent plus fluoropyrimidine ± anthracycline. Ramucirumab 8 mg/kg Days 1, 15 + Paclitaxel 80 mg/m 2 Days 1, 8, 15 (n = 330) Placebo Days 1, 15 + Paclitaxel 80 mg/m 2 Days 1, 8, 15 (n = 335) Treat until PD or intolerable toxicity Primary endpoint: OS Secondary endpoints: PFS, ORR, TTP Wilke H, et al. Lancet Oncol. 2014;15:

61 2 nd -Line Ramucirumab in Advanced Gastric Cancer (RAINBOW): OS 1.0 RAINBOW [1] REGARD [2] Ram/Pac Placebo/Pac Ram Probability of OS Δ mos = 2.3 mos Pts/events, n 330/ / /199 Median, mos 9.63 ( ) 7.38 ( ) 5.2 ( ) (95% CI) 6-mo OS, % mo OS, % HR: (95% CI: ; P =.0169) 0.2 Ram + Pac Placebo + Pac Censored Mos 1. Wilke H, et al. Lancet Oncol. 2014;15: Fuchs CS, et al. Lancet. 2014;383:31-39.

62 Second-line Ramucirumab in Adv Gastric Cancer (RAINBOW): PFS, Responses Probability of PFS Ram + Pac Placebo + Pac Censored RAINBOW [1] REGARD [2] Ram/Pac Placebo/Pac Ram Pts/events, n 330/ / /199 Median, mos 4.40 ( ) 2.86 ( ) 2.1 ( ) (95% CI) 6-mo PFS, % mo PFS, % ORR, % P = DCR, % P < HR: (95% CI: ; P <.0001) Mos 1. Wilke H, et al. Lancet Oncol. 2014;15: Fuchs CS, et al. Lancet. 2014;383:31-39.

63 RAINFALL: Capecitabine/5-FU + Cisplatin ± Ramucirumab in Metastatic Gastric CA Randomized, double-blind, phase III trial Pts with metastatic gastric/gej CA with no prior first-line therapy (N = 616, planned) Ramucirumab 8 mg/kg IV Days 1, 8 Capecitabine* 1000 mg/m 2 PO Days 1-14 Cisplatin 80 mg/m 2 IV Day 1 Placebo IV Days 1, 8 Capecitabine* 1000 mg/m 2 PO Days 1-14 Cisplatin 80 mg/m 2 IV Day 1 21-day cycles Primary endpoint: PFS *Pts unable to take capecitabine receive 5-FU 800 mg/m 2 /day Days 1-5. Secondary endpoints: OS, PFS2, ORR, DCR, TTP, DoR, QoL, PK ClinicalTrials.gov. NCT

64 Phase III Trials in Gastric Cancer: EGFR-Targeted Agents REAL3: ECX ± panitumumab (UK) [1] Negative: panitumumab had inferior outcomes EXPAND: capecitabine/cisplatin ± cetuximab (EU) [2] Negative: cetuximab trended inferior COG: BSC vs gefitinib (UK): negative [3] Trials conducted with no biomarker selection of pts No biomarker identified in esophagogastric cancer 1. Waddell T, et al. Lancet Oncol. 2013;14: Lordick F, et al. Lancet Oncol. 2013;14: Dutton SJ, et al. Lancet Oncol. 2014;15:

65 cmet Antibodies in Gastric Cancer: Phase III Trials RILOMET-1 [1] Locally advanced or metastatic gastric and AEG Cancer, METpositive by immunohistochemistry (IHC) HER2 negative Primary endpoint: OS MetGastric [2] Locally advanced or metastatic gastric and AEG Cancer, METpositive by immunohistochemistry (IHC) HER2 negative R N = 450 R N = 800 ECX + Rilotumumab 1:1 ECX alone ECX + Rilotumumab 1:1 ECX alone Primary endpoint: OS in the Met IHC 2+/3+ pt subgroup 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

66 CTLA-4 and PD-1/L1 Checkpoint Blockade Priming phase (lymph node) Effector phase (peripheral tissue) Dendritic cell T cell T-cell migration T cell Cancer cell MHC TCR TCR MHC Dendritic cell B7 CD28 CTLA-4 T cell T cell PD-1 PD-L1 Cancer cell Ribas A. N Engl J Med. 2012;366:

67 Immune Checkpoint Inhibitors in Esophagogastric Carcinoma CTLA-4 Tremelimumab: phase II study (N = 18) showed 1 PR > 30 mos [1] PD-L1 Atezolizumab: 1 gastric cancer pt in expansion study had TTP of 9.8 mos [2] Durvalumab: dose-expansion study (N = 28) showed 2 PRs and 12- wk DCR of 25% [3] PD-1 Pembrolizumab: KEYNOTE-012: ORR 22% to 33%; 53% of pts had reduction in size of target lesions [4] 1. Ralph C, et al. Clin Cancer Res. 2010;16: Tabernero J, et al. ASCO Abstract Segal D, et al. ESMO Abstract 1058PD. 4. Bang YJ, et al. ASCO Abstract 4001.

68 KEYNOTE-012: Pembrolizumab in Gastric Cancer Cohort Multicenter, multicohort open-label phase Ib trial Pts with PD-L1 positive recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction; ECOG PS 0-1; no active brain metastases (N = 39) Pembrolizumab 10 mg/kg IV q2w CR Confirmed PD PR, SD Discontinue treatment Pembrolizumab 10 mg/kg IV q2w for 24 mos or until progression or intolerable toxicity Discontinue treatment Endpoints: association of clinical response with PD-L1 expression Assessment of response every 8 wks by RECIST v1.1 Assessment of PD-L1 expression by IHC Bang YJ, et al. ASCO Abstract 4001.

69 Pembrolizumab in Gastric Cancer Cohort (KEYNOTE-012): Responses Pembrolizumab therapy associated with PR in 13 of 39 pts by investigator review and 8 of 36 pts by central review 53% of pts had decrease in lesion size Median time to response: 8 wks 4 of 8 responses ongoing at time of data cutoff Outcomes Investigator Review (n = 39) Central Review (n = 36) 33 (19-50) 22 (10-39) CR 0 0 PR 13 (33) 8 (22) SD 3 (8) 5 (14) PD 23 (59) 19 (53) No assessment 0 1 (3) Not determined 0 3 (8) Response ORR, % (95% CI) Best response, n (%) Median response duration: 40 wks (range: 20+ to 48+) Bang YJ, et al. ASCO Abstract 4001.

70 Pembrolizumab in Gastric Cancer Cohort (KEYNOTE-012): Change in Tumor Size Change From Baseline in Sum of Longest Diameter of Target Lesion (%) Maximum Percentage Change From Baseline in Tumor Size (RECIST v1.1, Central Review) % of pts experienced a decrease in target lesions Bang YJ, et al. ASCO Abstract 4001.

71 Immune Checkpoint Inhibitors in Adv. Gastric CA: Ongoing Clinical Trials Checkpoint Agent Trial Details NCT Number CTLA-4 Ipilimumab Ph II maintenance ipi NCT PD-1 PD-L1 Combo Pembrolizumab Pembrolizumab Pembrolizumab Avelumab KEYNOTE-061: Ph III 2nd-line pembro vs paclitaxel KEYNOTE-062: Ph III first-line pembro monotherapy KEYNOTE-059: Ph II pembro vs pembro+ cis/5-fu Ph III avelumab vs continuation of first-line chemo NCT NCT NCT NCT Avelumab Ph III avelumab vs chemo, 3rd-line NCT Tremelimumab + durvalumab Nivolumab + ipilimumab Ph Ib/II tremelimumab + durvalumab vs treme vs durvalumab Ph I/II nivolumab vs nivo/ipi NCT NCT

72 Advanced Esophageal cancer TROG 03.01/ NCI CTG ES2- Dr Penniment et al RT vs Chemo RT (1 cycle cisplatin and FU) No advantage for adding chemo for palliation of dysphagia

73 Take Home Messages Current adjuvant therapy achieves a limited survival improvement Both perioperative and postoperative chemotherapy improve survival Postoperative RT + chemotherapy needed for < D1 resection Preoperative chemotherapy + RT SOC for GEJ and esophageal cancer Metastatic disease Fluorinated pyrimidine + platinum agent (standard chemo): FOLFOX, CAPOX, capecitabine/cisplatin Positive trials for VEGFR2 inhibitors as second-line therapy Ramucirumab improves outcome alone and with paclitaxel Failed trials targeting EGFR, MET HER2+: trastuzumab added to first-line chemo Immunotherapy trials ongoing

74 Localised disease Gastric/GE Esophageal/GE ECF peri-op Neo adj CRT Post op CRT Pre-op Chemo

75 Metastatic disease Cis FU/ FOLFOX/ FOLFIRI/ XP/ XELOX/ ECF/ ECX/ EOX/ ±Herceptin Paclitaxel/ docetaxel/ irinotecan/ ramucirumab Irinotecan/ pembro

PCPA Advanced Trainee Program Upper GI Cancers. Dr N Singhal Medical Oncologist Royal Adelaide Hospital

Upper GI Cancers Dr N Singhal Medical Oncologist Royal Adelaide Hospital Localised disease PCPA Advanced Trainee Program 2018 Submucosal PCPA Advanced Trainee Program 2018 Work up EUS- 90% sensitivity