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

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Dominick Griffith
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1 Upper GI Cancers Dr N Singhal Medical Oncologist Royal Adelaide Hospital

2 Localised disease PCPA Advanced Trainee Program 2018

7 Submucosal PCPA Advanced Trainee Program 2018

8 Work up EUS- 90% sensitivity and specificity PET scan- upstage ~ 15% Laparoscopy- GE junction/ cardia involvement Bronchoscopy

9 Treatment overview T1a- Endoscopic- EMR/ RFA T1b- 20% risk of nodal mets. Surgical resection T2/ N+- multimodal treatment

11 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.

12 Peri-operative chemotherapy Peri-op chemo without RT MAGIC (perioperative ECF): 13% OS at 5 yrs; HR: 0.75 (esophageal, 120 pts), no increase in R0 resection [1] FFCD/FNLC (CF3+1): 14% OS at 5 yrs; HR: 0.69 (esophageal cancer, 180 pts) same as MAGIC, no epirubicin, increase in R0 resection [2] FLOT-4/ AIO (FLOT 4+4): 3 yrs OS 48 vs 57% 1. Cunningham D, et al. N Engl J Med. 2006;355: Ychou M, et al. J Clin Oncol. 2011;29:

13 Standard of care- Neoadjuvant CRT

15 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:

16 Proportion Surviving Proportion Surviving PCPA Advanced Trainee Program 2018 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

17 Courtesy: Dr R Gowda PCPA Advanced Trainee Program 2018

18 Case-1 63 yrs with long term reflux Endoscopy- lesion at cm, GOJ at 40 cm CT- distal esophageal tumor, enlarged nodes, liver cyst PET-

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

21 Carbo Paclitaxel (CROSS) vs Cis-FU RT dose different 41.4 vs Gy Toxicity profile Venous access- beware of DVTs

22 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

23 Localised disease but not surgical candidate: Case-2 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

28 Case-2 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

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

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33 Diffuse Intestinal Presence of signet cell suggest Rx refractoriness & poor outcome

34 Treatment of EGC Surgery is standard of care with 20 50% survival at 5 years A D1 lymphadenectomy is defined by removal of the perigastric lymph nodes, and D2 by the extended dissection of nodes along the left gastric, celiac, hepatic, and splenic arteries, as well as those in the splenic hilum. High volume centres

36 Case study-3 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

38 (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, French, Al Batram) 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:

40 36 23

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

42 Surgery Post-op complications similar Evidence of down staging

43 Current standard of care PCPA Advanced Trainee Program 2018

49 Case study-3 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 Started on FLOT

50 Case-4 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)

54 Best of 2 worlds Pre- op Chemo and Post op Chemo RT

55 N=788; Post op Rx in 60% ECX/ EOX x 3- Surgery- ECX/ EOX x 3 ECX/ EOX x 3- Surgery- CX + RT

56 ARTIST trial PCPA Advanced Trainee Program 2018

Fig 1. Flow diagram of all registered patients. XP, capecitabine plus cisplatin; XPRT, concurrent chemoradiotherapy with capecitabine plus cisplatin.

57 Fig 1. Flow diagram of all registered patients. XP, capecitabine plus cisplatin; XPRT, concurrent chemoradiotherapy with capecitabine plus cisplatin. Published in: Se Hoon Park; Tae Sung Sohn; Jeeyun Lee; Do Hoon Lim; Min Eui Hong; Kyoung-Mee Kim; Insuk Sohn; Sin Ho Jung; Min Gew Choi; Jun Ho Lee; Jae Moon Bae; Sung Kim; Seung Tae Kim; Joon Oh Park; Young Suk Park; Ho Yeong Lim; Won Ki Kang; JCO 2015, 33, DOI: /JCO Copyright 2015 American Society of Clinical Oncology

58 Table 1. Baseline Patient Demographics and Clinical Characteristics PCPA Advanced Trainee Program 2018

59 Fig 2. Disease-free survival. XP, capecitabine plus cisplatin; XPRT, concurrent chemoradiotherapy with capecitabine plus cisplatin. Published in: Se Hoon Park; Tae Sung Sohn; Jeeyun Lee; Do Hoon Lim; Min Eui Hong; Kyoung-Mee Kim; Insuk Sohn; Sin Ho Jung; Min Gew Choi; Jun Ho Lee; Jae Moon Bae; Sung Kim; Seung Tae Kim; Joon Oh Park; Young Suk Park; Ho Yeong Lim; Won Ki Kang; JCO 2015, 33, DOI: /JCO Copyright 2015 American Society of Clinical Oncology

60 Poor response after Neoadj Chemo Do we change Rx after surgery?

61 Ongoing and exciting trials ARTIST-II trial tegafur, gimeracil and oteracil (S-1) versus S-1 plus oxaliplatin versus S-1, oxaliplatin plus radiotherapy after complete resection of node-positive GAC INNOVATION- localized HER2-positive tumours with trastuzumab or trastuzumab and pertuzumab with standard chemotherapy (that is, dual HER2 blockade).

63 Advanced stage disease PCPA Advanced Trainee Program 2018

64 First-line Therapy Recommendations Preferred regimens Fluoropyrimidine + cisplatin (category 1) or oxaliplatin (2A) Fluorouracil + irinotecan (category 1) HER2-positive disease Trastuzumab + cisplatin/ fluoropyrimidine (category 1) Trastuzumab + other agents (2B) Other regimens Paclitaxel + cis- or carboplatin (category 2A) Docetaxel with cisplatin (category 2A) Docetaxel + irinotecan (category 2B) Fluoropyrimidine Docetaxel Paclitaxel

65 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:

66 Does Epirubicin Add Anything in Advanced GE Cancer? FOLFIRI vs ECX TTF (Proportion) Pts at Risk, n ECX FOLFIRI Time to Treatment Failure Mos ECX FOLFIRI HR: 0.77 (95% CI: ; P =.008) N = 416 1/3 GEJ, 2/3 gastric 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:

67 Trials of targeted agents in AGC

68 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) Primary endpoint: OS 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) *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:

69 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:

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

75 Correlation of Gli1 and HER2 expression in gastric cancer: Identification of novel target 67 post gastrectomy Hedgehog pathway Strong and positive co-relation Gli-1- strong association with outcome Xinyu Shao, Xiaoyi Kuai, Zhi Pang, Liping Zhang, Longyun Wu, Lijuan Xu & Chunli Zhou. Nature Scientific Reports volume 8: 397 (2018)

77 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

78 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.

79 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.

80 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) Ramucirumab 8 mg/kg IV q2w + BSC (n = 238) BSC + Placebo (n = 117) Treatment until PD, unacceptable toxicity, or death Primary objective: OS Secondary endpoints: PFS, 12-wk PFS, ORR, DoR, QoL, safety Fuchs CS, et al. Lancet. 2014;383:31-39.

81 BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): PFS, Response PCPA Advanced Trainee Program 2018 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.

82 BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): OS PCPA Advanced Trainee Program 2018 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.

83 RAINBOW: Second-line Paclitaxel ± Ramucirumab in Advanced Gastric Cancer Randomized, double-blind phase III trial PCPA Advanced Trainee Program 2018 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) Primary endpoint: OS Secondary: PFS, ORR, TTP 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 *Platinum agent plus fluoropyrimidine ± anthracycline. Wilke H, et al. Lancet Oncol. 2014;15:

84 2 nd -Line Ramucirumab in Advanced Gastric Probability of OS Cancer (RAINBOW): OS Δ mos = 2.3 mos Ram/Pac Placebo/Pac Ram 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) PCPA Advanced Trainee Program 2018 RAINBOW [1] REGARD [2] 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.

85 Probability of PFS Second-line Ramucirumab in Adv Gastric Cancer (RAINBOW): PFS, Responses 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) PCPA Advanced Trainee Program 2018 RAINBOW [1] REGARD [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.

86 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 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:

Cancer, METpositive by immunohistochemistry (IHC) HER2 negative R N = 450 R N = 800 ECX + Rilotumumab 1:1 ECX alone ECX + Rilotumumab

87 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

88 Immunotherapy trials PCPA Advanced Trainee Program 2018

91 Checkmate 32 PCPA Advanced Trainee Program 2018

95 Pembrolizumab for Advanced Gastric or GEJ Adenocarcinoma (KEYNOTE-059) Follow-up analysis of phase II KEYNOTE-059 trial (data cutoff: April 21, 2017) PCPA Advanced Trainee Program 2018 Pts with recurrent or metastatic gastric or GEJ adenocarcinoma; ECOG PS 0/1; HER2/neu negative*; no prior PD-1/PD-L1 tx, systemic steroids, autoimmune disease, ascites, or active CNS mets (N = 315) Cohort 1 2 prior lines of CT Cohort 2 No prior tx Pembrolizumab 200 mg Q3W Pembrolizumab 200 mg Q3W + Cisplatin 80 mg/m 2 Q3W + 5-FU 800 mg/m 2 Q3W or Capecitabine 1000 mg/m 2 BID Q3W Cohort 3 No prior Pembrolizumab tx, PD- 200 mg Q3W L1+ *HER2/neu positive allowed in cohort 1 if prior trastuzumab administered. Primary endpoints: ORR (RECIST v1.1 by central review), safety Additional endpoints including: DCR, DoR, PFS, OS Tx continued for 35 cycles (~ 2 yrs) or until PD, intolerable toxicity, or withdrawal of consent; survival follow-up until study end, death, or withdrawal Wainberg Z, et al. ESMO Abstract LBA28_PR. ClinicalTrials.gov. NCT

96 Outcome ORR, % CR PR SD PD KEYNOTE-059: Efficacy Cohort 1 (n = 259) Cohort 2 (n = 25) Cohort 3 (n = 31) DCR mdor, mos (range) mpfs, mos (95% CI) mos, mos (95% CI) 14.2 (2.4 to 19.4+) ORR higher in PD-L1 positive vs PD-L1 negative pts (cohort 1: 16% vs 6%; cohort 2: 69% vs 38%) (2.6 to 20.3+) PCPA Advanced Trainee Program (2.1 to 17.8+) 2.0 ( ) 6.6 ( ) 3.3 ( ) 5.5 ( ) 13.8 (8.6-NR) 20.7 ( )

97 Practical considerations Time- gastric obstruction/ bleeding Perforation or TOF Early involvement of surgeon/ dietician Her2 testing/ MMR- don t wait for results!

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

2.5% of all cancers Median age 68 years Decline in gastric cancer incidence Increase in esophageal, GEJ, cardia adenocarcinoma OS improvement, 1975-77, 1984-86, 1999-2006 Gastric: 16% 18% 27% Esophageal: