1. Expert Insight on Optimal Treatment Selection for Patients With Advanced Gastric Cancer
This program is supported by an educational grant from Lilly.

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3. Core Faculty
Axel Grothey, MD Professor, Oncology Mayo Clinic Rochester, Minnesota David H. Ilson, MD, PhD Professor of Medicine Weill Cornell Medical College Attending Physician Memorial Sloan Kettering Cancer Center New York, New York
This slide lists the faculty who were involved in the production of these slides.

4. Faculty Disclosures
Axel Grothey, MD, has no real or apparent conflicts of interest to report. David Ilson, MD, PhD, has disclosed that he has received consulting fees from Amgen, Lilly, Novartis, and Taiho and funds for research support from Amgen and Lilly.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

5. Agenda Program Overview
Choosing Optimal First-line Treatment for Patients With Advanced or Metastatic Gastric Cancer
Selecting Effective Salvage Therapy for Patients With Advanced or Metastatic Gastric Cancer Who Progress on First or Later Lines of Treatment
Targeted Therapies for the Management of Advanced or Metastatic Gastric Cancer
Promising Investigational Approaches in Metastatic or Advanced Gastric Cancer
Closing Remarks, Question and Answer Session
Slide credit: clinicaloptions.com

6. Esophageal and Gastric Carcinoma: US Incidence in 2015
Estimated 41,570 new cases (2.5% of all cancers)
Gastric: 24,590 (59%)
Esophagus: 16,980 (41%)
Decline in gastric cancer incidence
Increase in esophageal, GEJ, cardia adenocarcinoma
OS improvement, , ,
Gastric: 16%  18%  27%
Esophageal: 5%  10%  19%
GEJ, gastroesophageal junction; OS, overall survival.
Slide credit: clinicaloptions.com
Siegel RL, et al. CA Cancer J Clin. 2015;65:5-29.

7. Adjuvant Therapy in Gastric Cancer Improves OS
Postoperative RT + chemotherapy (US)[1]
Treatment: 5-FU/LV + RT (INT-0116 study)
10% ↑ 5-yr OS; HR: 0.76
Preop and postop chemo (UK) without RT[2]
Treatment: ECF (MAGIC study)
13% ↑ 5-yr OS; HR: 0.75
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
Survival improvements with all approaches similar, modest
5-FU, 5-fluorouracil; ECF, epirubicin, cisplatin, fluorouracil; LV, leucovorin; OS, overall survival; RT, radiotherapy.
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:
Slide credit: clinicaloptions.com

8. Esophageal and GEJ Adenocarcinoma: Adjuvant Therapy
T2-3 or N+: Something more than surgery alone should be done
Perioperative ECF, preoperative CF improves OS in some but not all trials
MAGIC (perioperative ECF): 13% ↑ OS at 5 yrs; HR: (esophageal, 120 pts), no increase in R0 resection[1]
FFCD/FNLC (preop CF): 14% ↑ OS at 5 yrs; HR: (esophageal cancer, 180 pts)  same as MAGIC, no epirubicin, increase in R0 resection[2]
CF, cisplatin, fluorouracil; ECF, epirubicin, cisplatin, fluorouracil; GEJ, gastroesophageal junction; OS overall survival.
1. Cunningham D, et al. N Engl J Med. 2006;355: Ychou M, et al. J Clin Oncol. 2011;29:
Slide credit: clinicaloptions.com

9. Esophageal Adenocarcinoma: Consensus on Adjuvant Therapy
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
CF, cisplatin, 5-fluorouracil; ECX, epirubicin, cisplatin; capecitabine; EUS, endoscopic ultrasound; OS, overall survival.
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.
Slide credit: clinicaloptions.com

10. Preop CRT + Surgery vs Surgery Alone for Esophageal or Junctional Cancer
Chemoradiotherapy followed by surgery compared with surgery alone (N = 368) M T W F S
Wk 1 M T W F S
Wk 2 M T W F S
Wk 3 M T W F S
Wk 4 M T W F S
Wk 5
Day 6
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7
Day 6
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7
Day 6
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7
Day 6
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7
Day 6
Day 1
Day 2
Day 3
Day 4
Day 5
Day 7
XRT
CTX
Paclitaxel 50 mg/m2 + 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
XRT, radiation therapy; CTX, chemotherapy; AUC, area under the curve; CRT, chemoradiotherapy; THE, transhiatal esophagectomy; TTE, transthoracic esophagectomy.
Slide credit: clinicaloptions.com
van Hagen P, et al. N Engl J Med. 2012;366:

11. OS by Tumor Type and Treatment
Preop CRT + Surgery vs Surgery Alone for Esophageal or Junctional Cancer: OS
OS by Treatment
1.0
R0 resection increased from 69% w/surgery alone to 92%
5-yr OS: 47% vs 34% with surgery alone
Squamous HR: 0.453
Adeno HR: 0.732
Pathologic CR with CRT + surgery
Squamous: 49%
Adenocarcinoma: 23%
Considered a new standard of care
CRT + surgery
Surgery alone
0.8
0.6
Proportion Surviving
0.4
0.2
P = .003 12 24 36 48 60
Mos
1.0
OS by Tumor Type and Treatment
0.8
CR, complete response; CRT, chemoradiotherapy; OS, overall survival; SCC, squamous cell carcinoma; AC, adenocarcinoma.
0.6
Proportion Surviving
0.4
SCC, CRT + surgery
AC, CRT + surgery AC, surgery alone SCC, surgery alone
0.2
AC, P = .049
SCC, P = .011 12 24 36 48 60
Mos
Slide credit: clinicaloptions.com
van Hagen P, et al. N Engl J Med. 2012;366:

12. First-line Chemotherapy

13. First-line Therapy Recommendations
Preferred regimens*
Fluoropyrimidine + cisplatin (category 1) or oxaliplatin (2A)
DCF (category 1)
ECF (category 1)
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
*2-drug regimens preferred due to lower toxicity, reserving triplet therapy for younger, medically fit pts.
†Trastuzumab should not be combined with anthracyclines.
Slide credit: clinicaloptions.com
1. NCCN. Guidelines: gastric cancer. v

14. Advanced Esophagogastric Cancer Chemotherapy: Which Regimen to Use?
3-Drug Regimens
2-Drug Regimens
Oxali:
EOX or EOF[1]
Cape:
ECX or EOX[1]
DCF[2]
ECF [3]
XP[4]
FLO[5]
FOLFIRI[6]
S-1 Cis [7] N
489
513
221
126
160
112
209
305
ORR, % 44 45 37 46 35 39 54
TTP, mo
6.7
6.5
5.6
7.4
5.8
5.3
6.0
OS, mo
10.4
10.9
9.2
8.9
10.5
10.7
9.5
13.0
Cis, cisplatin; DCF, docetaxel, cisplatin, fluorouracil; ECF, epirubicin, cisplatin, fluorouracil; EOF, epirubicin, oxaliplatin, fluorouracil; EOX, epirubicin, oxaliplatin, capecitabine; FLO, fluorouracil, LV, oxali; FOLFIRI, FUFIRI, irinotecan, 5-FU, leucovorin; ORR, overall response rate; OS, overall survival; TTP, time to progression; XP, capecitabine, cisplatin.
1. 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:
Slide credit: clinicaloptions.com

15. Phase III TAX325 Study: Docetaxel/ Cisplatin/5-FU vs Cisplatin/5-FU
DCF
Docetaxel 75 mg/m2 IV over 1 hr on Day 1 +
Cisplatin 75 mg/m2 IV over 1-3 hrs on Day 1 +
5-FU 750 mg/m2/day by CIV over 5 days
q3w
(n = 227)
Pts with advanced gastric cancer and no previous palliative chemotherapy
(N = 457) CF
Cisplatin 100 mg/m2 IV over 1-3 hrs on Day 1 +
5-FU 1000 mg/m2/day by CIV over 5 days
q4w
(n = 230)
5-FU, 5-fluorouracil; CF, cisplatin, 5-fluorouracil; DCF, docetaxel, cisplatin, 5-fluorouracil; OS, overall survival; QoL, quality of life; RR, response rate; TTP, time to progression.
Primary endpoint: TTP from 4 → 6 mos
Secondary endpoints: OS, RR, safety, QoL, clinical benefit
Slide credit: clinicaloptions.com
Van Cutsem E, et al. J Clin Oncol. 2006;24:

16. DCF vs CF in Advanced Gastric Cancer (TAX-325): Efficacy
Parameter
DCF (n = 221)*
CF (n = 224)*
P Value
Median age, yrs 55 --
Metastatic disease, % 96 97
ORR, % 37 25
.01
Median TTP, mos
5.6
3.7
≤ .001
Median OS, mos
9.2
8.6
.02
*Full analysis population (treated pts).
CF, cisplatin, 5-fluorouracil; DCF, docetaxel, cisplatin, 5-fluorouracil; ORR, overall response rate; OS, overall survival; TTP, time to progression.
Slide credit: clinicaloptions.com
Van Cutsem E, et al. J Clin Oncol. 2006;24:

17. DCF vs CF in Advanced Gastric Cancer (TAX-325): Toxicity
Adverse Event, %
DCF
(n = 221) CF
(n = 224)
Grade 3/4
Stomatitis 21 27
Diarrhea 19 8
Nausea 14 17
Vomiting
Neutropenia 82 57
All-grade neutropenic fever and/or neutropenic infection 29 12
Toxic deaths
3.6
5.4
Off therapy for adverse event or consent withdrawal 49 37
CF, cisplatin, 5-fluorouracil; DCF, docetaxel, cisplatin, 5-fluorouracil; ORR, overall response rate; OS, overall survival; TTP, time to progression.
Slide credit: clinicaloptions.com
Van Cutsem E, et al. J Clin Oncol. 2006;24:

18. Does Epirubicin Add Anything in Advanced GE Cancer? FOLFIRI vs ECX
1/3 GEJ, 2/3 gastric
ORR: 39% vs 38%
Median PFS: vs 5.8 mos
Median OS: vs 9.7 mos
TTF, toxicity favored first-line FOLFIRI over ECX
Time to Treatment Failure
1.0
0.8
HR: 0.77 (95% CI: ; P = .008)
0.6
TTF (Proportion)
0.4
0.2
ECX FOLFIRI
ECX, epirubicin, cisplatin, capecitabine; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan, GE, gastroesophageal; GEJ, gastroesophageal junction; ORR, overall response rate; OS, overall survivap; PFS, progression-free survival; TTF, time to treatment failure. 2 4 6 8 10 12 14 16
Mos
Pts at Risk, n
ECX FOLFIRI
209
207
145
157
108
123 61 81 33 50 14 28 8 19 5 9 4 6
Slide credit: clinicaloptions.com
Guimbaud R, et al. J Clin Oncol. 2014;32:

19. Phase III: 5-FU/LV + Either Oxaliplatin or Cisplatin in Adv Gastric Cancer
Treatment: 5-FU/LV q2w plus either
Oxaliplatin 85 mg/m2 (FLO)
Cisplatin 50 mg/m2 (FLP)
Primary endpoint: PFS
Oxaliplatin noninferior to cisplatin
In pts ≥ 65 yrs, oxaliplatin showed superior PFS and OS
FLO
FLP
P Value
Median PFS, mos
5.8
3.9
.077
ORR (ITT), % 42 16
.012
5-FU/LV, 5-fluorouracil/leucovorin; FLO, 5-FU/LV, oxaliplatin; FLP, 5-FU/LV, cisplatin; ITT, intent to treat; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q2w, every 2 weeks.
Slide credit: clinicaloptions.com
Al-Batran SE, et al. J Clin Oncol. 2008;26:

20. 5-FU/LV + Oxaliplatin ± Docetaxel in Adv Gastric Cancer: Results in Pts ≥ 65 Yrs
N = 143 pts; median age: 70 yrs
Treatment: FLO vs FLOT
5-FU/oxaliplatin ± docetaxel
ORR: 49% with FLOT vs 28% with FLO (P = .016)
PFS: 9 mos with FLOT vs 7 mos with FLO (P = .079)
OS: 17.3 mos with FLOT vs 14.5 mos with FLO (P = 0.39)
Toxicity: 82% grade 3/4 AEs with FLOT vs 39% with FLO; worse QoL with FLOT
More toxicity with no survival benefit for FLOT vs FLO in pts ≥ 65 yrs
FLO, 5-FU/leucovorin, oxaliplatin; FLOT, 5-FU/leucovorin, oxaliplatin, docetaxel; QOL, quality of life.
Slide credit: clinicaloptions.com
Al-Batran SE, et al. Eur J Cancer. 2013;49:

21. REAL-2 Trial: Capecitabine vs 5-FU, Oxaliplatin vs Cisplatin
ECF (n = 249)
ECX (n = 241)
Epirubicin 50 mg/m2 IV q3w
Cisplatin 60 mg/m2 IV q3w
5-FU 200 mg/m2/d IV given
continuously
Epirubicin 50 mg/m2 IV q3w
Cisplatin 60 mg/m2 IV q3w
Capecitabine 625 mg/m2 PO BID
continuously
EOF (n = 235)
EOX (n = 239)
Epirubicin 50 mg/m2 IV q3w
Oxaliplatin 130 mg/m2 IV q3w
5-FU 200 mg/m2/d IV given
continuously
Epirubicin 50 mg/m2 IV q3w
Oxaliplatin 130 mg/m2 IV q3w
Capecitabine 625 mg/m2 PO BID
continuously
X, capecitabine; F, 5-FU, O, oxaliplatin, C, cisplatin.
This slide shows the 2x2 randomization in the REAL-2 trial design, which attempts to address whether FU can be replaced by capecitabine and whether cisplatin can be replaced by oxaliplatin. This study intends to accrue 1000 patients with esophagus, GE-junction, and stomach cancer.
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%)
Slide credit: clinicaloptions.com
Cunningham D, et al. N Engl J Med. 2008;358:36-46.

22. REAL 2: OS, 5-FU vs Capecitabine
100 80 60
Probability of Survival (%)
5-FU
Capecitabine 40 20 1 2 3
Yrs Since Randomization
Pts at Risk, n
5-FU
Capecitabine
484
480
178
206 37 52 8 12
Slide credit: clinicaloptions.com
Cunningham D, et al. N Engl J Med. 2008;358:36-46.

23. REAL 2: OS, Cisplatin vs Oxaliplatin
100 80 60
Probability of Survival (%) 40
Oxaliplatin 20
Cisplatin 1 2 3
Yrs Since Randomization
Pts at Risk, n
Cisplatin
Oxaliplatin
490
474
187
198 41 48 10
Slide credit: clinicaloptions.com
Cunningham D, et al. N Engl J Med. 2008;358:36-46.

24. Parent DCF vs Modified DCF in Metastatic Gastric Cancer
Randomized, multicenter phase II trial
Primary endpoint: safety and 6-mo PFS
Secondary endpoints: response, median PFS, OS, 1- and 2-yr survival
Modified DCF
Docetaxel 40 mg/m2 IV on Day 1 +
Cisplatin 40 mg/m2 IV on Day 2 or 3 +
5-FU 1000 mg/m2/day IVCI X 2 days q2w
(n = 57)
Pts with previously untreated metastatic or GEJ adenocarcinoma
(N = 90)
Parent DCF
Docetaxel 75 mg/m2 IV over 1 hr on Day 1 +
Cisplatin 75 mg/m2 IV over 1-3 hrs on Day 1 +
5-FU 750 mg/m2/day by IVCI over 5 days with GCSF q3w
(n = 33)
GEJ, gastroesophageal junction; 5-FU, 5-fluorouracil; DCF, docetaxel, cisplatin, 5-fluorouracil; GCSF, granulocyte colony-stimulating factor.
Slide credit: clinicaloptions.com
Shah MA, et al. J Clin Oncol. 2015;[Epub ahead of print].

25. Parent DCF vs Modified DCF in Metastatic Gastric Cancer: Efficacy
Median PFS, Mos P
1.0
Parameter
mDCF
(n = 54)
Parent DCF
(n = 31)
Median cycles, n (range)
5.7
( )
4.0
( )
6-mo PFS, % 63 53
6-mo TTF, % 56 51
1-yr OS, % 55
2-yr OS, % 30 12
ORR (CR + PR), % 49 33
0.8
mDCF
Parent DCF
9.7
6.5 .2
0.6
Probability of PFS
0.4
0.2 6 12 18 24 30 36 42
Mos
Median
OS, Mos P
1.0
mDCF
Parent DCF
18.8
12.6
.007
0.8
DCF, docetaxel, cisplatin, 5-fluorouracil; mDCF, modified DCF; TTF, time to treatment failure.
0.6
Probability of OS
0.4
0.2 6 12 18 24 30 36 42
Mos
Slide credit: clinicaloptions.com
Shah MA, et al. J Clin Oncol. 2015;[Epub ahead of print].

26. Parent DCF vs Modified DCF in Metastatic Gastric Cancer: Grade 3/4 AEs of Interest
Nonhematologic AE, %
mDCF
(n = 54)
Parent DCF
(n = 31)
Anorexia 13
Nausea 2 23
Vomiting 19
Fatigue 11
Neuropathy 4
Hypo-
phosphatemia 32
Hypokalemia 9
TEE 20
Hematologic AE, %
mDCF
(n = 54)
Parent DCF
(n = 31)
Anemia 11 39
Leukopenia 22 48
Neutropenia (afebrile) 56 45
Febrile neutropenia 9 16
DCF, docetaxel, cisplatin, 5-fluorouracil; mDCF, modified DCF; AE, adverse event; TEE, thromboembolic event.
Slide credit: clinicaloptions.com
Shah MA, et al. J Clin Oncol. 2015;[Epub ahead of print].

27. Pt Selection for Chemotherapy
Assess age, functional status, comorbidities
Combination chemotherapy preferred over single agents
Most pts are candidates for doublet chemo
Monotherapy with 5-FU, capecitabine, taxanes in elderly, poor PS pts
Triplet: DCF or a modified schedule
High functional status, younger pts without comorbidities
Willingness to tolerate AEs
Access to frequent follow-up and toxicity assessment
5-FU, 5-fluorouracil; DCF, docetaxel, cisplatin, fluorouracil; PS, performance status; AE, adverse event.
Slide credit: clinicaloptions.com

28. Second-line/Salvage Therapy

29. 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
Slide credit: clinicaloptions.com
NCCN Guidelines: gastric cancer. v

30. Mos From Randomization
Improved OS in Phase III Trials of Second-line Chemo for Gastric Cancer
1.0
100
SLC BSC
Docetaxel Active symptom control
0.8 75
0.6
HR: 0.67 (95% CI: ; P = .01)
Survival Probability
OS (%) 50
0.4 25
0.2 3 6 9 12 15 18 2 4 6 8 10 12 14 16 18
Mos
SLC, salvage chemotherapy; BSC, best supportive care; OS, overall survival.
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.
Slide credit: clinicaloptions.com

31. Targeted Therapies

32. Genome Atlas Project: Gene Amplification in Esophagogastric Cancer
Number of Focal Events per Sample
296 Esophageal/Gastric Cancers; 190 CRCs
Amplified genes in 37% of gastroesophageal tumors
EGFR
HER2
MET
FGFR1-2
KRAS
Targetable receptors and receptor tyrosine kinases
***
***
***
***
n.s.
*** 80 60
Focal Events per Sample (n) 40 20
Colorectal Gastric Esophageal
Amplifications
Deletions
Multicopy Alterations
*** 3
*** *
CRC, colorectal cancer.
n.s. ** ** 2
Multilevel Events per Sample (n) 1
Multicopy Amplifications
Multicopy Deletions
Slide credit: clinicaloptions.com
Dulak AM, et al. Can Res. 2012;72:

33. 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
GEJ, gastroesophageal junction; MSI, microsatellite instability; RTK, receptor tyrosine kinase.
Slide credit: clinicaloptions.com
The Cancer Genome Atlas Research Network. Nature. 2014;513:

34. Targeted Therapies
Conventional, cytotoxic chemotherapy has limited benefit
Targeted agents: designed to block specific tumor growth pathways
Monoclonal antibodies
Tyrosine kinase inhibitors
Receptor-associated tyrosine kinase mediated pathways and downstream pathways
Slide credit: clinicaloptions.com

35. Phase III ToGA: Trastuzumab + Chemo in Advanced HER2+ Gastric Cancer
Rationale: a subpopulation of gastric cancers overexpress HER2
Primary endpoint: OS
Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU
5-FU or Capecitabine* +
Cisplatin 80 mg/m2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose)
(n = 294)
Pts with advanced gastric cancer screened for HER2 status
(N = 3803)
Pts with HER2+ advanced gastric cancer
(n = 810; 22% of successful screenings) R
5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; OS, overall survival; PD, progressive disease; PS, performance score; R, randomization.
5-FU or Capecitabine* +
Cisplatin 80 mg/m2 q3w x 6
(n = 290)
(n = 584)
*Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6.
Slide credit: clinicaloptions.com
Bang YJ, et al. Lancet. 2010;376:

36. Phase III ToGA: OS Median OS, mos 13.8 11.1 1.0 Events, n 167 182 0.9HR
0.74
95% CI
P Value
.0046
0.8
FC + T
0.7 FC
0.6
Survival Probability
0.5
0.4
0.3
0.2
11.1
13.8
CI, confidence interval; FC, 5-fluorouracil, cisplatin; FC + T, 5-fluorouracil, cisplatin + trastuzumab; HR, hazard ratio; OS, overall survival.
0.1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
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
Slide credit: clinicaloptions.com
Bang YJ, et al. Lancet. 2010;376:

37. Phase III ToGA: OS in Pts With IHC 3+ or FISH+ and IHC 2+
Exploratory analysis
Median OS, mos
1.0
Events, n
0.9 HR
0.65
95% CI
0.8
FC + T
0.7 FC
0.6
Survival Probability
0.5
0.4
0.3
0.2
11.8
16.0
CI, confidence interval; FC, 5-fluorouracil, cisplatin; FC + T, 5-fluorouracil, cisplatin + trastuzumab; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival.
0.1 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
228
218
218
198
122 96
100 75
84 53
65 39
51 28
39 20
28 13
20 11
12 4
11 3
5 3 4 1
Slide credit: clinicaloptions.com
Bang YJ, et al. Lancet. 2010;376:

38. 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)
CapeOx* + Lapatinib 1250 mg QD 21-day cycles
Pts with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or GEJ cancer
(N = 545)
CapeOx* + Placebo
CapeOx, capecitabine + oxaliplatin; GEJ, gastroesophageal junction; OS, overall survival; PFS, progression-free survival.
*Day 1: oxaliplatin 130 mg/m2, Days 2-14: capecitabine 850 mg/m2 BID.
Primary endpoint: OS
Secondary endpoints: PFS, ORR, DoR, CBR, safety/toxicity, QoL, molecular and pharmacogenetics analyses
Slide credit: clinicaloptions.com
Hecht J, et al. J Clin Oncol. 2015;[Epub ahead of print].

39. CapeOx ± Lapatinib in HER2+ Advanced Gastric Cancer (LOGiC): OS
CapeOx + P
(n = 238)
Median OS, Mos (95% CI)
12.2 ( )
10.5 ( )
HR (95% CI)
0.91 ( ) P = .3492
1.0
0.8
0.6
Cumulative Survival Probability
0.4
0.2
CapeOx + L CapeOx + P
0.0
CapeOx, capecitabine, oxaliplatin; ITT, intent to treat; L, lapatinib; P, placebo. 5 10 15 20 25 30 35 40 45
Mos Since Randomization
Pts at Risk, n CapeOx + L CapeOx + P
83 53
47 34
24 17
9 11
3 7
3 2 2
ITT analysis HR: 0.91
Slide credit: clinicaloptions.com
Hecht J, et al. J Clin Oncol. 2015;[Epub ahead of print].

40. 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
T-DM1, trastuzumab emtansine.
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT
Slide credit: clinicaloptions.com

41. VEGF Revisited?: Second and Later Line of Therapy
AVAGAST: capecitabine/cisplatin ± bevacizumab[1]
No OS benefit for addition of bevacizumab in first-line setting
Apatinib
Small-molecule multitargeted TKI with activity against VEGFR
Phase III trial reported at ASCO 2014: median OS significantly longer with mg QD vs placebo (195 vs 140 days, respectively; HR: 0.71)[2]
BID, twice daily; ORR, overall response rate; OS, overall survival; QD, once daily; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.
1. Ohtsu A, et al. J Clin Oncol. 2011;29:
2. Qin S, et al. ASCO Abstract 4003.
Slide credit: clinicaloptions.com

42. 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 fluoropyrimidine- containing combination therapy, ECOG PS 0-1
(N = 355)
Ramucirumab 8 mg/kg IV q2w +
BSC (n = 238)
Treatment until PD, unacceptable toxicity, or death
BSC + Placebo (n = 117)
BSC, best supportive care; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance score; GEJ, gastroesophageal junction; IV, intravenous; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; q2w, every 2 weeks; QoL, quality of life.
Primary objective: OS
Secondary endpoints: PFS, 12-wk PFS, ORR, DoR, QoL, safety
Slide credit: clinicaloptions.com
Fuchs CS, et al. Lancet. 2014;383:31-39.

43. BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): OS
1.0
0.8
0.6
0.4
0.2
Ramucirumab
Placebo
Censored
Ramucirumab Placebo
Pts/events 238/ /99
Median, mos 5.2 ( ) 3.8 ( )
(95% CI)
6-mo OS, % 42 32
12-mo OS, % 18 11
HR: (95% CI: ; P = .0473)
Proportion Remaining Alive
BSC, best supportive care; CI, confidence interval; GEJ, gastroesophageal junction; HR, hazard ratio; OS, overall survival. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28
Mos
Pts at Risk, n
Ramucirumab
Placebo
154 66
92 34
49 20
17 7
7 4
3 2
0 1
0 0
Slide credit: clinicaloptions.com
Fuchs CS, et al. Lancet. 2014;383:31-39.

44. Proportion Without Progression
BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): PFS, Response
Ramucirumab Placebo
Pts/events 238/ /108
Median, mos 2.1 ( ) 1.3 ( )
(95% CI)
12-wk PFS, % 40 16
ORR, % DCR, %
HR: (95% CI: ; P < .0001)
1.0
0.8
0.6
0.4
0.2
Ramucirumab
Placebo
Censored
Proportion Without Progression
BSC, best supportive care; CI, confidence interval; GEJ, gastroesophageal junction; HR, hazard ratio; PFS, progression-free survival. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Mos
Pts at Risk, n
Ramucirumab
Placebo
213 92
113 27
65 11
61 7
45 4
30 2
18 2
18 2
11 2
5 2
4 1
2 1
1 0
1 0
1 0
1 0
0 0
Slide credit: clinicaloptions.com
Fuchs CS, et al. Lancet. 2014;383:31-39.

45. BSC ± Ramucirumab in Metastatic Gastric or GEJ Cancer (REGARD): AEs of Interest
Ramucirumab (n = 236)
Placebo (n = 115)
Any Grade
Grade ≥ 3
 Any Grade
Hypertension*† 16 8 3
Bleeding/hemorrhage 13 11
Arteriothromboembolic 2 1
Venous thromboembolic 4 7
Proteinuria
< 1
< 3
< 0
GI perforation
Fistula (GI and non-GI)
Infusion-related reaction
Cardiac failure
AE, adverse event; BSC, best supportive care; GI, gastrointestinal.
*Includes increased blood pressure. †No grade 4 hypertension observed among ramucirumab-treated pts.
Slide credit: clinicaloptions.com
Fuchs CS, et al. Lancet. 2014;383:31-39.

46. Randomized Second-line Gastric Cancer Studies (2009-2013): Median OS
Median OS by Study Arm, Mos
Ramucirumab vs BSC[1]
(n = 355)
5.2
3.8
Docetaxel vs ASC[2]
(n = 131)
5.2
3.6
Chemo (docetaxel or irinotecan) vs BSC[3]
(n = 202)
5.3
3.8
ASC, active symptom control; BSC, best supportive care; OS, overall survival.
Irinotecan vs BSC[4]
(n = 40)
4.0
2.4 1 2 3 4 5 6
1. 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
Slide credit: clinicaloptions.com

47. Treat until PD or intolerable toxicity
RAINBOW: Second-line Paclitaxel ± Ramucirumab in Advanced Gastric Cancer
Randomized, double-blind phase III trial
Primary endpoint: OS
Secondary endpoints: PFS, ORR, TTP
Pts with metastatic or locally adv unresectable gastric or GEJ cancer and progression on first-line chemo*
(N = 665)
Ramucirumab 8 mg/kg Days 1, 15 + Paclitaxel 80 mg/m2 Days 1, 8, 15 (n = 330)
Placebo Days 1, 15 + Paclitaxel 80 mg/m2 Days 1, 8, 15 (n = 335)
Stratified by geographic region, measurable vs nonmeasurable disease, TTP on first-line therapy (< 6 vs ≥ 6 mos)
Treat until PD or intolerable toxicity
4-wk cycle
GEJ, gastroesophageal junction; OS, overall survival; PD, progressive disease; TTP, time to progression.
*Platinum agent plus fluoropyrimidine ± anthracycline.
Slide credit: clinicaloptions.com
Wilke H, et al. Lancet Oncol. 2014;15:

48. 2nd-Line Ramucirumab in Advanced Gastric Cancer (RAINBOW): OS
REGARD[2]
1.0
Ram/Pac Placebo/Pac Ram
Pts/events, n 330/ / /199 Median, mos 9.63 ( ) ( ) ( ) (95% CI) 6-mo OS, % mo OS, %
HR: (95% CI: ; P = .0169)
0.8
0.6
Probability of OS
0.4
OS, overall survival; Pac, paclitaxel; Ram, ramucirumab.
Δ mOS = 2.3 mos
0.2
Ram + Pac Placebo + Pac Censored 4 8 12 16 20 24 28
Mos
1. Wilke H, et al. Lancet Oncol. 2014;15: Fuchs CS, et al. Lancet. 2014;383:31-39.
Slide credit: clinicaloptions.com

49. Second-line Ramucirumab in Adv Gastric Cancer (RAINBOW): PFS, Responses
REGARD[2]
1.0
Ram/Pac Placebo/Pac Ram Pts/events, n 330/ / /199 Median, mos 4.40 ( ) 2.86 ( ) ( ) (95% CI) 6-mo PFS, % mo PFS, % ORR, % P = DCR, % P <
HR: (95% CI: ; P < .0001)
0.9
0.8
0.7
0.6
Probability of PFS
0.5
0.4
DCR, disease control rate; ORR, overall response rate; PFS, progression-free survival; Pac, paclitaxel.
0.3
0.2
Ram + Pac Placebo + Pac Censored
0.1 2 6 10 14 18 22
1. Wilke H, et al. Lancet Oncol. 2014;15: Fuchs CS, et al. Lancet. 2014;383:31-39.
Mos
Slide credit: clinicaloptions.com

50. RAINFALL: Capecitabine/5-FU + Cisplatin ± Ramucirumab in Metastatic Gastric CA
Randomized, double-blind, phase III trial
Primary endpoint: PFS
Secondary endpoints: OS, PFS2, ORR, DCR, TTP, DoR, QoL, PK
Ramucirumab 8 mg/kg IV Days 1, 8
Capecitabine* 1000 mg/m2 PO Days 1-14
Cisplatin 80 mg/m2 IV Day 1
Pts with metastatic gastric/GEJ CA with no prior first-line therapy
(N = 616, planned)
21-day cycles
Placebo IV Days 1, 8
Capecitabine* 1000 mg/m2 PO Days 1-14
Cisplatin 80 mg/m2 IV Day 1
PFS2, randomization to 2nd disease progression after start of additional anticancer treatment or death from any cause; ORR, overall response rate; DCR, disease control rate; TTP, time to progression, DoR, duration of response, QoL, quality of life; PK, pharmacokinetics.
*Pts unable to take capecitabine receive 5-FU 800 mg/m2/day Days 1-5.
Slide credit: clinicaloptions.com
ClinicalTrials.gov. NCT

51. Investigational Therapies

52. 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
BSC, best supportive care; ECX, epirubicin, cisplatin, capecitabine; UK, United Kingdom; EU, European Union.
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:
Slide credit: clinicaloptions.com

53. cMET Antibodies in Gastric Cancer: Phase III Trials
RILOMET-1[1]
ECX +
Rilotumumab
Locally advanced or metastatic gastric and AEG Cancer, MET-positive by immunohistochemistry (IHC)
HER2 negative R
1:1
ECX alone
N = 450
Primary endpoint: OS
Both studies stopped prematurely
MetGastric[2]
ECX +
Rilotumumab
Locally advanced or metastatic gastric and AEG Cancer, MET-positive by immunohistochemistry (IHC)
HER2 negative
AEG, adenocarcinoma of the esophagogastric junction; R, randomization; OS, overall survival; IHC, immunohistochemistry; ECX, epirubicin, cisplatin, capecitabine. R
1:1
ECX alone
N = 800
Primary endpoint: OS in the Met IHC 2+/3+ pt subgroup
Slide credit: clinicaloptions.com
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

54. Targeting Amplified Gene Signaling Pathways in Gastric Cancer: FGFR
Tyrosine kinase inhibitors alone or with chemotherapy
Phase I-II
Dovitinib
Nintedanib
Some phase I trials selecting pts with an FGFR- activating mutation or amplification
FGFR, fibroblast growth factory receptor.
Slide credit: clinicaloptions.com

55. Immune Checkpoint Inhibitors

56. CTLA-4 and PD-1/L1 Checkpoint Blockade
Priming phase (lymph node)
Effector phase (peripheral tissue)
T-cell migration
Dendritic cell
Cancer cell
T cell
T cell
Dendritic cell
T cell
MHC
TCR B7
CD28
CTLA-4
TCR
MHC
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death 1, PD-L1, programmed death ligand 1; MHC, major histocompatibility complex; TCR, T-cell receptor.
T cell
PD-1
Cancer cell
PD-L1
Slide credit: clinicaloptions.com
Ribas A. N Engl J Med. 2012;366:

57. 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 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]
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death 1, PD-L1, programmed death ligand 1; DCR, disease control rate; PR, partial response; ORR, overall response rate; TTP, time to progression.
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.
Slide credit: clinicaloptions.com

58. KEYNOTE-012: Pembrolizumab in Gastric Cancer Cohort
Multicenter, multicohort open-label phase Ib trial
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
Discontinue treatment CR
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
PR, SD
Pembrolizumab 10 mg/kg IV q2w for 24 mos or until progression or intolerable toxicity
Confirmed PD
Discontinue treatment
PD-L1, programmed death ligand 1; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; PR, partial response; q2w, every 2 weeks; RECIST, response evaluation criteria in solid tumors; SD, stable disease.
Slide credit: clinicaloptions.com
Bang YJ, et al. ASCO Abstract 4001.

59. 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
Median response duration: 40 wks (range: 20+ to 48+)
Outcomes
Response
Investigator Review
(n = 39)
Central Review
(n = 36)
ORR, % (95% CI)
33 (19-50)
22 (10-39)
Best response, n (%) CR PR
13 (33)
8 (22) SD
3 (8)
5 (14) PD
23 (59)
19 (53)
No assessment
1 (3)
Not determined
CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Slide credit: clinicaloptions.com
Bang YJ, et al. ASCO Abstract 4001.

60. Pembrolizumab in Gastric Cancer Cohort (KEYNOTE-012): Change in Tumor Size
Maximum Percentage Change From Baseline in Tumor Size (RECIST v1.1, Central Review)
100 80 60
53.1% of pts experienced a decrease in target lesions 40
Change From Baseline in Sum of Longest Diameter of Target Lesion (%) 20
-20
-40
-60
-80
-100
Slide credit: clinicaloptions.com
Bang YJ, et al. ASCO Abstract 4001.

61. Gastric Cancer: 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 preferred 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
GEJ, gastroesophageal junction; RT, radiotherapy.
Slide credit: clinicaloptions.com

62. Immune Checkpoint Inhibitors in Adv
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
Pembrolizumab
KEYNOTE-061: Ph III 2nd-line pembro vs paclitaxel
NCT
KEYNOTE-062: Ph III first-line pembro monotherapy
NCT
KEYNOTE-059: Ph II pembro vs pembro+ cis/5-FU
NCT
PD-L1
Avelumab
Ph III avelumab vs continuation of first-line chemo
NCT
Ph III avelumab vs chemo, 3rd-line
NCT
Combo
Tremelimumab + durvalumab
Ph Ib/II tremelimumab + durvalumab vs treme vs durvalumab
NCT
Nivolumab + ipilimumab
Ph I/II nivolumab vs nivo/ipi
NCT
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death 1, PD-L1, programmed death ligand 1; ipi, ipilimumab; pembro, pembrolizumab; cis, cisplatin; chemo, chemotherapy; treme, tremelimumab; nivo, nivolumab.
Slide credit: clinicaloptions.com

63. Go Online for More CCO Coverage of Gastric Cancer!
Expert reviews of all the key data Additional slidesets on gastric and other GI malignancies
clinicaloptions.com/oncology