1. Will targeting the VEGF-receptor prove to be any more successful in gastroesophageal adenocarcinoma than did targeting its ligand VEGF?
Charles S. Fuchs, MD
Dana-Farber Cancer Institute
Harvard Medical School
Boston, MA

2. VEGF-Mediated Signaling
PlGF
VEGF-A
VEGF-B
VEGF-C
VEGF-D
VEGFR1
VEGFR2
VEGFR3

3. Survival Following Gastric Cancer Resection Circulating Plasma VEGF
Yoshikawa. Cancer Letters 2000;153:7-12

4. Survival Following Gastric Cancer Resection Tumor Endothelial Expression (IHC)
Maeda. Cancer 1996;77:858-63

5. Tumoral VEGF A Expression and Survival in Gastric Cancer: A Meta-Analysis
Ji et al Tumor Biol 2013

6. AVAGAST: Bevacizumab in advanced gastric cancer
Locally advanced or metastatic gastric cancer
(n=736)
Bevacizumab 7.5 mg/kg + XP
Placebo + XP R
Treat to PD
Bevacizumab 7.5 mg/kg + capecitabine/ 5-FU
Placebo + capecitabine/ 5-FU*
6 Cycles
Primary endpoint: OS
Secondary endpoints: PFS, TTP, ORR, DOR, Safety, QoL and Biomarkers
XP=capecitabine/5-FU + cisplatin.
Ohtsu et al. J Clin Oncol 29;

7. AVAGAST: Results
Both arms well tolerated without major toxicity differences
+Bev
+Placebo
P value
HR (95% CI)
Median PFS, mos
6.7
5.3
0.004
0.80 ( )
Response rate
46%
37%
0.03
Median OS, mos
12.1
10.1
0.10
0.87 ( )
Ohtsu et al. J Clin Oncol 29;

8. AVAGAST: OS by Region ITT Region Plac + Chemo (N=387) Median (months)
Bev + Chemo (N=387)
Delta (months) HR
95% CI OS
Asia
12.1
13.9
1.8
0.97
Europe
8.6
11.1
2.5
0.85
America
6.8
11.5
4.7
0.63
Ohtsu et al. J Clin Oncol 29;

9. Proof-of-Concept DC101 Inhibits Tumor Growth
Mean tumor volume (mm3) 5 10 15 20 25 30 35 40 45
500
1000
1500
2000
2500
3000
3500
4000
4500 50 55 60 65 70
A431
BxPC-3
SK-RC-29
Human Xenografts in Nude Mice
epidermoid
GBM-18
glioblastoma
pancreatic
renal
Mouse Tumors 5 10 15 20 25 30 35 40
500
1000
1500
2000
2500
3000
3500
4T1
vehicle
800 ug
4000
5000
400 ug
1200 ug
LLC
lung
breast
Days post tumor implantation
Days post tumor implantation
Prewett. Cancer Res 1999; 59:

10. Anti-VEGFR2 in gastric cancer xenograft model TMK-1 cell line
Jung YD. Eur J Cancer 2002;38:1133

11. TMK-1 xenograft (ctd.) Vascularity (CD31) Proliferation (PNCA)
Tumor Apoptosis
Endothelial Apoptosis
Jung YD. Eur J Cancer 2002;38:1133

12. Role of VEGF Pathway in Tumor Growth Endothelial cell membrane
Ramucirumab (IMC-1121B; RAM) is a recombinant human IgG1 monoclonal antibody receptor antagonist designed to bind the extracellular domain of VEGF Receptor-2, thereby blocking the binding of VEGF ligands and inhibiting receptor activation.
VEGF-C VEGF-D
Angiogenesis
Tumor growth
VEGF-A
VEGFR2
Ligand binding activates VEGFR2 and p44/p42 MAP kinases
Ramucirumab
No signaling
Inhibit new blood vessel formation and tumor growth
Ramucirumab binds to VEGFR2, blocks VEGF ligand binding
VEGF binds to VEGFR2 receptor; VEGF-C, -D compete for binding to VEGFR2
VEGF-C VEGF-D
Endothelial cell membrane

13. Tumor assessment, survival, and safety follow-up
REGARD Study Design
Ramucirumab 8 mg/kg q2wk +
BSC (n = 238) R A N D O M I Z E
Treatment
until disease
progression or
intolerable
toxicity
Tumor assessment, survival, and safety follow-up
2:1 S C R E EN
Placebo q2wk +
BSC (n = 117)
N = 355
Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial
Gastric or GEJ adenocarcinoma
Stratification factors: region, weight loss (≥10% vs. <10% over 3 months), location of primary tumor (gastric vs. GEJ)
Global: 6 continents, 30 countries, 120 study centers
Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction
Fuchs et al. Lancet 2013

14. REGARD: Overall Survival
HR (95% CI) = (0.603, 0.998)
Log rank P-value (stratified) =
Ramucirumab
Placebo
Patients / Events
238 / 179
117 / 99
Median (mos) (95% CI)
5.2 (4.4, 5.7)
3.8 (2.8, 4.7)
6-month OS
42%
32%
12-month OS
18%
11%
No. at Risk
Ram
238
154 92 49 17 7 3
Plcb
117 66 34 20 4 2 1
Fuchs et al. Lancet 2013

15. Median OS in randomized 2nd-line gastric cancer studies presented/published in 2009-2013
Ramucirumab vs PBO (BSC)
(n=355)
5.2
3.8
Docetaxel vs ASC1
(n=131)
5.2
3.6
CTX [Docetaxel or Irinotecan] vs BSC2
(n=202)
5.3
Irinotecan vs BSC3
(n=40)
1. Ford et al. Proc Gastrointestinal Cancer Symp LBA4.
2. Kang et al. J Clin Oncol 30: , 2012
3. Thuss-Patience et al. EUR J CANCER 47: (2011)

16. RAINBOW: Study Design 1:1
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330 R A N D O M I Z E
Treat until disease progression or intolerable toxicity
Survival and safety follow-up S C R E EN
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
Important inclusion criteria:
- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma
- Progression after 1st line platinum/fluoropyrimidine based chemotherapy
Stratification factors:
- Geographic region,
- Measurable vs non-measurable disease,
- Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

17. RAINBOW: Overall Survival
HR (95% CI) = (0.678, 0.962)
Stratified log rank p-value =
RAM + PTX
PBO + PTX
Patients / Events
330 / 256
335 / 260
Median(mos) (95% CI)
9.63 (8.48, 10.81)
7.36 (6.31, 8.38)
6-month OS
72%
57%
12-month OS
40%
30%
Δ mOS = 2.3 months
Censored
No. at risk
RAM + PTX
330
308
267
228
185
148
116 78 60 41 24 13 6 1
PBO + PTX
335
294
241
180
143
109 81 64 47 30 22 5 2

18. Stratified log rank p-value < 0.0001
RAINBOW: Progression-free Survival & Response Rates
HR (95% CI) = (0.536, 0.752)
Stratified log rank p-value <
RAM + PTX
PBO + PTX
Patients / Events
330 / 279
335 / 296
Median(mos) (95% CI)
4.40 (4.24, 5.32)
2.86 (2.79, 3.02)
6-Month PFS
36%
17%
9-Month PFS
22%
10%
Response Rate
28%
16%
p =
Disease Control Rate
80%
64%
p <
Censored
No. at risk
RAM + PTX
330
259
188
104 70 43 28 15 11 7 3 1
PBO + PTX
335
214
124 50 34 21 12 8 5

19. Forest Plot of Overall Survival by Subgroups - Stratified Analysis
Category
Subgroup
N (RAM+PTX)
N (PBO+PTX) HR
Overall
330
335
0.807
Combined Geo. Regiona
Region 1+2
221
0.732
Region 3
109
114
0.986
Time to PD on 1st-line Therapy
< 6 months
250
256
0.871
≥ 6 months 80 79
0.615
Disease Measurability
Non-measurable 63 62
1.101
Measurable
267
273
0.750
Gender
Male
229
243
0.814
Female
101 92
0.672
Age Group (yrs)
< 65
204
212
0.753
≥ 65
126
123
0.861
ECOG PS
117
144
0.778 1
213
191
0.771
Histologic Subtype
Intestinal
145
135
0.705
Diffuse
115
133
0.856
Mix/Miss./Unk. 70 67
0.955
Number of Metastatic Sites
≤ 2
209
232
0.749
> 2
121
103
0.815
Primary Tumor Location
Gastric
264
0.899
GEJ 66 71
0.521
Prior Gastrectomy
Yes
0.939 No
197
Peritoneal Metastases
163
152
167
183
0.758
a Region 1: Europe, United States, and Australia;
Region 2: Brazil, Chile, Mexico, and Argentina;
Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore.
0.2
0.5 1 2
Favors RAM+PTX
Favors PBO+PTX

20. Forest Plot of Progression-Free Survival by Subgroups - Stratified Analysis
Category
Subgroup
N (RAM+PTX)
N (PBO+PTX) HR
Overall
330
335
0.635
Combined Geo. Regiona
Region 1+2
221
0.639
Region 3
109
114
0.628
Time to PD on 1st-line Therapy
< 6 months
250
256
0.676
≥ 6 months 80 79
0.512
Disease Measurability
Non-measurable 63 62
0.833
Measurable
267
273
0.599
Gender
Male
229
243
0.592
Female
101 92
0.670
Age Group (yrs)
< 65
204
212
0.572
≥ 65
126
123
0.673
ECOG PS
117
144
0.663 1
213
191
0.568
Histologic Subtype
Intestinal
145
135
0.531
Diffuse
115
133
0.695
Mix/Miss./Unk. 70 67
0.734
Number of Metastatic Sites
≤ 2
209
232
> 2
121
103
0.577
Primary Tumor Location
Gastric
264
0.694
GEJ 66 71
0.387
Prior Gastrectomy
Yes
0.624 No
197
0.641
Peritoneal Metastases
163
152
0.726
167
183
0.526
0.2
0.5 1 2
a Region 1: Europe, United States, and Australia;
Region 2: Brazil, Chile, Mexico, and Argentina;
Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore.
Favors RAM+PTX
Favors PBO+PTX

21. RAINBOW: Efficacy by Geographic Region
RAM + PTX
PBO+ PTX
Delta
HRa/ Odds Ratiob
95% CI
mOS
(mos)
Asia
12.1
10.5
1.6
0.99a
0.73, 1.34
EU/NA/AUS + Central/South Am.
8.5
5.9
2.6
0.73a
0.59, 0.91
mPFS
5.5
2.8
2.7
0.63a
0.47, 0.83
EU/NA/Aus + Central/South Am.
4.2
2.9
1.3
0.64a
0.52, 0.79 RR
(%)
33.9%
20.2%
13.7%
2.24b
1.18, 4.24
EU/NA/Aus
Central/South Am.
24.9%
14.0%
10.9%
2.09b
1.28, 3.41
*Accrual: Asia n=223; EU/NA/AUS n=398; Central / South America n=44

22. Treatment-Emergent Adverse Events Occurring in ≥ 20% of Patients and ≥ 5% Higher in the RAM + PTX Arm
RAM + PTX (N=327)
PBO + PTX (N=329)
Preferred Term†
Any Grade (%)
Grade ≥3 (%)
 Any Grade (%)
Fatigue†
56.9
11.9
43.8
5.5
Neutropenia†
54.4
40.7
31.0
18.8
Neuropathy†
45.9
8.3
36.2
4.6
Decreased appetite
40.1
3.1
31.9
4.0
Abdominal pain†
36.1
6.1
29.8
3.3
Leukopenia†
33.9
17.4
21.0
6.7
Diarrhea
32.4
3.7
23.1
1.5
Epistaxis
30.6
7.0
Vomiting
26.9
20.7
3.6
Hypertension†
25.1
14.7
5.8
2.7
Peripheral Edema
13.7
0.6
†Consolidated AE terms are comprised of synonymous MedDRA preferred terms: fatigue includes asthenia; neutropenia includes neutrophil count decreased; neuropathy includes peripheral sensory neuropathy; paraesthesia; neuropathy peripheral, polyneuropathy; hypoasethesia, neuralgia, dysaesthesia; abdominal pain includes abdominal pain upper and abdominal pain lower; leukopenia includes white blood cell decreased; hypertension includes blood pressure increased, hypertensive cardiomyopathy, procedural hypertension, systolic hypertension.

23. Adverse Events of Special Interest
RAM + PTX (N=327)
PBO + PTX (N=329)
Category of event†
Any Grade
(%)
Grade ≥3
 Any Grade
Bleeding/Hemorrhage
Epistaxis
41.9
30.6
4.3
17.9
7.0
2.4
Hypertension
25.1
14.7
5.8
2.7
Proteinuria
16.8
1.2
6.1
GI hemorrhage
10.1
3.7
1.5
Renal failure
6.7
1.8
0.9
Infusion-related reaction
0.6
3.6
Venous thromboembolic
4.0
5.5
3.3
Cardiac failure
Arteriothromboembolic
GI perforation
0.3
†Each AESI category is comprised of consolidated synonymous MeDRA preferred terms.

24. RAINBOW: Results and Conclusions
RAINBOW met the primary endpoint
RAM + PTX conferred a statistically significant and clinically meaningful OS benefit of > 2 months (median); risk reduction of death by 19%
Significant benefits in PFS and ORR were observed
RAINBOW and REGARD demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric and GEJ cancer after prior chemotherapy

25. Apatinib, VEGFR TKI, in Refractory Gastric Cancer
144 patients who failed ≥ 2 lines of therapy R A N D O M I Z E
Apatinib 850 QD
Primary endpoint:
PFS
Apatinib 425 BID
Placebo QD
Li J et al. JCO 2013;31:

26. Apatinib in Refractory Gastric Cancer: PFS
Median PFS
Placebo
1.40 mos
Apatinib 850 QD
3.67 mos
Apatinib 425 BID
3.20 mos
P < 0.001
Li J et al. JCO 2013;31:

27. Apatinib in Refractory Gastric Cancer: OS
Median OS
Placebo
2.50 mos
Apatinib 850 QD
4.83 mos*
Apatinib 425 BID
4.27 mos
*P < 0.001
Li J et al. JCO 2013;31:

28. ToGA: A Randomized, Open Label Multicenter Phase III Study
Capecitabine1 or iv 5-FU2† + cisplatin (n=290)
HER2-positive* advanced gastric or GEJ cancer
(n=584)
3807 patients screened
810 HER2-positive (22.1%) R
Capecitabine or iv 5-FU2† + cisplatin3 + Trastuzumab (n=294)
Stratification factors
Advanced vs. metastatic disease
GC vs. GEJ
Measurable vs. non-measureable
ECOG PS 0-1 vs. 2
Capecitabine vs. 5-FU
†Chosen at investigator’s discretion
mg/m2 bid d1-14 q3w x 6 cycles
2 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 cycles
3 80 mg/m2 q3w x 6 cycles
4 8 mg/kg loading dose followed by 6 mg/kg q3w until disease progression
*IHC 3+ or FISH+ 5-FU=5-fluorouracil; GEJ=gastroesophageal junction; R=randomization;
ECOG PS =Eastern Cooperative Oncology Group performance score.
Bang YJ, et al. Lancet ;376: 28 28 28

29. ToGA Primary Endpoint: Overall Survival
Events
Median OS (mo) HR
95% CI
p-value
FC + Trastuzumab
167
13.8
0.74
0.60, 0.91
0.0046 FC
182
11.1
1.0
0.9
0.8
0.7
0.6
F+C+Trastuzumab
F+C
0.5
Probability
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
F=fluoropyrimidine (either fluorouracil or capecitabine); C=cisplatin.
Bang YJ, et al. Lancet ;376: 29 29 29

30. 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

31. CAPOX + bevacizumab + trastuzumab31

32. MET Amplification as a Predictor of Drug Sensitivity in Gastric and Esophageal Adenocarcinoma
Graziano et al J Clin Onc 2011:
230 pts: 10% MET amplifications
Worse prognosis
Yapp et al J Clin Onc 2011:
Phase I trial of ARQ197
Minor regression in gastric cancer
Smollen et al PNAS, 2006

33. Presented at ASCO 2012

34. Oliner et al ASCO 2012

35. Oliner et al ASCO 2012

36. RILOMET-1: ECX +/- Rilotumumab in
MET-High Gastroesophageal Adenocarcinoma
450 pts with MET+ gastroesophageal adenoca R A N D O M I Z E
ECX +
Rilotumumab
Primary Endpoint:
Overall
Survival
ECX +
Placebo

37. Phase III Trial of FOLFOX+/- MetMAb in Gastric Adenocarcinoma
800 pts with previously untreated advanced disease: R A N D O M I Z E
FOLFOX +
MetMAb
Primary Endpoint:
Overall
Survival
FOLFOX +
Placebo

38. C-Met and Angiogenesis
Hypoxia promoted invasive growth by activation of met
In RIP-Tag2 mice, combined anti-VEGF and c-Met inhibition inhibited invasion and metastasis
KRC-408, c-Met inhibitor, inhibited both cell growth in angiogenesis in gastric cancer models
Pennacchieti et al Cancer Cell 2003
Sennino et al Cancer Disc 2012
Hong et al Cancer Letters 2013

39. Inter-relation between Angiogenesis and Immune Response in Cancer

40. Increased PD-1 Expression on CD4 and CD8 T cells in Gastric Cancer
Saito et al J Surg Oncol 2013; 107:517

41. We are defining the genome of Esophageal and Gastric cancers….

42. Distinct Pattern of Focal Amplifications Between Upper/Lower GI Adenocarcinomas
High-Level Amplifications
Dulak, Schumacher et al Cancer Research 2012

43. Statistical analysis of focal amplifications
across gut adenocarcinomas
Significant amplifications (across all gut adenocarcinomas)
Cytoband
Residual q-value
Peak Boundaries (Mb)
Number of Genes in Peak
Candidate Target(s) (Bold designates therapeutic target)
Gut Adenocarcinoma Types Represented
Gut Adenocarcinomas
12p12.1
8.04E-51 3
KRAS
E, G
18q11.2
5.05E-37 1
GATA6
E, G, C
17q12
4.34E-35 10
ERBB2
19q12
5.97E-34
CCNE1
8q24.21
8.23E-34 2
MYC
8p23.1
2.10E-32 4
GATA4
11q13.2
5.26E-22 5
CCND1, FGF3, FGF4, FGF19
7q21.2
3.36E-17
CDK6* E
6p21.1
2.12E-16
VEGFA
7p11.2
6.71E-16
EGFR
17q21.2
2.23E-11 7
9p13.3
7.03E-09 24
12q15
6.23E-08
MDM2, FRS2
7q22.1
1.41E-07 16
13q13.1
2.04E-06
10q22.2
1.10E-05
7q31.2
1.32E-05 6
MET
1q21.3
1.69E-05
106
MCL1
1q42.3
1.71E-04 G
10q26.12
3.17E-04
FGFR2
13q14.11
3.67E-04
BOLD= potential target
11/23/2018

44. VEGF Inhibition in Gastric Cancer
VEGF inhibition offers a clear benefit in advanced gastric cancer
For all patients, 2nd-line ramucirumab significantly improves overall survival
Survival benefit for ramucirumab appears comparable to 2nd-line docetaxel or irinotecan
Addition of ramucirumab to 2nd-line paclitaxel significantly improves overall survival
Combining VEGF inhibition with other targeted approaches may offer greater benefit