Presentación realizada en el marco de la I Jornada de actualización e innovación en Oncología que tuvo lugar en el CIBA en enero de 2015.

1. Paradigmas de la Angiogenesis
Tumoral
• Judah Folkman : Los tumores para su
crecimiento, desde su más mínima
expresión, necesitan inducir el
crecimiento paralelo de la
vascularización.1
• Los tumores avasculares crecen
lentamente, debido a la limitación de su
soporte nutricional y de su
oxigenación.2,3
• El crecimiento tumoral provoca hipoxia y
esta induce a la producción de factores
de crecimiento pro-angiogénicos, tales
como VEGF4
• La producción excesiva de VEGF
provoca una excesiva red capilar y una
vascularización anómala5
1. Folkman. N Engl J Med 1971;285(21):1182-6.
2. Gimbrone et al. J Exp Med 1972;136(2);261-76.
3. Gimbrone et al. J Natl Cancer Inst 1974;52(2):413-27.
4. Reviewed in Chung et al. Nat Rev Cancer 2010;10(7):505-14.
Angiogram (liver) of tumor vasculature
illustrating a highly vascularized tumor
5. Reviewed in Baluk et al. Curr Opin Genet Dev 2005;15(1):102-11.

2. Tumor Angiogenesis Overview
Reviewed in Tugues et al. Mol Aspects Med 2011;32(2):88-111.

3. Tumor Hypoxia and Angiogenesis
• Hypoxia: low local oxygen concentration
• Tumor hypoxia is the primary stimulus for VEGF production1,2
• Excessive VEGF initiates the tumor angiogenic process2
1. Reviewed in Chung et al. Nat Rev Cancer 2010;10(7):505-14.
2. Reviewed in Papetti and Herman. Am J Physiol Cell Physiol 2002;282(5):C947-70.

4. The VEGF Family of Ligands and Receptors in
Tumor Angiogenesis and Lymphangiogenesis
1. Reviewed in Adams and Alitalo. Nat Rev Mol Cell Biol 2007;8(6):464-78.
2. Reviewed in Hicklin and Ellis. J Clin Oncol 2005;23(5):1011-27.

5. VEGF Overexpression Associated with
Poor Prognosis in Cancer Patients
• Colorectal cancer1,2
• Gastric cancer3,4
• Pancreatic cancer5,6
• Breast cancer7,8
• Prostate cancer9
• Lung cancer10
• Melanoma11
• Hepatocellular
carcinoma12
• Ovarian cancer13
1. Lee et al. Eur J Cancer 2000;36(6):748-53.
2. Takahashi et al. Cancer Res 1995;55(18):3964-8.
3. Takahashi et al. Clin Cancer Res 1996;2(10):1679-84.
4. Maeda et al. Cancer 1996;77(5):858-63.
5. Fujimoto et al. Eur J Cancer 1998;34(9):1439-47.
6. Ikeda et al. Br J Cancer 1999;79(9-10):1553-63.
7.Berns et al. Clin Cancer Res 2003;9(4):1253-8.
8.Manders et al. Br J Cancer 2002;87(7):772-8.
9.George et al. Clin Cancer Res 2001;7(7):1932-6.
Survival rate in gastric cancer after potentially curative resection
(by tumor VEGF expression [immunohistochemistry])
10. Fontanini et al. J Natl Cancer Inst 1997;89(12):881-6.
11. Gorski et al. J Am Coll Surg 2003;197(3):408-18.
12. Poon et al. Br J Surg 2004;91(10):1354-60.
13. Yu et al. Gynecol Oncol 2013;128(2):391-6.
This image was manually created from the original source
Months after Surgery
VEGF negative (n = 61)
VEGF positive (n = 34)
p<.05

6. Fundamentos del Tratamiento
Anti-angiogénico
• Los tumores colorectales con actividad angiogénica elevada se
corresponden con fenotipos agresivos y peor pronóstico.1
• La neo vascularización es un indicador pronóstico significativo
en cánceres de mama y de ovario.2
• Se han objetivado asociación entre la densidad de micro vasos,
la expresión de VEGF y el pronóstico de los pacientes con
cáncer de mama 2, de ovario 2, hepatocarcinoma3,4, NSCLC5 y
cáncer gástrico6.
• En el cáncer gástrico, existe una correlación entre la densidad
de los vasos sanguíneos y la incidencia de metastatización. 6,7
1. Giatromanolaki et al. Am J Clin Oncol 2006;29(4):408-17.
2. Delli Carpini et al. Angiogenesis 2010;13(1):43-58.
3. Zhu et al. Nat Rev Clin Oncol 2011;8(5):292-301.
4. Yang et al. Gut 2010;59(7):953-62.
5. Salgia. Cancer 2011;117(17):3889-99.
6. Maeda et al. Cancer 1996;77(5):858-63.
7. Tanigawa et al. J Clin Oncol 1997;15(2):826-32.

7. VEGFR-2 Is a Critical Mediator of Angiogenesis
1. Holmes et al. Cell Signal. 2007;19:2003-2012
2. Youssoufian et al. Clin Cancer Res. 2007;13 (suppl 18):5544s-5548s.

8. Strategies for Blocking the VEGF
Receptor Pathways
Antibody to VEGFR-2
• Blocks ligand binding
• Blocks receptor activation
and signaling
Ramucirumab
Tyrosine kinase inhibitor to VEGFR-2
• Blocks receptor kinase
activity and signaling
Sorafenib
Sunitinib
Pazopanib
Vandetanib
Axitinib
Inhibition of VEGF ligand
• Blocks VEGF binding
• Inhibits signaling due to
VEGF(s)
Bevacizumab
Aflibercept
Ziv-aflibercept
Neovastat
Reviewed in Tugues et al. Mol Aspects Med 2011;32(2):88-111.
Cediranib
Brivanib alaninate
Motesanib
Linifanib
Tivozanib

9. Ramucirumab (IMC-1121B):
A Fully Human VEGF Receptor-2 Antagonist
• Isolated from phage display library of human Fab
fragments from non-immunized donors1
• Fully human anti-VEGFR-2 IgG1 monoclonal
antibody1
– High affinity (KD = 50 pM)1
– Blocks VEGF binding to VEGFR-2
• (IC50 = 0.8 nM)1
1. Lu D et al. J Biol Chem.2003;278(44):43496-43507.
2. Miao H-Q et al. Biochem Biophys Res Commun.2006;345:438-445.
.
3.Zhu Z et al. Leukemia. 2003;17:604-611.
• Biochemical and anti-tumor effects
– Inhibits ligand-dependent VEGFR-2 activation and signaling1
– Inhibits proliferation and migration of human endothelial cells2
– Direct anti-tumor effect in NOD-SCID mice inoculated with VEGFR-2+ HL60
leukemic cells3

10. Ramucirumab Phase 3 Program
Breast Cancer
ROSE
First-Line
(N = 1113) 2:1
Ramucirumab (10 mg/kg) +/-
Docetaxel (75mg/m2) q 3 weeks
Enrollment complete
(n = 1144)
Gastric GEJ Cancer
REGARD
Second-Line
(N = 348) 2:1
Ramucirumab (8 mg/kg)
q 2 weeks vs. Placebo
Enrollment complete
(n = 355)
RAINBOW
Second-Line
(N = 663)
Ramucirumab (8 mg/kg) +/-
Paclitaxel (80mg/m2) q 2 weeks
Enrollment complete
(n=663)
Hepatacellular Carcinoma
REACH
Second-Line,
post-Sorafenib (N = 544)
Ramucirumab (8mg/kg)
q 2 weeks vs. Placebo
>380 pts (Child Pugh A) rand. as
of Sept 2012
Colorectal Carcinoma
RAISE
Second-Line, FOLFOX/
Bev Res (N = 1050)
Ramucirumab (8mg/kg) +/-
FOLFIRI q 2 weeks
>580 pts rand. as of Sept 2012
Lung Cancer
REVEL
Second-Line
(n = 1242)
Ramucirumab (10mg/kg) +/-
Docetaxel (75mg/m2)
(60mg/m2 Korea/Taiwan)
q 3 weeks
>900 pts rand. as of Sept 2012

11. Ramucirumab Monotherapy for
Previously Treated Advanced Gastric or
Gastro-esophageal Junction Adenocarcinoma
(REGARD)
An International, Multicenter, Placebo-
controlled, Phase 3 Trial

12. Gastric Cancer Overview1
• Fourth most common malignancy and second leading
cause of cancer mortality worldwide1
− Two-thirds of patients present with advanced or
metastatic disease at diagnosis
• Less common in the United States, where gastric cancer
ranks 13th in cancer mortality2,3
• Cytotoxic chemotherapies are typically used as standard
first-line therapy1 (platinos, pirimidinas fluoradas)
• No second-line therapy is currently approved by the
USFDA, EMA, or most other governmental drug
regulatory agencies1 (taxanos, CPT-11)
1. Fuchs et al. Lancet 2013;[Epub Ahead of print].
2. Parkin et al. CA Cancer J Clin 2005;55(2):74-108.
3. Siegel et al. CA Cancer J Clin 2013;63(1):11-30.

13. Ramucirumab: Rationale for
Therapy
• VEGFR-2 and its ligands are important mediators of angiogenesis
and likely important therapeutic targets in gastric cancer1
− VEGFR-2 inhibition has been associated with reduced tumor
growth and vascularity in animal models of gastric
adenocarcinoma2
− Circulating and tumoral VEGF levels are associated with
increased tumor aggressiveness and reduced survival in patients
with gastric cancer3,4
• Ramucirumab, a human IgG1 monoclonal antibody VEGFR-2
antagonist, prevents ligand binding to the receptor, which blocks
activation of receptor-mediated pathways in endothelial cells5-9
1. Yousouffian et al. Clin Cancer Res 2007;13(18 Pt 2):5544s-8s.
2. Jung et al. Eur J Cancer 2002;38(8):1133-40.
3. Tanigawa et al. J Clin Oncol 1997;15(2):826-32.
4. Yoshikawa et al. Cancer Lett 2000;153(1-2):7-12.
5. Lu et al. J Biol Chem 2003;278(44):43496-507.
6. Tvorogov et al. Cancer Cell 2010;18(6):630-40.
7. Goldman et al. FASEB J 2007;21(4):1003-12(Updated 8: p 1942).
8. Miao et al. Biochem Biophys Res Commun 2006;345(1):438-45.
9. Zhu et al. Leukemia 2003;17(3):604-11.

14. REGARD: Study Design
Study locations: Europe; North, South, and Central America; Asia, Africa, Australia/New Zealand
Primary endpoint: Overall survival
Secondary endpoints: Progression-free survival, objective response rate, duration of response, safety, patient-
reported outcomes, immunogenicity
Until
progression
Every
2 weeks
• Gastric or GEJ
adenocarcinoma
(metastatic or locally
advanced and
unresectable)
• Prior platinum and/or
fluoropyrimidine
• ECOG PS 0-1
• No brain or CNS
metastases
• Measurable or
evaluable disease
(defined by RECIST
version 1.0)
Stratify
•Geographic region
•Weight loss
(≥≥≥≥10% vs. <10%) over
the prior 3 months
•Location of primary
tumor (gastric vs. GEJ)
RANDOMIZE 2:1
Ramucirumab 8 mg/kg
+
Best supportive care
Placebo
+
Best supportive care
N = 355
Fuchs et al. Lancet 2013;[Epub Ahead of print].

15. REGARD: Key Inclusion Criteria
• Metastatic or unresectable, locally recurrent, histologically
or cytologically confirmed gastric or GEJ adenocarcinoma
• Disease progression
− During or within 4 months after the last dose of first-line
therapy for metastatic disease, or
− During or within 6 months after the last dose of adjuvant
therapy
• Measurable or evaluable disease (defined by RECIST
version 1.0)
• ECOG PS score 0-1
• Adequate hepatic, hematologic, coagulation, and renal
function
Fuchs et al. Lancet 2013;[Epub Ahead of print].

16. REGARD: Overall Survival
HR (95% CI) = 0.776 (0.603, 0.998)
Log-rank p-value (stratified) = .047
Placebo Ramucirumab
Patients/events 117/99 238/179
Median OS, mos (95% CI) 3.8 (2.8, 4.7) 5.2 (4.4, 5.7)
6-month OS, % 32 42
12-month OS, % 12 18
Ramucirumab
Placebo
Number at Risk
238 154 92 49 17 7 3 0 0
117 66 34 20 7 4 2 1 0
Time Since Randomization, Months
OverallSurvival,%
Fuchs et al. Lancet 2013;[Epub Ahead of print].
Placebo
Ramucirumab
Censored

17. REGARD: Progression-free
Survival
HR (95% CI) = 0.483 (0.376, 0.620)
Log-rank p-value (stratified) <.0001
Placebo Ramucirumab
Patients/events 117/108 238/199
Median PFS, mos (95% CI) 1.3 (1.3, 1.4) 2.1 (1.5, 2.7)
12-week PFS, % 16 40
Progression-freeSurvival,%
Time Since Randomization, Months
Ramucirumab
Placebo
Number at Risk
238 213 113 65 61 45 30 18 18 11 5 4 2 1 1 1 1
117 92 27 11 7 4 2 2 2 2 2 1 1 0 0 0 0
Fuchs et al. Lancet 2013;[Epub Ahead of print].
Placebo
Ramucirumab
Censored
0
0

18. REGARD: Adverse Events of Special
Interest
Placebo (n = 115)a Ramucirumab (n = 236)a
AE of special interest, n (%) Any Event Grade ≥3 Any Event Grade ≥3
Hypertensionb,c 9 8% 3 3% 38 16% 18 8%
Bleeding/hemorrhageb 13 11% 3 3% 30 13% 8 3%
Arterial thromboembolismb 0 - 0 - 4 2% 3 1%
Venous thromboembolism 8 7% 5 4% 9 4% 3 1%
Proteinuria 3 3% 0 - 7 3% 1 <1%
Gastrointestinal perforation 1 <1% 1 <1% 2 <1% 2 <1%
Fistula formation 1 <1% 1 <1% 1 <1% 1 <1%
Infusion-related reaction 2 2% 0 - 1 <1% 0 -
Cardiac failure 0 - 0 - 1 <1% 0 -
a2 patients in each group did not receive treatment; bConsolidated term; cNo Grade 4 hypertension was observed
Fuchs et al. Lancet 2013;[Epub Ahead of print].

19. REGARD: Key Findings1
• Compared to placebo, ramucirumab significantly prolonged OS
(HR = 0.776, p = .047) and PFS (HR = 0.483, p<.0001) in patients with
metastatic gastric or GEJ adenocarcinoma following progression on
prior chemotherapies
− Risk of death from any cause was reduced by 22% compared to placebo
− Risk of disease progression was reduced by 52%
• Survival benefit appeared consistently across virtually all subgroups
and remained unchanged after multivariable adjustment for other
prognostic factors
• Ramucirumab appeared to be well tolerated, with similar rates for
most adverse events between the ramucirumab and placebo groups
– Hypertension was more common in the ramucirumab group, although
Grade 3 hypertension was observed in only 7.6% of ramucirumab-treated
patients
1. Fuchs et al. Lancet 2013;[Epub Ahead of print].

20. RAINBOW
Phase 3, Randomized, Double-Blind Trial
Ramucirumab and Paclitaxel (PTX)
Versus
Placebo and PTX
Metastatic Gastric or Gastroesophageal Junction (GEJ)
Adenocarcinoma Following Disease Progression on First-Line
Platinum- and Fluoropyrimidine-Containing Combination
Therapy

21. Treat until
disease
progression
or
intolerable
toxicity
• 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)
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Survival and
safety
follow-up
RAINBOW: Study Design
* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC
1:1

22. RAINBOW: Geographic Regions
Region 3: N=223
Hong Kong (3), Japan (140), Korea (45),
Singapore (5), Taiwan (30)Region 2: N=44
Argentina (1), Brazil (35), Chile (4), Mexico (4)
Region 1: N=398
Australia (41), Austria (6), Belgium (26), Bulgaria (12), Estonia (10),
France (34 ), Germany (40), Great Britain (15), Hungary (29), Israel
(30), Italy (28), Lithuania (12), Poland (33), Portugal (2), Romania (14),
Russia (21), Spain (21), USA (24)
Global: 170 study centers in 27 countries (Region 1 (18); Region 2 (4); Region 3 (5))

23. RAINBOW: Study Endpoints
Primary endpoint
♦ Overall survival (OS)
Secondary endpoints
♦ Progression-free survival (PFS)
♦ Time to progression (TTP)
♦ Objective response rate (ORR)
♦ Safety assessment
♦ Quality of life (Assessed by EORTC-QLQ-C30 & EQ-5D)
♦ Pharmacodynamic and immunogenicity profile
♦ Pharmacokinetics

24. RAINBOW: Baseline Tumor Characteristics
RAM + PTX
N=330
PBO + PTX
N=335
n % n %
TTP on 1st line
< 6 months
During 1st line
250
227
75.8
68.7
256
217
76.4
64.7
Primary tumor
Gastric
GEJ
Present
264
66
209
80.0
20.0
63.3
264
71
209
78.8
21.2
62.4
Measurable disease Yes 267 80.9 273 81.5
Histologic subtype
(Lauren classif.)
Intestinal
Diffuse
145
115
43.9
34.8
135
133
40.3
39.7
Metastases
≤ 2 Sites
> 2 Sites
Peritoneal Mets
Ascites
209
121
163
130
63.3
36.7
49.4
39.3
232
103
152
107
69.3
30.7
45.4
31.9

25. RAINBOW: Overall Survival
HR (95% CI) = 0.807 (0.678, 0.962)
Stratified log rank p-value = 0.0169
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%
RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0
PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0
No. at risk
Censored
Δ mOS = 2.3 months

26. Category Subgroup
N
(RAM+PTX)
N
(PBO+PTX) HR
Overall 330 335 0.807
Combined Geo. Regiona Region 1+2 221 221 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 0 117 144 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 264 264 0.899
GEJ 66 71 0.521
Prior Gastrectomy Yes 133 126 0.939
No 197 209 0.753
Peritoneal Metastases Yes 163 152 0.807
No 167 183 0.758
Forest Plot of Overall Survival by Subgroups -
Stratified Analysis
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
0.5 1 20.2

27. RAINBOW: Post-discontinuation Treatment
RAM + PTX
(N=330)
PBO + PTX
(N=335)
n (%) n %
Patients with any PDT* 158 47.9 154 46.0
Chemotherapy 158 47.9 152 45.4
Targeted Antibody 23 7.0 18 5.4
Targeted Small Molecule 1 0.3 5 1.5
Other 0 0.8 2 0.6
*Patients may have received more than one regimen.
PDT = Post-discontinuation Treatment

28. HR (95% CI) = 0.635 (0.536, 0.752)
Stratified log rank p-value < 0.0001
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 = 0.0001
Disease Control Rate 80% 64%
p < 0.0001
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 3 3 3
No. at risk
Censored
RAINBOW: Progression-free Survival & Response
Rates

29. Category Subgroup
N
(RAM+PTX)
N
(PBO+PTX) HR
Overall 330 335 0.635
Combined Geo. Regiona Region 1+2 221 221 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 0 117 144 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 0.639
> 2 121 103 0.577
Primary Tumor Location Gastric 264 264 0.694
GEJ 66 71 0.387
Prior Gastrectomy Yes 133 126 0.624
No 197 209 0.641
Peritoneal Metastases Yes 163 152 0.726
No 167 183 0.526
Forest Plot of Progression-Free Survival by Subgroups
- Stratified Analysis
Favors RAM+PTX Favors PBO+PTXa
Region 1: Europe, United States, and Australia;
Region 2: Brazil, Chile, Mexico, and Argentina;
Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore.
0.5 1 20.2

30. 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
(mos)
Asia 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
(%)
Asia 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
RAINBOW: Efficacy by Geographic Region
*Accrual: Asia n=223; EU/NA/AUS n=398; Central / South America n=44

31. RAM + PTX (N=327) PBO + PTX (N=329)
Preferred Term†
Any Grade
(%)
Grade ≥3
(%)
Any Grade
(%)
Grade ≥3
(%)
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 0 7.0 0
Vomiting 26.9 3.1 20.7 3.6
Hypertension† 25.1 14.7 5.8 2.7
Peripheral Edema 25.1 1.5 13.7 0.6
Treatment-Emergent Adverse Events Occurring in ≥ 20% of
Patients and ≥ 5% Higher in the RAM + PTX Arm
†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.

32. Adverse Events of Special Interest
RAM + PTX (N=327) PBO + PTX (N=329)
Category of event†
Any Grade
(%)
Grade ≥3
(%)
Any Grade
(%)
Grade ≥3
(%)
Bleeding/Hemorrhage
Epistaxis
41.9
30.6
4.3
0
17.9
7.0
2.4
0
Hypertension 25.1 14.7 5.8 2.7
Proteinuria 16.8 1.2 6.1 0
GI hemorrhage 10.1 3.7 6.1 1.5
Renal failure 6.7 1.8 4.3 0.9
Infusion-related reaction 5.8 0.6 3.6 0
Venous thromboembolic 4.0 2.4 5.5 3.3
Cardiac failure 2.4 0.6 1.2 0.6
Arteriothromboembolic 1.8 0.9 1.5 0.9
GI perforation 1.2 1.2 0.3 0
†Each AESI category is comprised of consolidated synonymous MeDRA preferred terms.

33. 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 the recently published REGARD trial
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
♦ This largest gastric cancer 2nd line trial clearly underlines that
effective second line therapy improves survival of patients
with metastatic or locally advanced unresectable gastric
cancer