RAINBOW: A Global, Phase 3, Randomized, DoubleBlind Trial of Ramucirumab and Paclitaxel (PTX)
Versus Placebo and PTX in the Treatment of
Metastatic Gastric or Gastroesophageal Junction
(GEJ) Adenocarcinoma Following Disease
Progression on First-Line Platinum- and
Fluoropyrimidine-Containing Combination Therapy
H. Wilke*
Eric Van Cutsem, Sang Cheul Oh, György Bodoky,
Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto,
Oleg Lipatov, Tae You Kim, David Cunningham, Atsushi Ohtsu,
Philippe Rougier, Michael Emig, Roberto Carlesi,
Kumari Chandrawansa, Kei Muro
*On
behalf of the RAINBOW Investigators
Conflict of Interest Disclosure
Consultant or Advisory Role
• Amgen
• Bristol Myers
• Lilly/ImClone
• Merck KGaA
• Roche Pharma
Background
♦ Second-line treatments confer a median overall survival of
approximately 5 months in GC (including GEJC) after
progression on 1st line platinum and fluoropyrimidine-based
chemotherapy 1-3. New and effective treatments are needed.
♦ Angiogenesis-linked growth factor receptors such as VEGF
Receptor-2 and its ligands likely contribute to GC pathogenesis
and may represent important therapeutic targets in GC 4.
♦ RAINBOW assessed the efficacy of ramucirumab (RAM; a
human IgG1 monoclonal antibody VEGF Receptor-2 antagonist)
plus paclitaxel as 2nd-line treatment for GC patients.
♦ Weekly paclitaxel was chosen based on available data indicating
similar efficacy but more favorable toxicity/safety compared to
other second-line agents (irinotecan; docetaxel); supported
recently in a randomized study 5.
(1) Thuss-Patience, EJC 2011; (2) Kang, JCO 2012; (3) Ford, Lancet Oncol 2013; (4) Clarke, Expert Opin Biol Ther 2013; (5) Hironaka, JCO 2013
RAINBOW: Study Design
1:1
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
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
Treat until
disease
progression
or
intolerable
toxicity
Survival and
safety
follow-up
•
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
RAINBOW: Geographic Regions
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)
Region 3: N=223
Region 2: N=44
Hong Kong (3), Japan (140), Korea
(45), Singapore (5), Taiwan (30)
Argentina (1), Brazil (35), Chile (4), Mexico (4)
Global: 170 study centers in 27 countries (Region 1 (18); Region 2 (4); Region 3 (5))
RAINBOW: Patient Eligibility
Key Inclusion Criteria
 Histologically or cytologically confirmed gastric / GEJ
adenocarcinoma
 Disease progression during first-line therapy or ≤ 4 mos after last
dose of 1st -line therapy with any platinum/fluoropyrimidine
doublet with or without an anthracycline
 ECOG PS score 0-1
 Adequate hepatic, hematologic, coagulation, and renal function
Key Exclusion Criteria
♦
♦
♦
♦
No prior treatment with an anti-angiogenic agents
GI perforation and/or fistulae within 6 mos prior to randomization
Significant GI bleeding within 3 mos prior to randomization
Venous thromboembolic event within 3 mos, or arterial
thromboembolic event within 6 mos prior to randomization
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
RAINBOW: Statistical Considerations
Sample size
 510 events from 663 patients at 90% power, based on
assumed HR=0.75
− Anticipated median OS 9.33 months (RAM + PTX),
7.0 months (Placebo [PBO] + PTX)
 665 patients were randomized (Dec2010 - Sep2012)
 Data cut-off on 12 July 2013 after observation of 516
OS events; database lock occurred 05 Sept 2013
Primary analysis
 Stratified log-rank test with 2-sided α=0.05
RAINBOW: Baseline Demographics &
Patient Characteristics
RAM+PTX
(N=330)
PBO + PTX
(N=335)
n
%
n
%
1 Aus/Europe/US
2 South/Central America
3 Asia
198
23
109
60
7
33
200
21
114
60
6
34
White
208
63
199
59
Asian
110
33
121
36
Median (range)
61 (25 - 83)
61 (24-84)
≥ 65
126
38
123
37
Gender
Male
229
69
243
73
ECOG PS
1
213
65
191
57
Weight loss
≥ 10% (last 3 mos)
53
16
47
14
Region
Race
Age (yrs)
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
RAINBOW: Overall Survival
HR (95% CI) = 0.807 (0.678, 0.962)
1.0
Stratified log rank p-value = 0.0169
0.9
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%
0.8
Overall Survival Probability
0.7
0.6
0.5
Δ mOS = 2.3 months
0.4
0.3
0.2
RAM+PTX
PBO+PTX
0.1
Censored
0.0
0
2
4
6
8
10
12
16
18
20
22
24
26
28
60
47
41
30
24
22
13
13
6
5
1
2
0
0
Months
No. at risk
RAM + PTX
PBO + PTX
14
330
335
308
294
267
241
228
180
185
143
148
109
116
81
78
64
Forest Plot of Overall Survival by Subgroups Stratified Analysis
Category
Overall
Combined Geo. Regiona
Time to PD on 1st-line Therapy
Disease Measurability
Gender
Age Group (yrs)
ECOG PS
Histologic Subtype
Number of Metastatic Sites
Primary Tumor Location
Prior Gastrectomy
Peritoneal Metastases
a
Subgroup
Region 1+2
Region 3
< 6 months
≥ 6 months
Non-measurable
Measurable
Male
Female
< 65
≥ 65
0
1
Intestinal
Diffuse
Mix/Miss./Unk.
≤2
>2
Gastric
GEJ
Yes
No
Yes
No
N
N
(RAM+PTX) (PBO+PTX)
330
335
221
109
250
80
63
267
229
101
204
126
117
213
145
115
70
209
121
264
66
133
197
163
167
HR
0.807
221
114
256
79
62
273
243
92
212
123
144
191
135
133
67
232
103
264
71
126
209
152
183
Region 1: Europe, United States, and Australia;
Region 2: Brazil, Chile, Mexico, and Argentina;
Region 3: Japan, South Korea, Hong Kong, Taiwan, and Singapore.
0.732
0.986
0.871
0.615
1.101
0.750
0.814
0.672
0.753
0.861
0.778
0.771
0.705
0.856
0.955
0.749
0.815
0.899
0.521
0.939
0.753
0.807
0.758
0.2
0.5
1
2
Favors RAM+PTX Favors PBO+PTX
RAINBOW: Post-discontinuation Treatment
Patients with any PDT*
Chemotherapy
Targeted Antibody
Targeted Small Molecule
Other
RAM + PTX
(N=330)
n
(%)
158
47.9
158
47.9
23
7.0
1
0.3
0
0.8
*Patients may have received more than one regimen.
PDT = Post-discontinuation Treatment
PBO + PTX
(N=335)
n
%
154
46.0
152
45.4
18
5.4
5
1.5
2
0.6
RAINBOW: Progression-free Survival &
Response Rates
HR (95% CI) = 0.635 (0.536, 0.752)
Stratified log rank p-value < 0.0001
1.0
0.7
Patients / Events
Median(mos) (95% CI)
6-Month PFS
9-Month PFS
0.6
Response Rate
Progression-Free Survival Probability
0.9
0.8
RAM + PTX
PBO + PTX
330 / 279
335 / 296
4.40 (4.24, 5.32) 2.86 (2.79, 3.02)
36%
17%
22%
10%
28%
16%
p = 0.0001
0.5
Disease Control Rate
80%
64%
p < 0.0001
0.4
0.3
0.2
RAM+PTX
PBO+PTX
0.1
Censored
0.0
0
2
4
6
8
10
No. at risk
RAM + PTX
PBO + PTX
12
14
16
18
20
22
7
3
3
3
1
3
Months
330
335
259
214
188
124
104
50
70
34
43
21
28
12
15
8
11
5
Forest Plot of Progression-Free Survival by
Subgroups - Stratified Analysis
Category
Subgroup
N
N
(RAM+PTX) (PBO+PTX)
HR
Overall
330
335
0.635
Combined Geo. Regiona
221
109
250
80
63
267
229
101
204
126
117
213
145
115
70
209
121
264
66
133
197
163
167
221
114
256
79
62
273
243
92
212
123
144
191
135
133
67
232
103
264
71
126
209
152
183
0.639
0.628
0.676
0.512
0.833
0.599
0.592
0.670
0.572
0.673
0.663
0.568
0.531
0.695
0.734
0.639
0.577
0.694
0.387
0.624
0.641
0.726
0.526
Region 1+2
Region 3
Time to PD on 1st-line Therapy < 6 months
≥ 6 months
Disease Measurability
Non-measurable
Measurable
Gender
Male
Female
Age Group (yrs)
< 65
≥ 65
ECOG PS
0
1
Histologic Subtype
Intestinal
Diffuse
Mix/Miss./Unk.
Number of Metastatic Sites
≤2
>2
Primary Tumor Location
Gastric
GEJ
Prior Gastrectomy
Yes
No
Peritoneal Metastases
Yes
No
0.2
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.
0.5
Favors RAM+PTX
1
2
Favors PBO+PTX
RAINBOW: Efficacy by Geographic Region
RAM +
PTX
PBO+
PTX
Delta
HRa/
Odds
Ratiob
mOS Asia
(mos) EU/NA/AUS +
Central/South Am.
12.1
10.5
1.6
0.99a
0.73, 1.34
8.5
5.9
2.6
0.73a
0.59, 0.91
mPFS Asia
(mos) EU/NA/Aus +
Central/South Am.
5.5
2.8
2.7
0.63a
0.47, 0.83
4.2
2.9
1.3
0.64a
0.52, 0.79
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
Region*
RR
(%)
Asia
*Accrual: Asia n=223; EU/NA/AUS n=398; Central / South America n=44
95% CI
Treatment-Emergent Adverse Events Occurring in ≥ 20%
of Patients and ≥ 5% Higher in the RAM + PTX Arm
RAM + PTX (N=327)
Preferred Term†
Fatigue†
Neutropenia†
Neuropathy†
Decreased appetite
Abdominal pain†
Leukopenia†
Diarrhea
Epistaxis
Vomiting
Hypertension†
Peripheral Edema
†Consolidated
PBO + PTX (N=329)
Any Grade Grade ≥3 Any Grade Grade ≥3
(%)
(%)
(%)
(%)
56.9
54.4
45.9
40.1
36.1
33.9
32.4
30.6
26.9
25.1
11.9
40.7
8.3
3.1
6.1
17.4
3.7
0
3.1
14.7
43.8
31.0
36.2
31.9
29.8
21.0
23.1
7.0
20.7
5.8
5.5
18.8
4.6
4.0
3.3
6.7
1.5
0
3.6
2.7
25.1
1.5
13.7
0.6
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.
Adverse Events of Special Interest
RAM + PTX (N=327)
PBO + PTX (N=329)
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
Category of
†Each
event†
AESI category is comprised of consolidated synonymous MeDRA preferred terms.
Safety Summary
♦ Treatment-emergent adverse events grade ≥ 3 occurred at a
greater frequency in the RAM + PTX arm (82% vs 63%):
− Grade ≥3 TEAEs occurring in more than 10% of patients and
at a higher incidence in the ram + PTX arm were neutropenia,
leukopenia, hypertension, and fatigue.
− Neutropenia Grade 3 (22% vs 16%) and 4 (19% vs 3%)
were reported with a higher incidence in the RAM + PTX arm.
− The incidence of febrile neutropenia was low and similar in
both treatment arms: RAM + PTX 3.1% vs PBO + PTX 2.4%.
♦ The incidence of deaths on study due to AEs determined by
investigator as the primary cause of death was similar between
arms: RAM + PTX 4.0% vs PBO + PTX 4.6%.
Efficacy Summary
Efficacy
Parameter
RAM + PTX PBO + PTX
HR
p-value
Delta
Response Rate
28%
16%
p =0.0001
+ 12%
Disease Control
Rate
80%
64%
p <0.0001
+ 16%
PFS (med, mos)
- at 6-months
- at 9-months
4.40
36%
22%
2.86
17%
10%
HR 0.635
p <0.0001
+ 1.5
+ 19%
+ 12%
OS (med, mos)
- at 6-months
- at 12-months
9.63
72%
40%
7.36
57%
30%
HR 0.807
p =0.0169
+ 2.3
+ 15%
+ 10%
A consistent additive effect of RAM in combination with
paclitaxel was observed across all efficacy endpoints
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
Acknowledgements
We thank the patients and their caregivers for
participating in this trial.
We thank the investigators and their support staff
who generously participated in this work.
Argentina
Guillermo Lerzo
Australia
Winston Liauw
Vinod Ganju
Walter Cosolo Lara Lipton
Dusan Kotasek
Ray Asghari Weng Ng
Marco Matos
Philip Clingan
Sumitra Ananda
Austria
Hellmut Samonigg
Reinhard Ziebermayr
Brazil
Giuliano Borges
Luis Antônio Pires
Renata Garcia
Marcelo Tanaka
Alberto Nogueira
Rodrigo Guimarães
Roberto Rocha
Leonardo Lobato
Fernando Vieira
Gustavo Girotto
Guilherme Luiz Pereira
Leandro Brust
Luis Schlittler
Gilberto Schwartsmann
Fabio Franke
Bulgaria
Galina Kurteva
Violina Taskova
Chile
Pamela Boghikian
Eugenia Loredo
Estonia
Kristiina Ojamaa
Belgium
Veerle Moons
Jean-Luc van Laethem
Alain Hendlisz
Joris Arts
Eric Van Cutsem
Marc Peeters
France
Jean Francois Seitz
Marian Gil Delgado
Christophe Borg
Jean Marc Phelip
Emanuelle Samalin
Denis Pezet
Jean Marc Gornet
Philippe Rougier
Jean-Philippe Metges
Germany
Severin Daum
Meinholf Karthaus
Jens Siveke
Florian Weissinger
Stefan Zeuzem
Hansjochen Wilke
Gunnar Folprecht
Hans-Georg Kopp
Volkmar Boehme
Stefan Kasper
Carsten Grüllich
Markus Möhler
Friedrich Overkamp
Burkhard Schmidt
Salah-eddin Al-batran
Peter Thuss-Patience
Great Britain
Gary Middleton
David Cunningham
David Ferry
Estonia
Tiit Suuroja
Hong Kong
Kent Man Chu
Sing Hung Lo
Hungary
Judit Kocsis
Dank Magdolna
József Cseh
Béla Piko
László Mangel
György Bodoky
Balázs Pécsi
Israel
Ayala Hubert
Alexander Beny
Alexander Gluzman
Ravit Geva
Dan Aderka
Natalya Karminsky
Baruch Brenner
Italy
Davide Pastorelli
Roberto Bordonaro
Gabriella Farina
Stefano Cascinu
Libero Ciuffreda
Alfredo Falcone
Alberto Sobrero
Nicola Silvestris
Korea
Sang Cheul Oh
Hoon-Kyo Kim
Keun Wook Lee
Dong Bok Shin
SeokYun Kang
Lithuania
Alvydas Cesas
Audrius Ivanauskas
Japan
Yoshito Komatsu
Etsuko Warita
Hirofumi Fujii
Toshihiko Doi
Kensei Yamaguchi
Ken Shimada
Shuichi Hironaka
Yasuhiro Shimada
Yasushi Omuro
Hirofumi Yasui
Kei Muro
Naotoshi Sugimoto
Fumio Nagashima
Masahiro Gotoh
Shinya Ueda
Kazumasa Fujitani
Tomohiro Nishina
Sojiro Morita
Taito Esaki
Yoshinori Hirashima
Poland
Jerzy Tujakowski
Maria Blasinska-Morawiec
Dariusz Sawka
Elzbieta Staroslawska
Tomasz Sarosiek
Zbigniew Nowecki
Elzbieta Wojcik
Portugal
Margarida Damasceno
Nuno Bonito
Paula Ferreira
Singapore
Peter Cher Siang Ang
Akhil Chopra
Mexico
F. Gutierrez-Delgado
Romania
Mihai Voiculescu
Cornelia Toganel
Constantin Volovat
Dumitru Filip
Russia
Irina Davidenko
Oleg Lipatov
Sergey Tjulandin
Sergey Orlov
Spain
Carlos García Girón
Hermini Manzano
Carles Pericay
José Alés
David Vicente
Maria Limón Mirón
Encarnación Jiménez
Antonio Sánchez
José López Martín
Taiwan
Chia-Jui Yen
Yee Chao
Chang-Fang Chiu
Yen-Yang Chen
Cheng-Shyong Chang
Chien-Liang Lin
United States
Bassel El-Rayes
Edward Lin
Zev Wainberg
Troy Guthrie
Yehuda Patt
Andrew Ko
Gabriel Domenech
Jitendra Gandhi
Peter Rosen
Jaffer Ajani