RAINBOW: A Global, Phase 3, Randomized, Double-Blind 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 DisclosureConsultant 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
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 cycleN = 330
Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
SCREEN
RANDOMIZE
Survival and safety
follow-up
RAINBOW: Study Design
* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC
1:1
RAINBOW: Geographic Regions
Region 3: N=223Hong Kong (3), Japan (140), Korea
(45), Singapore (5), Taiwan (30) Region 2: N=44Argentina (1), Brazil (35), Chile (4), Mexico (4)
Region 1: N=398Australia (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))
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
RAM+PTX (N=330)
PBO + PTX(N=335)
n % n %
Region1 Aus/Europe/US2 South/Central America3 Asia
198 23109
60 733
200 21 114
60 634
RaceWhite 208 63 199 59
Asian 110 33 121 36
Age (yrs) 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
RAINBOW: Baseline Demographics & Patient Characteristics
RAINBOW: Baseline Tumor Characteristics
RAM + PTXN=330
PBO + PTXN=335
n % n %
TTP on 1st line< 6 months During 1st line
250227
75.868.7
256217
76.464.7
Primary tumorGastric GEJ Present
264 66
209
80.020.063.3
26471
209
78.821.262.4
Measurable disease
Yes 267 80.9 273 81.5
Histologic subtype(Lauren classif.)
IntestinalDiffuse
145115
43.934.8
135133
40.339.7
Metastases
≤ 2 Sites> 2 SitesPeritoneal MetsAscites
209121163130
63.336.749.439.3
232103152107
69.330.745.431.9
RAINBOW: Overall Survival
0 2 4 6 8 10 12 14 16 18 20 22 24 26 280.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
RAM+PTX
PBO+PTX
Months
Ove
rall
Su
rviv
al P
rob
ab
ility
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 0PBO + 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
Category SubgroupN
(RAM+PTX)N
(PBO+PTX) HROverall 330 335 0.807
Combined Geo. Regiona Region 1+2 221 221 0.732Region 3 109 114 0.986
Time to PD on 1st-line Therapy < 6 months 250 256 0.871 ≥ 6 months 80 79 0.615Disease Measurability Non-measurable 63 62 1.101 Measurable 267 273 0.750Gender Male 229 243 0.814 Female 101 92 0.672Age Group (yrs) < 65 204 212 0.753 ≥ 65 126 123 0.861ECOG PS 0 117 144 0.778 1 213 191 0.771Histologic Subtype Intestinal 145 135 0.705 Diffuse 115 133 0.856 Mix/Miss./Unk. 70 67 0.955Number of Metastatic Sites ≤ 2 209 232 0.749 > 2 121 103 0.815Primary Tumor Location Gastric 264 264 0.899 GEJ 66 71 0.521Prior Gastrectomy Yes 133 126 0.939 No 197 209 0.753Peritoneal 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
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
HR (95% CI) = 0.635 (0.536, 0.752)Stratified log rank p-value < 0.0001
RAM + PTX PBO + PTXPatients / Events 330 / 279 335 / 296Median(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
0 2 4 6 8 10 12 14 16 18 20 220.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
RAM+PTX
PBO+PTX
Months
Pro
gre
ssio
n-F
ree
Su
rviv
al P
rob
ab
ility
RAM + PTX 330 259 188 104 70 43 28 15 11 7 3 1PBO + PTX 335 214 124 50 34 21 12 8 5 3 3 3
No. at risk
Censored
RAINBOW: Progression-free Survival & Response Rates
Category SubgroupN
(RAM+PTX)N
(PBO+PTX) HROverall 330 335 0.635
Combined Geo. Regiona Region 1+2 221 221 0.639 Region 3 109 114 0.628Time to PD on 1st-line Therapy < 6 months 250 256 0.676 ≥ 6 months 80 79 0.512Disease Measurability Non-measurable 63 62 0.833 Measurable 267 273 0.599Gender Male 229 243 0.592 Female 101 92 0.670Age Group (yrs) < 65 204 212 0.572 ≥ 65 126 123 0.673ECOG PS 0 117 144 0.663 1 213 191 0.568Histologic Subtype Intestinal 145 135 0.531 Diffuse 115 133 0.695 Mix/Miss./Unk. 70 67 0.734Number of Metastatic Sites ≤ 2 209 232 0.639 > 2 121 103 0.577Primary Tumor Location Gastric 264 264 0.694 GEJ 66 71 0.387Prior Gastrectomy Yes 133 126 0.624 No 197 209 0.641Peritoneal 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
Region*RAM +
PTXPBO+ 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
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 5.5Neutropenia† 54.4 40.7 31.0 18.8Neuropathy† 45.9 8.3 36.2 4.6Decreased appetite 40.1 3.1 31.9 4.0Abdominal pain† 36.1 6.1 29.8 3.3Leukopenia† 33.9 17.4 21.0 6.7Diarrhea 32.4 3.7 23.1 1.5Epistaxis 30.6 0 7.0 0Vomiting 26.9 3.1 20.7 3.6Hypertension† 25.1 14.7 5.8 2.7Peripheral 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.
Adverse Events of Special InterestRAM + PTX (N=327) PBO + PTX (N=329)
Category of event†Any Grade
(%)Grade ≥3
(%) Any Grade
(%)Grade ≥3
(%)
Bleeding/Hemorrhage Epistaxis
41.930.6
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.
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
HRp-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
4.4036%22%
2.8617%10%
HR 0.635p <0.0001
+ 1.5+ 19%+ 12%
OS (med, mos)- at 6-months- at 12-months
9.6372%40%
7.3657%30%
HR 0.807p =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.
ArgentinaGuillermo Lerzo
BulgariaGalina KurtevaViolina Taskova
ItalyDavide PastorelliRoberto BordonaroGabriella FarinaStefano CascinuLibero CiuffredaAlfredo FalconeAlberto SobreroNicola Silvestris
Australia Winston LiauwVinod GanjuWalter Cosolo Lara LiptonDusan KotasekRay Asghari Weng NgMarco MatosPhilip ClinganSumitra Ananda
BrazilGiuliano BorgesLuis Antônio PiresRenata GarciaMarcelo TanakaAlberto NogueiraRodrigo GuimarãesRoberto RochaLeonardo LobatoFernando VieiraGustavo GirottoGuilherme Luiz PereiraLeandro BrustLuis SchlittlerGilberto SchwartsmannFabio Franke
BelgiumVeerle MoonsJean-Luc van LaethemAlain HendliszJoris ArtsEric Van CutsemMarc Peeters
ChilePamela BoghikianEugenia Loredo
FranceJean Francois SeitzMarian Gil DelgadoChristophe BorgJean Marc PhelipEmanuelle SamalinDenis PezetJean Marc GornetPhilippe RougierJean-Philippe Metges
Hungary Judit KocsisDank MagdolnaJózsef CsehBéla PikoLászló MangelGyörgy BodokyBalázs Pécsi
Hong KongKent Man ChuSing Hung Lo
MexicoF. Gutierrez-Delgado
SpainCarlos García GirónHermini Manzano Carles PericayJosé AlésDavid VicenteMaria Limón MirónEncarnación JiménezAntonio SánchezJosé López Martín
Japan Yoshito Komatsu Etsuko WaritaHirofumi FujiiToshihiko DoiKensei Yamaguchi Ken ShimadaShuichi Hironaka Yasuhiro Shimada Yasushi Omuro Hirofumi Yasui Kei MuroNaotoshi Sugimoto Fumio Nagashima Masahiro GotohShinya Ueda Kazumasa FujitaniTomohiro Nishina Sojiro Morita Taito EsakiYoshinori Hirashima
United StatesBassel El-RayesEdward LinZev WainbergTroy GuthrieYehuda PattAndrew KoGabriel DomenechJitendra GandhiPeter RosenJaffer Ajani
Lithuania Alvydas CesasAudrius Ivanauskas
IsraelAyala HubertAlexander BenyAlexander GluzmanRavit GevaDan AderkaNatalya KarminskyBaruch Brenner
GermanySeverin DaumMeinholf KarthausJens SivekeFlorian WeissingerStefan ZeuzemHansjochen WilkeGunnar FolprechtHans-Georg KoppVolkmar BoehmeStefan KasperCarsten GrüllichMarkus MöhlerFriedrich OverkampBurkhard SchmidtSalah-eddin Al-batranPeter Thuss-Patience
KoreaSang Cheul Oh Hoon-Kyo KimKeun Wook LeeDong Bok ShinSeokYun Kang
EstoniaTiit Suuroja
PolandJerzy TujakowskiMaria Blasinska-MorawiecDariusz SawkaElzbieta StaroslawskaTomasz SarosiekZbigniew NoweckiElzbieta Wojcik
PortugalMargarida DamascenoNuno BonitoPaula Ferreira
RomaniaMihai VoiculescuCornelia ToganelConstantin VolovatDumitru Filip
RussiaIrina DavidenkoOleg LipatovSergey TjulandinSergey Orlov
SingaporePeter Cher Siang AngAkhil Chopra
TaiwanChia-Jui YenYee ChaoChang-Fang ChiuYen-Yang Chen Cheng-Shyong Chang Chien-Liang Lin
Great BritainGary MiddletonDavid CunninghamDavid Ferry
AustriaHellmut SamoniggReinhard Ziebermayr
EstoniaKristiina Ojamaa