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