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H. Wilke* Eric Van Cutsem, Sang Cheul Oh, György Bodoky,


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slide1

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 disclosure consultant or advisory role
Conflictof Interest DisclosureConsultant or Advisory Role
  • Amgen
  • Bristol Myers
  • Lilly/ImClone
  • Merck KGaA
  • Roche Pharma
background
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 OpinBiolTher 2013; (5) Hironaka, JCO 2013

slide4

RAINBOW: Study Design

1:1

Ramucirumab 8 mg/kg day 1&15

+ Paclitaxel80 mg/m2day 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

rainbow geographic regions
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

Hong Kong (3), Japan (140), Korea (45), Singapore (5), Taiwan (30)

Region 2: N=44

Argentina (1), Brazil (35), Chile (4), Mexico (4)

  • Global: 170 study centers in 27 countries (Region 1 (18); Region 2 (4); Region 3 (5))
slide6

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
slide7

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
slide8

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 overall survival
RAINBOW: Overall Survival

Δ mOS = 2.3 months

Censored

No. at risk

forest plot of overall survival by subgroups stratified analysis
Forest Plot of Overall Survival by Subgroups -Stratified Analysis

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

slide13

RAINBOW: Post-discontinuation Treatment

*Patients may have received more than one regimen.

PDT = Post-discontinuation Treatment

forest plot of progression free survival by subgroups stratified analysis
Forest Plot of Progression-Free Survival by Subgroups - Stratified Analysis

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

rainbow efficacy by geographic region
RAINBOW: Efficacy by Geographic Region

*Accrual: Asia n=223; EU/NA/AUS n=398; Central / South America n=44

slide17

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 interest
Adverse Events of Special Interest

†Each AESI category is comprised of consolidated synonymous MeDRA preferred terms.

safety summary
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 Summary

A consistent additive effect of RAM in combination with paclitaxel was observed across all efficacy endpoints

rainbow r esults and conclusions
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
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.

slide23

Japan

YoshitoKomatsu

Etsuko Warita

Hirofumi Fujii

Toshihiko Doi

KenseiYamaguchi

Ken Shimada

Shuichi Hironaka

Yasuhiro Shimada

Yasushi Omuro

Hirofumi Yasui

KeiMuro

Naotoshi Sugimoto

FumioNagashima

Masahiro Gotoh

Shinya Ueda

KazumasaFujitani

TomohiroNishina

Sojiro Morita

TaitoEsaki

Yoshinori Hirashima

Romania

MihaiVoiculescu

Cornelia Toganel

ConstantinVolovat

DumitruFilip

Belgium

VeerleMoons

Jean-Luc van Laethem

Alain Hendlisz

JorisArts

Eric Van Cutsem

Marc Peeters

Estonia

TiitSuuroja

Australia

Winston Liauw

VinodGanju

Walter CosoloLara Lipton

DusanKotasek

Ray AsghariWengNg

Marco Matos

Philip Clingan

SumitraAnanda

Hong Kong

Kent Man Chu

Sing Hung Lo

Hungary

JuditKocsis

Dank Magdolna

JózsefCseh

BélaPiko

LászlóMangel

György Bodoky

BalázsPécsi

Russia

Irina Davidenko

Oleg Lipatov

Sergey Tjulandin

Sergey Orlov

France

Jean Francois Seitz

Marian Gil Delgado

Christophe Borg

Jean Marc Phelip

EmanuelleSamalin

Denis Pezet

Jean Marc Gornet

Philippe Rougier

Jean-Philippe Metges

Argentina

Guillermo Lerzo

Spain

Carlos GarcíaGirón

HerminiManzano

CarlesPericay

José Alés

David Vicente

Maria Limón Mirón

EncarnaciónJiménez

Antonio Sánchez

José López Martín

Austria

HellmutSamonigg

ReinhardZiebermayr

Israel

Ayala Hubert

Alexander Beny

Alexander Gluzman

RavitGeva

Dan Aderka

Natalya Karminsky

Baruch Brenner

Brazil

Giuliano Borges

Luis AntônioPires

Renata Garcia

Marcelo Tanaka

Alberto Nogueira

Rodrigo Guimarães

Roberto Rocha

Leonardo Lobato

Fernando Vieira

Gustavo Girotto

GuilhermeLuizPereira

Leandro Brust

Luis Schlittler

Gilberto Schwartsmann

Fabio Franke

Germany

SeverinDaum

MeinholfKarthaus

Jens Siveke

Florian Weissinger

Stefan Zeuzem

HansjochenWilke

Gunnar Folprecht

Hans-Georg Kopp

VolkmarBoehme

Stefan Kasper

CarstenGrüllich

Markus Möhler

Friedrich Overkamp

BurkhardSchmidt

Salah-eddinAl-batran

Peter Thuss-Patience

Taiwan

Chia-Jui Yen

Yee Chao

Chang-Fang Chiu

Yen-Yang Chen

Cheng-Shyong Chang

Chien-Liang Lin

Poland

Jerzy Tujakowski

Maria Blasinska-Morawiec

DariuszSawka

ElzbietaStaroslawska

Tomasz Sarosiek

ZbigniewNowecki

ElzbietaWojcik

Italy

DavidePastorelli

Roberto Bordonaro

Gabriella Farina

Stefano Cascinu

LiberoCiuffreda

Alfredo Falcone

Alberto Sobrero

Nicola Silvestris

United States

BasselEl-Rayes

Edward Lin

Zev Wainberg

Troy Guthrie

Yehuda Patt

Andrew Ko

Gabriel Domenech

JitendraGandhi

Peter Rosen

JafferAjani

Portugal

Margarida Damasceno

Nuno Bonito

Paula Ferreira

Korea

Sang Cheul Oh

Hoon-KyoKim

KeunWookLee

Dong Bok Shin

SeokYun Kang

Bulgaria

Galina Kurteva

ViolinaTaskova

Singapore

Peter Cher Siang Ang

Akhil Chopra

Chile

Pamela Boghikian

Eugenia Loredo

Great Britain

Gary Middleton

David Cunningham

David Ferry

Lithuania

AlvydasCesas

AudriusIvanauskas

Mexico

F. Gutierrez-Delgado

Estonia

KristiinaOjamaa