Abstract 238

Primary Results of ROSE, A Randomized Placebo Controlled Phase III Trial Evaluating the Addition

of Ramucirumab to First-Line Docetaxel Chemotherapy in Metastatic Breast Cancer

( TRIO-012 )JR Mackey,1 M Ramos-Vazquez,2 O Lipatov,3 N McCarthy,4 D Kranhozhon,5

V Semiglazov,6 A Manikhas,7 K Gelmon,8 G Konecny,9 M Webster,10 R Hegg,11 S Verma,12 V Gorbunova,13 DA Gerges,14 F Thireau,15 H Fung,16

L Simms17, M Buyse18, A Ibrahim19, M Martin20

1Cross Center Institute, Edmonton, Canada; 2Centro Oncológico de Galicia "José Antonio Quiroga y Piñeiro", Coruña, Spain; 3Republican Clinical Oncology Dispensary of Ministry of Health of Bashkortostan Republic, Ufa, Russia; 4Haematology and Oncology Clinic Australia Wesley Medical Center, Queensland, Australia; 5Leningrad Regional Oncology Dispensary, Leningrad, Russia; 6Institute of Oncology N.N. Petrov, St. Petersburg, Russia;

7City Clinical Oncology Dispensary, St. Petersburg, Russia; 8British Columbia Cancer Agency, Vancouver, Canada;  9University of California, Los Angeles; 10Tom Baker Cancer Centre, Calgary, Canada; 11Hospital Pérola

Byigton Centro de Referência da Saúde da Mulher, Sao Paulo, Brazil; 12Sunnybrook  Health Sciences Center, Toronto, Canada; 13N.N. Blokhin Russian Cancer Research Center of Russian Academy of Medical Sciences, Moscow, Russia; 14Middle East Institute of Health, Bsalim, Lebanon; 15Translational Research in Oncology,

Paris, France; 16Translational Research in Oncology, Edmonton, Canada; 17Eli Lilly Canada Inc; 18 2International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium; 19ImClone Systems LLC, a wholly owned

subsidiary of Eli Lilly and Co.; 20Hospital General Universitario Gregorio Marañon, Madrid, Spain

On behalf of the ROSE/TRIO-012 Investigator Group

Mackey et. al. SABCS 2013 2

Disclosure• Research support from ImClone a wholly owned subsidiary of

Eli Lilly and Company

Mackey et. al. SABCS 2013 3

Background • Vascular endothelial growth factor receptor-2 (VEGFR-

2) and its ligands ( VEGF-A, -C, and -D ) are important mediators of angiogenesis

• In human breast cancer, intensive neovascularization and tumor angiogenesis correlate with metastases and poor prognosis

• Clinical trials of antiangiogenic therapy for breast cancer have not yet demonstrated improvements in overall survival

AngiogenesisTumor growth

VEGF-A

VEGFR2

VEGF-A

VEGFR2

Ligand binding activates VEGFR2 andp44/p42 MAP kinases

Ramucirumab

No signaling

Inhibit new blood vesselformation and tumor growth

Ramucirumab binds to VEGFR2, blocks VEGFligand binding

VEGF binds toVEGFR2 receptor;VEGF-C, -D competefor binding toVEGFR2

¨ Ramucirumab (IMC-1121B; RAM) a recombinant human IgG1 monoclonal antibody that binds the extracellular domain of VEGF Receptor-2

Mechanism of ramucirumab action

Endothelial cell

VEGF-CVEGF-D

VEGF-CVEGF-D

Mackey et. al. SABCS 2013

RANDOMIZATION2:1

Follow-up for PD and for OS

ProgressiveDisease

Or Unacceptable

ToxicityOr

Consent Withdraw

Docetaxel 75mg/m² I.V. q3wks

Blinded Ram 10mg/kg I.V. q3wks

Docetaxel 75mg/m² I.V. q3wks

Blinded Placebo I.V. q3wks

Study Design

• Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial• Her2-Negative, unresectable, locally-recurrent or metastatic breast cancer • No prior chemotherapy or biologic therapy for advanced breast cancer• Stratification Factors: Prior taxane, Visceral metastasis, Hormone receptor

status, Geographic region

N=1144

Mackey et. al. SABCS 2013 6

Study Endpoints and Analyses• Primary Endpoint

– Investigator-Assessed Progression-free Survival (PFS)• 796 events from 1113 patients; 86% power to detect a difference

of 2 mos in median PFS (6 mos in the control group vs. 8 mos), HR=0.75

• Primary analysis is a stratified log-rank test with 2-sided α=0.05

• Survival Interim Analysis – To occur at time of final PFS analysis or 375 deaths,

whichever is later.

• Secondary Endpoints– Overall Survival (OS)

• 792 events; 85% power to detect a difference of 6 mos in median survival (24 mos for the control group vs 30 mos), HR=0.8

– TTP, ORR, safety and QOL

Mackey et. al. SABCS 2013 7

Key Eligibility Criteria• Women with HER2-negative metastatic or locally-recurrent

and inoperable breast cancer

• No prior chemotherapy or biologic therapy for metastatic / recurrent breast cancer

• Completed (neo) adjuvant taxane therapy ≥ 6 mos, (neo) adjuvant biologic therapy ≥ 6 wks, and radiotherapy with curative intent ≥ 3 wks prior to randomization

• Adequate hematologic, hepatic, and renal function

• ECOG Performance Status of 0-1

• No uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia

ROSE: Patient DispositionPatients screened (n=1455)

Patients randomized (n=1144)(2:1 randomization)

Not eligible (n=311)

Ramucirumab Armn=759

Placebo Armn=385

Ramucirumab-treatedn=752*

Placebo-treatedn=382*

Did not receive treatment (n=8)

Did not receive treatment (n=2)

Intent- to-treat

population

(n=1144)

Safety population

(n=1134)

• 1144 patients were randomized (Aug 2008 to Dec 2011)

• Data cut-off on 31 Mar 2013 after observation of at least 796 PFS events and > 375 OS events; database lock 29 Aug 2013 with 819 PFS and 471 OS events

*One PBO+DOC randomized patient , received RAM + DOC in Cycle 1 only therefore is included in the RAM + DOC safety  population

Mackey et. al. SABCS 2013 9

Baseline Characteristics (ITT)RAM + DOC

(N=759)PBO + DOC

(N=385)Median Age, years (range) 54(24 – 82) 54(29 – 81) ECOG PS, % 0 1

5842

6237

Number of Metastatic Sites, % <3 ≥3

4852

5248

Disease Site Visceral 71 72

Prior taxane therapy, % Yes No

2674

2773

Geographical Region, % North & South America Europe/Australia/New Zealand Asia/Middle East/Africa

246412

246413

Mackey et. al. SABCS 2013 10

Baseline Characteristics (ITT)RAM + DOC

(N=759)PBO + DOC

(N=385)Hormone Receptor Status, % Positive Negative

76 24

7723

ER, PR, HER2 Status, % ER Positive Negative

72 27

7525

PR Positive Negative

53 47

6139

HER2 Negative (IHC 0-1+ or ISH neg)

100

99.7

Triple Negative, % Yes No

25 75

2278

Mackey et. al. SABCS 2013 11

Investigator-AssessedProgression-Free Survival

RAM + DOC(n = 759)

PBO + DOC(n = 385)

Number of Events (%) 528 (69.6) 291 (75.6)Median PFS, months (95% CI) 9.5 (8.3, 9.8) 8.2 (7.1, 8.5)Hazard Ratio (95% CI) 0.88 (0.75, 1.01)P value 0.077

759 591 439 313 211 151 86 47 21 12 6 4 3 3 1 1 0RAM + DOC385 284 219 140 96 61 39 27 16 11 6 1 1 0 0 0 0PBO + DOC

Number patients at risk

0 6 12 18 24 30 36 42 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

RAM + DOC PBO + DOC

Months

Prob

abili

ty fo

r Pro

gres

sion

-free

Sur

viva

l

Mackey et. al. SABCS 2013 12

RAM + DOC(n = 759)

PBO + DOC(n = 385)

Number of Events (%) 378 (49.8) 224 (58.1)

Median PFS, months (95% CI) 11.1 (9.9, 11.8) 8.5 (7.9, 9.8)

Hazard Ratio (95% CI) 0.79 (0.67, 0.94)

P value 0.008

Independent Review Progression-Free Survival

759 593 440 296 198 140 75 46 23 12 6 4 2 0RAM +DOC385 275 202 127 84 57 36 26 14 11 4 2 1 0PBO + DOC

Number of patients at risk20

0 6 12 18 24 30 36 42 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

RAM + DOC PBO + DOC

Months

Prob

abili

ty fo

r Pro

gres

sion

-free

Sur

viva

l

Mackey et. al. SABCS 2013 13

Overall Survival – Interim Analysis

759 730 686 636 561 485 354 233 148 98 60 35 22 14 8 3 1 0RAM + DOC385 371 354 327 296 249 182 126 94 60 38 18 10 5 2 0 0 0PBO + DOC

Number patients at risk

0 6 12 18 24 30 36 42 480.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

RAM + DOC PBO + DOC

Months

Prob

abili

ty fo

r Ove

rall

Surv

ival

RAM + DOC(n = 759)

PBO + DOC(n = 385)

Number of Events (%) 311 (41) 160 (41.6)

Median OS, months (95% CI) 27.3 (23.6, 29.1) 27.2 (24.3, 32.2)

Hazard Ratio (95% CI) 1.01 (0.83, 1.23)

P value 0.915

Mackey et. al. SABCS 2013

ROSE: PFS (Inv) by Subgroup (ITT)Subgroups

RAM + DOCN

PBO + DOCN HR (95% CI)

Overall 759 385 0.88 (0.75, 1.01)Age Group < 65 629 325 0.90 (0.77, 1.06) ≥ 65 130 60 0.85 (0.57, 1.28)Race White 676 341 0.87 (0.75, 1.02) Non-White 83 44 1.27 (0.74, 2.18)ECOG PS 0 439 240 0.87 (0.72, 1.06) ≥ 1 320 145 0.85 (0.67, 1.08)Prior Taxane (IWRS) Yes 197 103 0.90 (0.68, 1.21) No 562 282 0.86 (0.73, 1.03)Sites of Metastases (IWRS) Visceral 541 276 0.92 (0.78, 1.09) Non-visceral 218 109 0.75 (0.56, 1.01)Hormone Receptor Status (IWRS) Positive 580 295 0.86 (0.72, 1.02) Negative/Unknown 179 90 0.93 (0.69, 1.25)Geographic Region North and South America 183 91 0.82 (0.59, 1.13) Europe/Australia/New Zealand 484 246 0.87 (0.73, 1.04) Asia/Africa/Middle East 92 48 1.02 (0.65, 1.61)

0.5

Hazard Ratio (95% CI)N = Total number of patients

RAM + DOC better

PBO + DOCbetter

Mackey et. al. SABCS 2013 15

Best Overall Response and Time to Progression Investigator Review Assessment

RAM + DOC(N=759)

PBO + DOC(N=385) P-value

Best Overall Response % %

Best Overall Response CR PR SD PD Inevaluable

2.442.341.8 7.6 5.9

1.836.143.413.0 5.7

Objective Response Rate (CR + PR) 44.7 37.9 0.027 Disease Control Rate (CR + PR + SD) 86.4 81.3 0.022

Time to Progression Number of patients with progression (%) 65.3 73.0

Median time to progression months (95% CI) 9.7 (8.5, 10.3) 8.2 (7.1, 9.0) Hazard Ratio, (95% CI) 0.78 (0.65, 0.93) 0.034*

*Log-rank p-value stratified by prior use of taxane therapy, visceral metastasis, hormone receptor status, and geographic region.

Mackey et. al. SABCS 2013 16

Treatment AdministrationRamucirumab/Placebo DocetaxelRAM + DOC

(N = 752)PBO + DOC (N = 382)

RAM + DOC(N = 752)

PBO + DOC (N = 382)

Duration of Treatment (wks) Median Range

28(3 – 181.4)

27.2(3.0 – 169.9)

24.0(3.0 – 137.1)

24.0(3.0 – 169.9)

Median Number of Cycles* Median Range

9(0 – 58)

9(1 – 52)

8(1 – 40)

8(1 – 52)

Relative Dose Intensity (%)

Median Range

97.2(30 – 114)

97.3(73.8 – 106.7)

96.7(54.6 – 106.7)

98.1(61.3 – 103.2)

* Cycle consists of 21 days

Mackey et. al. SABCS 201317

Treatment Emergent Adverse Events(≥10% of patients and higher incidence on RAM + Docetaxel Arm)

RAM + DOC (N = 752)

PBO + DOC (N = 382)

Any Grade % Grade ≥ 3 % Any Grade % Grade ≥ 3 %Any AE 98.7 61.7* 98.2 52.4Fatigue† 68.4 16.4* 66.0 9.7Stomatitis 50.7* 6.1* 30.6 1.0Epistaxis 39.9* 0.1 16.8 0Lacrimation increased 31.1* 0.8 17.0 0.5Hypertension 27.0* 6.8* 11.5 1.8Weight decreased 21.9* 1.3 10.5 0.5Decreased appetite 21.7* 0.7 16.2 0Palmar-Plantar Erythrodysaesthesia Syndrome 14.2* 3.9* 8.6 1.0

Insomnia 13.0* 0 8.4 0

MedDRA Version 16.0; CTCAE version 3.0 are used.*p-value <0.05 using Fisher’s exact test comparing RAM to PBO† Consolidated AE category comprising synonymous MEdDRA preferred terms.

Mackey et. al. SABCS 2013 18

Most Common Hematologic AEs RAM + DOC

(N = 752)PBO + DOC

(N = 382)Any Grade

%Grade ≥ 3

%Any Grade

%Grade ≥ 3

%Neutropenia† 17.6 15.2 16.0 13.1Anemia† 10.1 2.3 7.3 1.8Febrile Neutropenia 8.1* 7.8* 4.2 3.9Thrombocytopenia 2.8 0.8 1.6 0.5Leukopenia† 1.9 1.2 3.1 1.8

MedDRA Version 16.0; CTCAE version 3.0 are used.*p-value <0.05 using Fisher’s exact test comparing RAM to PBO† Consolidated AE category comprising synonymous MEdDRA preferred terms.

Mackey et. al. SABCS 2013 19

Adverse Events of Special InterestRAM + DOC

(N = 752)PBO + DOC

(N = 382)Any Grade

%Grade ≥ 3

%Any Grade

%Grade ≥ 3

%Bleeding / Hemorrhage Events 48.0* 0.9 22.3 1.8Hypertension 27.0* 6.8* 11.5 1.8Infusion Related Reaction 11.4 1.9 11.5 1.8Proteinuria 5.1* 0.4 1.3 0Venous Thromboembolic Events 2.4 1.3 4.2* 3.1GI Perforation 1.3* 1.2 0 0Arterial Thromboembolic Events 1.1 0.7 1.3 0.3Congestive Heart Failure 1.1 0.3 0.8 0.3

MedDRA Version 16.0; CTCAE version 3.0 are used.*p-value <0.05 using Fisher’s exact test comparing RAM to PBO

Mackey et. al. SABCS 2013

Treatment Emergent Adverse Events with an Outcome of Death

(Any TEAE with a fatal outcome in 2 or more patients on either treatment arm)

RAM + DOC(N = 752)

PBO + DOC(N = 382)

n % n %Number of patients with any TEAE 29 3.9 9 2.4Disease progression† 10 1.3 4 1.0Death 2 0.3 0 0Hepatic Failure 2 0.3 1 0.3Renal Failure* 2 0.3 0 0Sepsis 2 0.3 0 0Sudden Death 2 0.3 0 0

*Terms listed under Consolidated AE Category are composite terms comprising synonymous MedDRA preferred terms.† Includes Disease and Neoplasm progression reported as adverse events

Mackey et. al. SABCS 2013 21

Conclusions• Ramucirumab + docetaxel did not significantly prolong the

primary endpoint of investigator assessed Progression Free Survival over placebo + docetaxel (HR 0.88, p=0.077)

• IRC assessed PFS was slightly longer on the RAM arm (HR 0.79, p=0.008)

• No difference observed in this interim overall survival analysis

• ORR, DCR, and TTP were higher on the Ramucirumab arm

• Efficacy results did not differ in clinical subgroups

• Ramucirumab + docetaxel therapy had higher rates of adverse events including fatigue, hypertension, bleeding, febrile neutropenia, and stomatitis

Mackey et. al. SABCS 2013 22

Acknowledgments

We thank the study participants and their families, the members of the Independent Data Monitoring Committee, and the TRIO network

of investigators and study staff.

Mackey et. al. SABCS 2013 23

CANADAJ. MackeyK. GelmonM. WebsterS. VermaC. PradyL. ProvencherJ. Wilson

GERMANYB. AtasevenH. EidtmannJ. EttlM. ClemensB. LuhnV. MuellerP. Krabisch

REPUBLIC of KOREAS. LeeY. ParkS. Im

RUSSIAS. AveryanovaA. KhorinkoA. MakhsonV. ShirinkinV. BorisovN. ChekhaV. Milovanov

AUSTRALIA N. McCarthyR. SnyderA. BonaventuraE. AbdiG. KannourakisA. RedfernJ. ChirgwinD. DalleyM. WhiteG. BeadleR. LowenthalS. NgM. CronkR. JennensJ. ThomsonF. Boyle

BRAZILR. HeggM. ManoF. FrankeP. SantiS. SanchesJ. Vinholes C. Barrios A. Morelle

CZECHREPUBLIC: P. KlepetkoJ. Vanasek V. StahalovaO. Bednarik

EGYPTN. AllahloubiA. El SaidH. El Zawahry

IRELANDG. GulloM. KeaneC. MurphyJ. KennedyJ. McCaffreyL. CoateS. O´ReillyISRAEL N. EfratS. StemmerM. TokarT. RyvoB. Uziely

PERU M. PhilcoH. MorónW. RodriguezC. Lozada

NEW ZEALAND D. PorterR. Isaacs

LEBANOND. Abi GergesJ. KattanF. FarhatG. ChahineA. MugharbilN. KassemG. Nsouli

SPAINM. Martin J. Garcia-SaenzS. MoralesA. Gonzalez

SERBIA S. Filipovic

UNITED STATESA. ThummalaM. SalehS. SundaramM. ShtivelbandS. LimentaniI. OliffP. KleinS. ChuiR. PatelE. HuG. KonecnyR. DichmannW. WalshG. HarkerM. MetcalfeR. AnsariJ. ReevesF. KassS. BeckP. AcsB. BowersL. SiegelG. SrkalovicI. Shalaby

TAIWAN Y. ChangC. HuangS. Chen

POLANDA. PiktelZ. RusinowskaW. Rogowski

UNITED KINGDOM A. BowmanS. ChanA. Wardley

BELGIUMJ. CanonG. JerusalemM. GraasM. HuizingV. CocquytP. Vuylsteke L. D'HondtM. BormsD. Verhoeven

SOUTH AFRICA G. CohenK. MaartD. VorobiofM. Coccia-PortugalG. DemetriouL. DreostiJ. Jordaan

SLOVAKIA S. SpanikR. Hruby

RUSSIAO. LipatovD. KrasnozhonV. SemiglazovA. ManikhasV. GorbunovaI. KiselevR. KhasanovI. LitvinovM. KoppV. Merkulov

SPAINN. Batista M. Ruiz Borrego M. MuñozA. RuizS. Del BarcoA. MarquezM. MargeliB. BermejoR. Cubedo S. ServitjaI. AlvarezA. AntonC. Rodriguez P. SanchezJ. ChaconJ. PonceJ. Alarcon

UNITED KINGDOM J. JoffeT. HickishM. Lind

Investigators

Mackey et. al. SABCS 2013

AdditionalSlides

Mackey et. al. SABCS 2013 25

Treatment Discontinuations (ITT)

RAM + DOC(N = 759)

PBO + DOC (N = 385)

Ongoing, n (%) 53 ( 7.0) 25 ( 6.5)

Discontinuations, n (%) Progressive Disease†

Adverse Event Death Consent Withdrawn††

Other Protocol Non-Compliance Lost to Follow-up

398126128770

76

(51.0)(17.0)( 1.6)(11.4)( 9.2)( 0.9)( 0.7)

251 454

302343

(65.2)(12.0)( 1.0)( 7.8)( 6.2)( 1.0)( 0.7)

†Including clinical progression.† † Including consent withdrawn from protocol medication and consent withdrawn from overall study participation.

Mackey et. al. SABCS 2013

Post-discontinuation TreatmentRAM + DOC (N=759) PBO + DOC (N=385)

n (%) n %Patients with any PDT* 480 (63) 266 (69)

Chemotherapy 361 (48) 218 (57) Anthracycline 133 (18) 73 (19) Taxane 73 (10) 44 (11) Hormonal 211 (28) 115 (30) Radiotherapy 100 (13) 69 (18) Antiangiogenic 18 (2) 15 (4) Biologic therapy† 7 (0.9) 1 (0.3) Surgery (any) 33 (4.3) 14 (3.6)

*PDT = Post-discontinuation Treatment; each patient may have received more than one regimen.†Other than Antiangiogenic therapy.

ROSE: OS by Subgroup (ITT)Subgroups

RAM + DOCN

PBO + DOCN HR (95% CI)

Overall 759 385 1.01 (0.83, 1.23)Age Group < 65 629 325 0.99 (0.80, 1.23) ≥ 65 130 60 1.01 (0.61, 1.67)Race White 676 341 0.99 (0.80, 1.21) Non-White 83 44 1.62 (0.78, 3.37)ECOG PS 0 439 240 0.98 (0.75, 1.27) ≥ 1 320 145 0.98 (0.73, 1.32)Prior Taxane (IWRS) Yes 197 103 1.00 (0.70, 1.41) No 562 282 1.02 (0.81, 1.28)Sites of Metastases (IWRS) Visceral 541 276 1.07 (0.86, 1.33) Non-visceral 218 109 0.83 (0.56, 1.25)Hormone Receptor Status (IWRS) Positive 580 295 0.95 (0.76, 1.20) Negative/Unknown 179 90 1.16 (0.81, 1.66)Geographic Region North and South America 183 91 0.82 (0.57, 1.18) Europe/Australia/New Zealand 484 246 1.10 (0.86, 1.41) Asia/Africa/Middle East 92 48 1.04 (0.57, 1.89)

0.5

Hazard Ratio (95% CI)N = Total number of patients

RAM + DOC better

PBO + DOCbetter