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

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

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

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  1. 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 PérolaByigton 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; 19ImCloneSystems 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

  2. Disclosure Research support from ImClone a wholly owned subsidiary of Eli Lilly and Company

  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

  4. Mechanism of ramucirumab action • Ramucirumab (IMC-1121B; RAM) a recombinant human IgG1 monoclonal antibody that binds the extracellular domain of VEGF Receptor-2 VEGF-A VEGF-A VEGF-CVEGF-D VEGF-CVEGF-D Ramucirumab VEGF binds toVEGFR2 receptor;VEGF-C, -D competefor binding toVEGFR2 Ramucirumabbinds to VEGFR2, blocks VEGFligand binding VEGFR2 VEGFR2 Endothelial cell Ligand binding activates VEGFR2 andp44/p42 MAP kinases No signaling Angiogenesis Tumor growth Inhibit new blood vesselformation and tumor growth

  5. Study Design Progressive Disease Or Unacceptable Toxicity Or Consent Withdraw Docetaxel 75mg/m² I.V. q3wks Follow-up for PD and for OS RANDOMIZATION 2:1 Blinded Ram 10mg/kg I.V. q3wks Docetaxel 75mg/m² I.V. q3wks N=1144 Blinded Placebo I.V. q3wks • 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

  6. Study Endpoints and Analyses • Primary Endpoint • Investigator-Assessed Progression-free Survival (PFS) • 796 eventsfrom 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 mosin median survival (24 mosfor the control group vs 30 mos), HR=0.8 • TTP, ORR, safety and QOL

  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 ≥ 6mos, (neo) adjuvant biologic therapy ≥ 6wks, 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

  8. ROSE: Patient Disposition Patients screened (n=1455) Not eligible (n=311) Patients randomized (n=1144) (2:1 randomization) Intent- to-treat population (n=1144) Placebo Arm n=385 Ramucirumab Arm n=759 Did not receive treatment (n=2) Did not receive treatment (n=8) Safety population (n=1134) Placebo-treated n=382* Ramucirumab-treated n=752* *One PBO+DOC randomized patient , received RAM + DOC in Cycle 1 only therefore is included in the RAM + DOC safety  population • 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

  9. Baseline Characteristics (ITT)

  10. Baseline Characteristics (ITT)

  11. Investigator-AssessedProgression-Free Survival Number patients at risk 759 591 439 313 211 151 86 47 21 12 6 4 3 3 1 1 0 RAM + DOC 385 284 219 140 96 61 39 27 16 11 6 1 1 0 0 0 0 PBO + DOC

  12. Independent Review Progression-Free Survival Number of patients at risk RAM +DOC 759 593 440 296 198 140 75 46 23 12 6 4 2 2 0 PBO + DOC 385 275 202 127 84 57 36 26 14 11 4 2 1 0 0

  13. Overall Survival – Interim Analysis Number patients at risk 354 759 730 686 636 561 485 233 148 98 60 35 22 14 8 3 1 0 RAM + DOC 182 385 371 354 327 296 249 126 94 60 38 18 10 5 2 0 0 0 PBO + DOC

  14. ROSE: PFS (Inv) by Subgroup (ITT) RAM + DOC better PBO + DOCbetter  N = Total number of patients

  15. Best Overall Response and Time to Progression Investigator Review Assessment *Log-rank p-value stratified by prior use of taxane therapy, visceral metastasis, hormone receptor status, and geographic region.

  16. Treatment Administration * Cycle consists of 21 days

  17. Treatment Emergent Adverse Events(≥10% of patientsand higher incidence on RAM + Docetaxel Arm) • 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.

  18. Most Common Hematologic AEs • 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.

  19. Adverse Events of Special Interest • MedDRA Version 16.0; CTCAE version 3.0 are used. • *p-value <0.05 using Fisher’s exact test comparing RAM to PBO

  20. Treatment Emergent Adverse Events with an Outcome of Death(Any TEAE with a fatal outcome in 2 or more patients on either treatment arm) • *Terms listed under Consolidated AE Category are composite terms comprising synonymous MedDRA preferred terms. • † Includes Disease and Neoplasm progression reported as adverse events

  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

  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.

  23. Investigators UNITED KINGDOM J. Joffe T. Hickish M. Lind SPAIN N. Batista M. Ruiz Borrego M. Muñoz A. Ruiz S. Del Barco A. Marquez M. Margeli B. Bermejo R. Cubedo S. Servitja I. Alvarez A. Anton C. Rodriguez P. Sanchez J. Chacon J. Ponce J. Alarcon RUSSIA S. Averyanova A. Khorinko A. Makhson V. Shirinkin V. Borisov N. Chekha V. Milovanov BRAZIL R. Hegg M. Mano F. Franke P. Santi S. Sanches J. Vinholes C. Barrios A. Morelle NEW ZEALAND D. Porter R. Isaacs AUSTRALIA N. McCarthy R. Snyder A. Bonaventura E. Abdi G. Kannourakis A. Redfern J. Chirgwin D. Dalley M. White G. Beadle R. Lowenthal S. Ng M. Cronk R. Jennens J. Thomson F. Boyle GERMANY B. Ataseven H. Eidtmann J. Ettl M. Clemens B. Luhn V. Mueller P. Krabisch PERU M. Philco H. Morón W. Rodriguez C. Lozada UNITED STATES A. Thummala M. Saleh S. Sundaram M. Shtivelband S. Limentani I. Oliff P. Klein S. Chui R. Patel E. Hu G. Konecny R. Dichmann W. Walsh G. Harker M. Metcalfe R. Ansari J. Reeves F. Kass S. Beck P. Acs B. Bowers L. Siegel G. Srkalovic I. Shalaby IRELAND G. Gullo M. Keane C. Murphy J. Kennedy J. McCaffrey L. Coate S. O´Reilly SERBIA S. Filipovic POLAND A. Piktel Z. Rusinowska W. Rogowski CANADA J. Mackey K. Gelmon M. Webster S. Verma C. Prady L. Provencher J. Wilson SLOVAKIA S. Spanik R. Hruby REPUBLIC of KOREA S. Lee Y. Park S. Im SOUTH AFRICA G. Cohen K. Maart D. Vorobiof M. Coccia-Portugal G. Demetriou L. Dreosti J. Jordaan ISRAEL N. Efrat S. Stemmer M. Tokar T. Ryvo B. Uziely CZECH REPUBLIC: P. Klepetko J. Vanasek V. Stahalova O. Bednarik BELGIUM J. Canon G. Jerusalem M. Graas M. Huizing V. Cocquyt P. Vuylsteke L. D'Hondt M. Borms D. Verhoeven RUSSIA O. Lipatov D. Krasnozhon V. Semiglazov A. Manikhas V. Gorbunova I. Kiselev R. Khasanov I. Litvinov M. Kopp V. Merkulov TAIWAN Y. Chang C. Huang S. Chen LEBANON D. AbiGerges J. Kattan F. Farhat G. Chahine A. Mugharbil N. Kassem G. Nsouli SPAIN M. Martin J. Garcia-Saenz S. Morales A. Gonzalez EGYPT N. Allahloubi A. El Said H. El Zawahry UNITED KINGDOM A. Bowman S. Chan A. Wardley

  24. AdditionalSlides

  25. Treatment Discontinuations (ITT) †Including clinical progression. † † Including consent withdrawn from protocol medication and consent withdrawn from overall study participation.

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

  27. ROSE: OS by Subgroup (ITT) RAM + DOC better PBO + DOCbetter  N = Total number of patients

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