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PUBLIC RELEASE DATE:
13-Dec-2013

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Contact: Jeremy Moore
jeremy.moore@aacr.org
215-446-7109
American Association for Cancer Research

New combination therapy fails to delay progression of advanced breast cancer

SAN ANTONIO — Adding the antibody therapy ramucirumab to the chemotherapy drug docetaxel did not delay disease progression for patients with HER2-negative, advanced breast cancer, according to results of a placebo-controlled, randomized, phase III clinical trial presented here at the 2013 San Antonio Breast Cancer Symposium, held Dec. 10-14.

"Patients with metastatic or recurrent breast cancer, as well as those with locally advanced disease that cannot be surgically removed, have no curative options," said John R. Mackey, M.D., professor of oncology at the University of Alberta in Edmonton. "Standard cytotoxic chemotherapy is an option, but the efficacy of current treatments is modest and patients experience many adverse side effects.

"We had hoped that ramucirumab would give patients a new option for metastatic breast cancer. The outcome is disappointing, especially for the patients who participated on the trial and the many others suffering with this disease," added Mackey, who is also director of Translational Research in Oncology (TRIO). "Antiangiogenic agents have been successful in prolonging survival in a number of solid tumor types, including colon cancer and gastric cancer, but unfortunately, for reasons that we don't understand, they have not yet been shown to work for breast cancer."

"But we must work with the results that we have, and there were some patients on the trial who responded to treatment with ramucirumab," continued Mackey. "As a result, we will be conducting biomarker analyses to see if we can identify a subgroup of patients for whom the antibody therapy might be beneficial, but it will be a while before we have results."

For tumors to thrive, they need a good blood supply, and many tumors release factors that trigger nearby blood vessels to grow, a process called angiogenesis. Ramucirumab blocks angiogenesis by attaching to the protein on blood vessels that is key to the new blood vessel growth, vascular endothelial growth factor receptor 2 (VEGFR2). According to Mackey, other antiangiogenic therapies have not yielded great success in breast cancer but it had been hoped that ramucirumab would benefit patients because it is the only antiangiogenic antibody therapy to directly target VEGFR2.

Between August 2008 and December 2011, Mackey and colleagues enrolled 1,144 patients in the placebo-controlled, randomized, multinational, phase III clinical trial called the ramucirumab overall survival evaluation (ROSE) trial or the TRIO-12 trial. Patients were randomly assigned 1:2 to docetaxel plus placebo or docetaxel plus ramucirumab. To be eligible for the trial, patients had to have HER2-negative breast cancer that could not be removed surgically or HER2-negative, locally recurrent or metastatic breast cancer.

After a median follow-up of 16.2 months, progression-free survival was 9.5 months in the ramucirumab arm and 8.2 months in the control arm.

"The biggest positive that we can take from the trial is that we showed that a global academic group, TRIO, can successfully partner with industry to run a large, late-stage cancer clinical trial," said Mackey.

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This study was funded by Eli Lilly and Company. Mackey declares no conflicts of interest.

This research will be presented at the 2013 San Antonio Breast Cancer Symposium Friday, Dec. 13, 7:30 a.m. CT, during a press conference hosted by Peter Ravdin, M.D., Ph.D., clinical professor of oncology, San Antonio, Texas. Press conferences will be held in Room 217D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

Reporters who cannot attend in person can call into the press conferences using the following information:

To interview John Mackey, contact jennifer.houseman@albertahealthservices.ca or call 780-432-8221. For a photo of John Mackey, click here. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.

The mission of the 2013 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit http://www.sabcs.org.

Publication Number: S5-04

Presenter: John R. Mackey, M.D.

Title: Primary results of ROSE/TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer

Authors: John R Mackey1, Manuel Ramos-Vazquez2, Oleg Lipatov3, Nicole McCarthy4, Dimitry Kraznozhon5, Vladimir Semiglazov6, Alexey Manikhas7, Karen Gelmon8, Gottfried Konecny9, Marc Webster10, Roberto Hegg11, Sunil Verma12, Vera Gorbounova13, Dany Abi Gerges14, Francois Thireau15, Helena Fung15, Lorinda Simms16, Marc Buyse17, Ayman Ibrahim16 and Miguel Martin18. 1Cross Center Institute, Edmonton, Canada; 2Centro Oncologico de Galicia "José Antonio Quiroga y Pineiro", A Coruña, Spain; 3Republican Clinical Oncology Dispensary of Ministry of Health of Bashkortostan Republic, Ufa, Russian Federation; 4Haematology and Oncology Clinic Australia Wesley Medical Center, Queensland, Australia; 5Leningrad Regional Oncology Dispensary, Leningrad, Russian Federation; 6Institute of Oncology N.N. Petrov, St. Petersburg, Russian Federation; 7City Clinical Oncology Dispensary, St. Petersburg, Russian Federation; 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, Russian Federation; 14Middle East Institute of Health, Bsalim, Lebanon; 15Translational Research in Oncology, Edmonton, Canada; 16ImClone Systems LLC, a Wholly Owned Subsidiary of Eli Lilly and Co., Bridgewater; 17International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium and 18Hospital General Universitario Gregorio Marañon, Madrid, Spain.

Background: To date, anti-angiogenic strategies in metastatic breast cancer have demonstrated benefits confined to modest improvements in progression-free survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab, an anti-VEGF receptor 2 antibody, is a human IgG1 antibody that specifically binds VEGF receptor 2 and blocks ligand stimulated activation. Early phase studies suggested anticancer effects in several solid tumors, and a phase III study demonstrated survival improvements in gastric cancer. The ROSE trial was designed to evaluate ramucirumab in the setting of HER2 negative, unresectable locally recurrent or metastatic breast cancer.

Methods: In this placebo-controlled randomized multinational phase III trial, patients with HER2 negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomized 1:2 to receive docetaxel 75 mg/m2 + placebo IV every three weeks, or to the same chemotherapy + ramucirumab 10 mg/kg IV every three weeks. Treatment was continued with each agent until investigator determined progressive disease using RECIST criteria, or until unacceptable toxicity. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographical region. An independent data monitoring committee oversaw the trial conduct, the efficacy database resides with TRIO, and this analysis was conducted by the TRIO statistical team in collaboration with Eli Lilly and Co. The primary endpoint was investigator-assessed PFS. The sample size was calculated to provide for this event-driven final PFS analysis and interim OS analysis, and a final OS analysis (to be conducted when at least 792 OS events are observed). ROSE also includes evaluation of potential predictive biomarkers.

Results: Between Aug 2008 and Dec 2011, 1144 patients were randomized. At data cut-off (March 31, 2013), median follow-up was 16.2 months. Safety, final PFS and interim OS results will be presented. Anticipated data availability is early November 2013. Aggregated Patient Characteristics Age (years) 24 – 82 Prior Taxane Therapy (%) No 74 (%) Yes 26 Visceral Metastasis (%) No 29 Yes 71 Hormonal Receptor (%) Negative/Unknown 24 Positive 76 Geographic Region (%) Americas 24 Asia/Middle East/Africa 12 Europe/Australia/New Zealand 64



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