Anti-angiogenic strategies in metastatic breast cancer have demonstrated a number of modest improvements in progression-free survival. This observation warranted evaluation of new agents, such as the antibody ramucirumab (IMC-1121B; ImClone Systems/Eli Lilly and Company) in a placebo-controlled settings.
Ramucirumab is a fully human monoclonal antibody being developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 or VEGFR2 and blocks ligand stimulated activation.
No delay in disease progression
Early phase studies suggested anticancer effects in several solid tumors, and a phase III study demonstrated survival improvements in gastric cancer. However, adding ramucirumab to the chemotherapy drug docetaxel (Taxotere?; Sanofi) did not delay disease progression for patients with HER2-negative, advanced breast cancer. This conclusion is based on the results of the ROSE trial, a placebo-controlled, randomized, phase III clinical trial, which was designed to evaluate ramucirumab in the setting of HER2 negative, unresectable locally recurrent or metastatic breast cancer, presented at the 36th San Antonio Breast Cancer Symposium (SABCS), being held December 10?14, 2013, in San Antonio, Texas.[1][2]
? We will be conducting biomarker analyses to see if we can identify a subgroup of patients for whom this antibody therapy might be beneficial…
?Patients with metastatic or recurrent breast cancer, as well as those with locally advanced disease that cannot be surgically removed, have no curative options,? noted 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.
Disappointing outcome
?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). ?Anti-angiogenic 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.?
Biomarker analyses
?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.?
Blood supply
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, VEGFR2. According to Mackey, other anti-angiogenic therapies have not yielded great success in breast cancer but it had been hoped that ramucirumab would benefit patients because it is the only anti-angiogenic antibody therapy to directly target VEGFR2.
Trial design
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 (75 mg/m2) plus placebo IV every three weeks or docetaxel plus ramucirumab 10 mg/kg IV every three weeks. 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. The treatment was continued with each agent until investigators determined progressive disease using RECIST criteria, or until unacceptable toxicity.[3]
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,? Mackey said.
This study was funded by Eli Lilly and Company. Mackey declares no conflicts of interest.
For more information:
[1] Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Kraznozhon D, Semiglazov V, Manikhas A, et al. 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. Publication Number: S5-04. Presented by John R. Mackey, M.D.
[2] ROSE (TRIO-012) study primary results (presented at 36th San Antonio Breast Cancer Symposium (SABCS); Mackey JR. [PowerPoint]
[3] Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.[Article][PubMed]
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