Background: Three prior Phase III trials (E2100, AVADO, and RIBBON-1) established the clinical benefit of adding bevacizumab (BV) to various chemotherapies (chemos) as first-line treatment for metastatic breast cancer (MBC). A previous Phase III study (AVF2119g) in patients with predominantly heavily pre-treated MBC, in which BV was added to capecitabine (Cape), resulted in a significant increase in objective response rate (ORR), but did not meet the primary endpoint for progression-free survival (PFS). The current study, RIBBON-2, was designed to evaluate the efficacy and safety of the addition of BV to chemotherapies used as second-line treatment for MBC.Methods: Patients were randomized in a 2:1 ratio to chemo+BV or chemo+placebo (PL). Key eligibility criteria included one prior cytotoxic treatment for MBC, ECOG performance status of 0 to 1, and HER2-negative or unknown status. Prior to randomization, investigators chose one of the following chemo agents: taxane (T; paclitaxel 90 mg/m2/wk for 3 of the 4 weeks; paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, docetaxel 75–100 mg/m2, all given q3wk), gemcitabine (G; 1250 mg/m2 on Days 1 and 8 q3wk), Cape (2000 mg/m2 Days 1–14 q3wk), or vinorelbine (V; 30 mg/m2/wk). BV or PL was administered at 10 mg/kg q2wk or 15 mg/kg q3wk, depending on the chemo regimen. The primary endpoint of the study was investigator-assessed PFS pooled across the chemo cohorts. Key secondary endpoints included overall survival (OS), PFS within individual chemo cohorts, ORR, and safety.Results: 684 patients (T, 304; G, 160; Cape, 144; and V, 76) at 211 sites in 19 countries were randomized between February 2006 and June 2008. Overall, the two study arms were balanced for patient characteristics at baseline. The study met its primary endpoint of PFS pooled across chemo cohorts and also demonstrated a 10% increase in ORR when BV was added to chemo. At the interim analysis for OS, the median durations were 18 mo for chemo+BV and 16.4 mo for chemo+PL (see table).Across all chemo cohorts the incidence of BV-related AEs was consistent with data from previous studies. Hypertension was the only BV-related AE consistently increased in the chemo+BV arm across all chemo cohorts.Conclusions: The addition of BV to chemotherapies used for second-line treatment of MBC led to a significant improvement in PFS. The AE profile of BV in the overall study population and across the chemotherapy cohorts was consistent with that previously observed. Additional analyses, including PFS for the individual chemo cohorts, will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 42.

Background: In the interim analysis of study EPO-ANE-3010, for the primary endpoint of progression-free survival (PFS), the non-inferiority objective in ruling out a 15% increased risk in progressive death (PD) or death per investigator-determined PD was not achieved (JCO 34:1197-1207, 2016). PFS, based on independent review committee (IRC)-determined PD, however, met the non-inferiority criteria. At the interim analysis, OS with 1,337 deaths was reported; we now report the final analysis at 1,653 deaths and the updated PFS. Methods: This multinational (19 countries and 132 participating sites), phase 3, randomized, open-label noninferiority study included anemic (≤11.0 g/dL hemoglobin) women receiving first- or second-line standard chemotherapy for MBC (Eastern Cooperative Oncology Group performance status of 0 or 1). Subjects were randomized (1:1) to receive either standard SOC for treatment of anemia plus EPO (40,000 IU subcutaneous) weekly up to 4 weeks after the last dose of cytotoxic chemotherapy, or SOC alone. The primary endpoint was PFS (using Cox's regression model). Secondary endpoints included OS, time to tumor progression (TPP), overall response rate (ORR) and safety assessments. Results: A total of 2,098 subjects were enrolled (EPO plus SOC: n=1,050; SOC alone: n=1048). Demographic and baseline characteristics were well-balanced across the groups; median age was 52 years, most were white (67.5%) or Asian (30.5%) and median BMI was 26.0 kg/m2. Primary efficacy analysis (based on investigator-determined PD) showed a median PFS of 7.4 months for both groups (hazard ratio [HR], 1.094; 95% CI: 0.996, 1.201);upper bound exceeded prespecified noninferiority margin of 1.15. A 9% increased risk for PD/death in the EPO plus SOC group was observed and did not statistically rule out a 15% increased risk. Median PFS per IRC-determined PD was 7.6 months in both groups (HR, 1.028; 95% CI: 0.922, 1.146), this met pre-defined non-inferiority margin of 1.15 with a 3% risk increase in PD/death in EPO plus SOC group. At the final analysis for OS, median OS was 17.8 months in the EPO plus SOC group and 18.0 months in the SOC group; HR: 1.073 (95% CI: 0.974, 1.182); median TPP was 7.5 months in both groups (HR, 1.099; 95% CI, 0.998 to 1.210), and ORR was 50% in the EPO plus SOC group and 51% in the SOC group (odds ratio, 0.939; 95% CI, 0.789, 1.117). Red blood cell (RBC) transfusions were 5.8% versus 11.5% (P<0.001), and thrombotic vascular events were 2.8% versus 1.4% (P=0.038), respectively, in EPO plus SOC group and SOC group. The incidence of death due to PD were similar in both groups (EPO plus SOC: 93%; SOC: 91%). Conclusion:The primary endpoint, PFS based on investigator-determined PD, did not meet noninferiority criteria but for PFS based on IRC-determined PD, noninferiority criteria was met. Overall, this study did not statistically rule-out a 15% increased risk in PD/death. The final analysis did not show statistically different OS in the EPO plus SOC group versus the SOC group. No new safety signals were noted with EPO treatment and the results are consistent with the known safety profile of EPO. Citation Format: Leyland-Jones B, Bondarenko I, Nemsadze G, Smirnov V, Litvin I, Kokhreidze I, Abshilava L, Janjalia M, Li R, Lakshmaiah KC, Samkharadze B, Tarasova O, Shparyk Y, Polenkov S, Vladimirov V, Han J, Safonov I, Appiani C, Leitz G. Final analysis of overall survival (OS) for the epoetin alfa (EPO) phase 3 study, EPO-ANE-3010, of EPO plus standard supportive care (SOC) versus SOC in anemic patients with metastatic breast cancer (MBC) receiving standard chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-01.