Bondarenko, Igor

1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]

Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m 2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m 2 , docetaxel 75 or 100 mg/m 2 ), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. Results RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P < .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P < .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. Conclusion The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

Abstract BackgroundRIBBON-1, a Phase III, multicenter, randomized, placebo-controlled trial in patients with previously untreated MBC was designed to evaluate the efficacy and safety of adding bevacizumab (B) to chemotherapy regimens including capecitabine (Cape; n=615); a taxane (T; n=307), or an anthracycline (Anth; n=315) compared with chemotherapy alone. Pre-specified analyses of progression-free survival PFS) in the Cape and pooled T/Anth cohorts, the primary endpoints of the study were increased upon addition of B. In the Cape cohort, median PFS increased from 5.7 to 8.6 mo (HR=0.69, p-value=0.0002) and in the T/Anth cohort, it increased from 8.0 to 9.2 mo (HR=0.64; p-value&lt;0.0001).MethodsRECIST was used to determine objective response rate (ORR). Patients without a post-baseline tumor assessment were considered non-responders. The primary analysis for the ORR and the duration of response was performed using only patients with measurable disease at baseline. ORR was formally compared between the two treatment arms using the Mantel-Haenszel Chi-squared test, using the randomization stratification factors. Fisher's exact test was also performed. Clinical benefit rate (CBR) was defined as the proportion of patients with a complete or partial response or with stable disease at Week 24. Exploratory analyses of CBR and time to response are provided here. Summary statistics of time to response at Week 9 will be presented as will the final analysis of the secondary endpoint of overall survival.ResultsAnalyses of ORR and CBR are provided in the following table. CapeTaxaneAnth PL (n=206)B (n=409)PL (n=104)B (n=203)PL (n=103)B (n=212)Patients with measurable disease, n (%)161 (78.2)325 (61.1)85 (81.7)161 (79.3)92 (89.3)184 (86.8)ORR, %23.635.435.350.340.252.2CR, n (%)1 (0.6)7 (2.2)3 (3.5)4 (2.5)2 (2.2)3 (1.6)PR, n (%)37 (23.0)108 (33.2)27 (31.8)77 (47.8)35 (38.0)93 (50.5)Difference between arms, %11.815.012.0p-value, unstratified0.00940.030.073Duration of ORMedian, mo7.29.28.68.46.08.1HR (95% CI)0.61 (0.39–0.96)0.75 (0.45–1.27)0.53 (0.34–0.83)Log-rank p-value0.03260.2840.0047Clinical benefit rate*, %47.164.365.471.969.980.7p-value, unstratified&lt;0.00010.240.04CR+PR at Week 9, %20.229.438.354.544.451.1B=bevacizumab, cape=capecitabine, CI=confidence interval, HR=hazard ratio, OR=objective response, PL=placebo, T/Anth=taxane/anthracycline.*For randomized patients.ConclusionsIn patients with HER2-negative MBC, the addition of bevacizumab to capecitabine, taxane or anthracycline chemotherapy induces more responses and those responses occur more rapidly. For capecitabine and anthracycline the addition of bevacizumab leads to objective responses that last longer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6084.

Abstract 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.