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<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<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.
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: Selective estrogen receptor modulators and aromatase inhibitors (AI) (+LHRH agonists [premenopausal]) are standard of care (SOC) for hormone–receptor–positive (HR+) metastatic breast cancer (MBC). Many HR+ MBC patients (pts) get limited benefit from adjuvant or advanced endocrine therapy (ET) and develop endocrine resistance, refractory disease. HR+ BC growth relies on cyclin dependent kinases 4/6 that promote G1–S phase cell cycle progression. Palbociclib (PAL) with ET showed efficacy in HR+/HER2– MBC (Turner et al, 2015). We report updated safety and efficacy from PALOMA3 with longer follow–up, focusing on degrees of clinically defined endocrine resistance. Methods: Pts with HR+/HER2– MBC that progressed on prior ET were randomized 2:1 to PAL (125 mg/d oral [3 wks drug, 1 wk off]) + fulvestrant (F, 500 mg, SOC) +/– goserelin or placebo (PLB)+F. One line of chemotherapy (CT) for MBC was allowed. Pt stratification: prior ET sensitivity; visceral metastases; menopausal status. Primary endpoint (EP) was investigator–assessed progression–free survival (PFS). Secondary EP: overall survival, response assessment, patient–reported outcomes, safety. Results: By March 2015, median follow–up was 8.9 mo. 521 pts were randomized (PAL+F, 347; PLB+F, 174). Baseline characteristics were balanced. Median PFS was 9.5 (95% CI 9.2–11.0) mo (PAL+F) vs 4.6 (3.5–5.6) mo (PLB+F) (HR 0.46 [0.36–0.59], P<0.001). Overall response (CR+ PR) was significantly improved with PAL+F (ITT: 19% vs 8.6%, P=0.001; pts with measurable disease: 24.6% vs 10.9%, P<0.001). Clinical benefit (CBR=CR+PR+SD ?24wks) was 66.6% vs 39.7% (P<0.001). Benefit from PAL was confirmed in pre– and postmenopausal pts with PFS in premenopausal 9.5 vs 5.6 mo (HR=0.50 [0.29–0.87], P=0.006) and in postmenopausal 9.9 vs 3.9 mo (HR=0.45 [0.34–0.59], P<0.001). Common adverse events (AEs) for PAL+F vs PLB+F were neutropenia (80.9 vs 3.5%), leukopenia (49.6 vs 4.1%), and fatigue (39.1 vs 28.5%); febrile neutropenia occurred in 0.9% (P+ F) vs 0.6% pts (PLB+F). Discontinuation due to AEs was 4.0% on P vs 1.7% on PLB. The benefit of PAL+F vs PLB+F was compared in pts with various degrees of endocrine resistance: a) progression ≤12 mo of adjuvant ET completion, PFS 9.5 vs 5.4 mo (HR 0.55 [0.32–0.92], P=0.01); b) failed 1 line of ET, 10.2 vs 5.4 mo (HR 0.42 [0.29–0.59], P<0.001); c) failed 2 lines of ET, 9.9 vs 1.8 mo (HR=0.20 [0.10– 0.39, P<0.001); d) proven endocrine sensitive, 10.2 vs 4.2 mo (HR 0.42 [0.32–0.56], P<0.001); e) proven no prior endocrine sensitivity, 7.5 vs 5.4 mo (HR 0.64 [0.39–1.07], P=0.04) f) AI most recent therapy, 9.5 vs 3.7 mo (HR 0.42 [0.31–0.56], P<0.001). Conclusion: Mature efficacy confirmed superior PFS and demonstrated significantly improved clinical response and CBR by the combination of ET and Palbociclib. It also consistently showed therapeutic benefit irrespective of menopausal status and various degrees of endocrine sensitivity. Safety profile is favorable. PAL+F may be an effective option for HR+ MBC pts. Funding: Pfizer. Citation Format: Cristofanilli M, Bondarenko I, Ro J, Im S-A, Masuda N, Colleoni M, DeMichele AM, Loi S, Verma S, Iwata H, Huang Bartlett C, Zhang K, Puyana Theall K, Turner NC, Slamon DJ. PALOMA3: Phase 3 trial of fulvestrant with or without palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy—confirmed efficacy and safety. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-01.
Background EndoTAG™-1 (ET) is an innovative therapy of paclitaxel (P) embedded in cationic liposomes displaying antitumor activity by targeting negatively charged activated endothelial cells of tumor vessels. Methods: 140 patients (pts) with locally relapsed (r) or metastatic (m) centrally verified TNBC were randomized to i.v. weekly ET (22mg/m2 ) plus P (70mg/m2) (ET+P), biweekly ET alone (44mg/m2) or weekly P (90mg/m2) in a 2:2:1 ratio. Pts had ≤ 1 prior chemotherapy (CT) for r or m disease and ≥ 6 months (mo) after taxane. A cycle (cy) comprised 3 weeks(w) of therapy and 1 w rest. Pts were treated for a minimum of 4 cy or until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS) rate at week 16 based on blinded central imaging and local assessment. Secondary endpoints included median overall survival (mOS), tumor response (RECIST), Quality of Life (QoL) and safety. The study was not powered for intergroup comparisons. Results: Pts baseline characteristics were overall well distributed. Appr. 80% of all pts were treated 1st line for r or m TNBC. Results of PFS rates at week 16 are shown in table. Based on central review, median PFS at week 16 was 4.2 mo for ET+P [95% CI: 3.5−9.1], 3.4 on ET [2.0−3.8] and 3.7 on P [1.9−6.7]. Antitumor activity was highest for ET+P with a clinical benefit rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥6 mo at data cut off date of week 41) of 53% (26/49 evaluable pts), 31% (15/49) on ET and 36% (9/25) on P. The best overall response (CR, PR, SD at any time) on ET+P was 80% (39/49), on ET 65% (32/49) and 68% (17/25) on P. Analysis of median OS is shown in table. Analysis of the not predefined subgroup (centrally TNBC + ECOG 0/1 + first line population) showed an impressive median OS of 17.8 mo for ET+P. No differences were reported for QoL. No additional toxicities to those known for ET and P were observed except uncomplicated grade 3/4 neutropenia in the ET + P arm. Conclusions: At cut-off date week 41, the final analysis demonstrated ET+P as a promising combination compared to single agent arms. ET+P was well tolerated. These data will be the basis for a confirmatory phase III study. Acknowlegments: B. Glasschroeder, U. Elsasser Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-06.
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