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Patrick Neven - One of the best experts on this subject based on the ideXlab platform.
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the effect of abemaciclib plus Fulvestrant on overall survival in hormone receptor positive erbb2 negative breast cancer that progressed on endocrine therapy monarch 2 a randomized clinical trial
JAMA Oncology, 2020Co-Authors: George W Sledge, Patrick Neven, Norikazu Masuda, Kenichi Inoue, Masakazu Toi, Joohyuk Sohn, Xavier Pivot, Olga Burdaeva, Meena Okera, P A KaufmanAbstract:Importance Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with Fulvestrant for hormone receptor (HR)–positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated. Objective To compare the effect of abemaciclib plus Fulvestrant vs placebo plus Fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET. Design, Setting, and Participants MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus Fulvestrant vs placebo plus Fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019. Interventions Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus Fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). Main Outcomes and Measures The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundaryPvalue for the interim analysis was .02. Results Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus Fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus Fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus Fulvestrant and 37.3 months for placebo plus Fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945;P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib. Conclusions and Relevance Treatment with abemaciclib plus Fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy. Trial Registration ClinicalTrials.gov Identifier:NCT02107703
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Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.
The New England journal of medicine, 2019Co-Authors: Dennis J Slamon, Patrick Neven, Peter A Fasching, Michelino De Laurentiis, Francisco J Esteva, Stephen Chia, Katarina Petrakova, Giulia V Bianchi, Miguel MartinAbstract:In an earlier analysis of this phase 3 trial, ribociclib plus Fulvestrant showed a greater benefit with regard to progression-free survival than Fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to Fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus Fulvestrant showed a significant overall survival benefit over placebo plus Fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. Ribociclib plus Fulvestrant showed a significant overall survival benefit over placebo plus Fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.). Copyright © 2019 Massachusetts Medical Society.
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phase iii randomized study of ribociclib and Fulvestrant in hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer monaleesa 3
Journal of Clinical Oncology, 2018Co-Authors: Dennis J Slamon, Patrick Neven, S Chia, Peter A Fasching, Michelino De Laurentiis, Seockah Im, K Petrakova, G V Bianchi, Francisco J Esteva, Miguel MartinAbstract:PurposeThis phase III study evaluated ribociclib plus Fulvestrant in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer who were treatment naive or had received up to one line of prior endocrine therapy in the advanced setting.Patients and MethodsPatients were randomly assigned at a two-to-one ratio to ribociclib plus Fulvestrant or placebo plus Fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety.ResultsA total of 484 postmenopausal women were randomly assigned to ribociclib plus Fulvestrant, and 242 were assigned to placebo plus Fulvestrant. Median progression-free survival was significantly improved with ribociclib plus Fulvestrant versus placebo plus Fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consiste...
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Fulvestrant (Faslodex™) in advanced breast cancer: clinical experience from a Belgian cooperative study
Breast Cancer Research and Treatment, 2008Co-Authors: Patrick Neven, Gino Pelgrims, Jean Charles Goeminne, Anita Vindevoghel, Jan Demol, Alain Bols, Marc Martens, Barbara Stragier, Robert Paridaens, Jacques GreveAbstract:Fulvestrant (Faslodex™) is a new estrogen receptor (ER) antagonist with no agonist effects that is licensed for the treatment of postmenopausal women with hormone-sensitive advanced breast cancer (ABC) who have progressed/recurred on prior antiestrogen therapy. The Faslodex™ Compassionate Use Program (CUP) provides expanded access to Fulvestrant in countries where it is not yet available for patients who are not eligible to enter clinical trials. This analysis pools data from 402 patients who received Fulvestrant as part of the CUP in Belgium, predominantly as 3rd- to 5th-line endocrine therapy for ABC. Two patients experienced partial responses and 118 experienced stable disease lasting ≥6 months, resulting in an overall clinical benefit rate of 29.9%. Fulvestrant was active in patients with multiple sites of metastases, visceral metastases, human epidermal growth factor receptor 2-positive disease and after heavy endocrine pre-treatment. Fulvestrant was well tolerated, with only six patients (1.5%) discontinuing treatment following adverse events. These data support the findings of previous CUP analyses and Phase II and III trials, suggesting that Fulvestrant is a valuable addition to the treatment sequence for postmenopausal women with ABC who have progressed/recurred on prior endocrine therapy.
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Metastatic breast cancer: sequencing hormonal therapy and positioning of Fulvestrant.
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 2006Co-Authors: I Vergote, F Amant, K Leunen, T Van Gorp, P Berteloot, Patrick NevenAbstract:Fulvestrant, a novel estrogen receptor (ER) antagonist with no agonist effects, binds, blocks, and degrades the ER, thereby downregulating cellular ER levels, which in turn leads to reduced expression of the progesterone receptor. Due to this specific working mechanism, Fulvestrant is an important addition to the armamentarium of endocrine agents in advanced breast cancer (ABC). Fulvestrant has been shown to be equally effective as the third-generation aromatase inhibitor (AI) anastrozole in postmenopausal patients with hormone-sensitive ABC progressing prior to tamoxifen. In another randomized phase III trial, it was shown that Fulvestrant had similar efficacy to tamoxifen in the first-line treatment of postmenopausal women with hormone receptor-positive ABC. When comparing the side effects of Fulvestrant with tamoxifen and anastrozole, it was shown that Fulvestrant is well tolerated compared with these agents and is associated with a lower incidence of joint disorders. Clinical benefit on Fulvestrant treatment after AI therapy has been reported in a substantial number of patients (28-46%). On the other hand, it was also shown that sensitivity to further endocrine therapy is retained following progression on first-line or second-line Fulvestrant (57% and 46% clinical benefit, respectively). In conclusion, Fulvestrant provides us with an additional endocrine treatment option making it possible to prolong the time that patients with ABC can be treated with endocrine therapy.
John F.r. Robertson - One of the best experts on this subject based on the ideXlab platform.
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A Good Drug Made Better: The Fulvestrant Dose-Response Story
Clinical breast cancer, 2014Co-Authors: John F.r. Robertson, Elizabeth Anderson, Justin P.o. Lindemann, Robert Ian Nicholson, Sally Garnett, Irene Kuter, Julia Margaret Wendy GeeAbstract:Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced breast cancer, before the use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor (ER) antagonist approved for the treatment of postmenopausal women with ER+ advanced breast cancer after failure of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended Fulvestrant dose was revised to 500 mg (500 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progression-free survival versus Fulvestrant 250 mg. We have reviewed the dose-dependent effects of Fulvestrant, both from a retrospective combined analysis of dose-dependent reduction of tumor biomarkers in the presurgical setting (3 previously reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57) and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of presurgical data revealed a consistent dose-dependent effect for Fulvestrant on tumor biomarkers, with increasing Fulvestrant dose resulting in greater reductions in ER, progesterone receptor, and Ki67 labeling index. The dose-dependent biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced breast cancer after failure of prior antiestrogen therapy. Although it remains to be determined in a phase III trial, cross-trial comparisons suggest a dose-dependent relationship for Fulvestrant as first-line treatment for advanced breast cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for Fulvestrant, supporting the efficacy benefit seen with Fulvestrant 500 mg over the 250 mg dose.
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A randomized trial to assess the biological activity of short-term (pre-surgical) Fulvestrant 500 mg plus anastrozole versus Fulvestrant 500 mg alone or anastrozole alone on primary breast cancer.
Breast cancer research : BCR, 2013Co-Authors: John F.r. Robertson, J. Michael Dixon, D. Mark Sibbering, A Jahan, Ian O. Ellis, Eddie Channon, Pauline Hyman-taylor, Robert Ian Nicholson, Julia Margaret Wendy GeeAbstract:Introduction Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining Fulvestrant with anastrozole. This pre-surgical study compared Fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer.
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Fulvestrant 500 mg versus anastrozole 1 mg for the first line treatment of advanced breast cancer follow up analysis from the randomized first study
Breast Cancer Research and Treatment, 2012Co-Authors: John F.r. Robertson, Justin P.o. Lindemann, Antonio Llombartcussac, Janusz Rolski, David Feltl, J A Dewar, Laura Emerson, Andrew Dean, Matthew J EllisAbstract:Fulvestrant fIRst-line Study comparing endocrine Treatments is a phase II, randomized, open-label study comparing Fulvestrant 500 mg with anastrozole 1 mg as first-line endocrine therapy for postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer. At data cut-off, only 36 % of patients had progressed and the median time to progression (TTP) had not been reached for Fulvestrant. Here, we report follow-up data for TTP for Fulvestrant 500 mg versus anastrozole 1 mg. Key inclusion criteria were postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive locally advanced or metastatic breast cancer and no prior endocrine therapy. Key exclusion criteria were presence of life-threatening metastases and prior treatment with a non-approved drug. Fulvestrant was administered 500 mg/month plus 500 mg on day 14 of month 1; anastrozole was administered 1 mg/day. TTP was defined by modified Response Evaluation Criteria in Solid Tumors v1.0 before data cut-off for the primary analysis, and investigator opinion after data cut-off. Best overall response to subsequent therapy and serious adverse events are also reported. In total, 205 patients received Fulvestrant 500 mg (n = 102) or anastrozole (n = 103). Follow-up analysis was performed when 79.5 % of patients had discontinued study treatment. Median TTP was 23.4 months for Fulvestrant versus 13.1 months for anastrozole; a 34 % reduction in risk of progression (hazard ratio 0.66; 95 % confidence interval: 0.47, 0.92; P = 0.01). Best overall response to subsequent therapy and clinical benefit rate for subsequent endocrine therapy was similar between the treatment groups. No new safety concerns for Fulvestrant 500 mg were documented. These longer-term, follow-up results confirm efficacy benefit for Fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for HR+ advanced breast cancer in terms of TTP, and, importantly, show similar best overall response rates to subsequent endocrine therapy.
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Fulvestrant (Faslodex) -- how to make a good drug better.
The oncologist, 2007Co-Authors: John F.r. RobertsonAbstract:Fulvestrant (Faslodex); AstraZeneca Pharmaceuticals, Wilmington, DE) is an estrogen receptor (ER) antagonist with a novel mode of action; it binds, blocks, and increases degradation of ER. Fulvestrant (at the approved dose [250 mg/month]) is at least as effective as anastrozole (1 mg/day) in the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer (HR(+) ABC) progressing or recurring on antiestrogen therapy, and is also an active first-line treatment. Although Fulvestrant (250 mg/month) is clearly effective, it takes 3-6 months to achieve steady-state plasma levels. Steady-state concentrations are approximately twofold higher than those achieved with a single dose; reaching this earlier, for example, via a loading-dose (LD) regimen (250 mg/month plus 500 mg on day 0 and 250 mg on day 14 of month 1), may allow responses to be achieved more quickly and limit the possibility of early relapse. Fulvestrant high-dose (HD) regimens (500 mg/month) offer the possibility of greater antitumor activity, because (a) ER downregulation is a dose-dependent process (an approximately 70% reduction is observed with a single 250 mg dose of Fulvestrant) and (b) evidence correlates greater ER downregulation with superior efficacy. A Fulvestrant HD regimen offers the potential of achieving near 100% ER downregulation. There is also potential to increase Fulvestrant-ER binding by reducing plasma estrogen levels, for example, with concomitant aromatase inhibitor treatment. Several ongoing trials use LD, HD, and combination regimens; results from these studies are awaited with interest. Meanwhile, Fulvestrant (250 mg/month) remains a valuable additional endocrine treatment for postmenopausal women with HR(+) ABC recurring or progressing on antiestrogen therapy.
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Pharmacokinetic profile of intramuscular Fulvestrant in advanced breast cancer.
Clinical pharmacokinetics, 2004Co-Authors: John F.r. Robertson, Steven E Come, Stan Gertler, Bjorn Erikstein, Kent Osborne, John Pippen, Leroy M. Parker, Mike P. Harrison, David A ClarkeAbstract:Objective To characterise the pharmacokinetics of a long-acting formulation of Fulvestrant following intramuscular administration of single and multiple doses. Study design: Pharmacokinetic investigations of single and multiple doses of Fulvestrant were conducted within two global phase III efficacy studies that compared intramuscular Fulvestrant with oral anastrozole in postmenopausal women with hormone-sensitive advanced breast cancer (study 0020, conducted in Europe, Australia and South Africa, and study 0021, conducted in North America).
Dennis J Slamon - One of the best experts on this subject based on the ideXlab platform.
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Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.
The New England journal of medicine, 2019Co-Authors: Dennis J Slamon, Patrick Neven, Peter A Fasching, Michelino De Laurentiis, Francisco J Esteva, Stephen Chia, Katarina Petrakova, Giulia V Bianchi, Miguel MartinAbstract:In an earlier analysis of this phase 3 trial, ribociclib plus Fulvestrant showed a greater benefit with regard to progression-free survival than Fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to Fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus Fulvestrant showed a significant overall survival benefit over placebo plus Fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. Ribociclib plus Fulvestrant showed a significant overall survival benefit over placebo plus Fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.). Copyright © 2019 Massachusetts Medical Society.
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predictors of prolonged benefit from palbociclib plus Fulvestrant in women with endocrine resistant hormone receptor positive human epidermal growth factor receptor 2 negative metastatic breast cancer in paloma 3
European Journal of Cancer, 2018Co-Authors: Massimo Cristofanilli, Dennis J Slamon, Seockah Im, Norikazu Masuda, C Giorgetti, Angela Demichele, Nicholas C Turner, Shailendra Verma, Marco Colleoni, Kathy Puyana TheallAbstract:Abstract Background The addition of palbociclib to Fulvestrant improved clinical outcomes over placebo-Fulvestrant in endocrine-pretreated metastatic breast cancer (MBC) patients in PALOMA-3. Here, we examined factors predictive of long-term benefit. Methods Premenopausal-peri/postmenopausal patients with endocrine-resistant, hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative MBC were randomised 2:1 to Fulvestrant (500 mg) and either palbociclib (125 mg/d; 3/1 schedule; n = 347) or placebo (n = 174). Baseline characteristics, mutation status and HR expression levels were compared in patients with and without prolonged benefit (treatment duration ≥18 months). Results By August 2016, 100 patients (29%) on palbociclib-Fulvestrant and 26 (15%) on placebo-Fulvestrant demonstrated prolonged benefit, with long-term responders in both arms sharing common clinical characteristics. They usually had less disease burden at baseline versus those treated Conclusions This exploratory analysis demonstrates that some patients with endocrine-resistant MBC derive significant and prolonged benefit when treated with palbociclib-Fulvestrant, with fewer patients experiencing similar efficacy with placebo-Fulvestrant. The current analysis did not identify specific molecular or clinical factors prognostic of long-term benefit with palbociclib-Fulvestrant ( ClinicalTrials.gov , NCT01942135 ).
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overall survival with palbociclib and Fulvestrant in advanced breast cancer
The New England Journal of Medicine, 2018Co-Authors: Nicholas C Turner, Dennis J Slamon, Norikazu Masuda, Angela Demichele, Marco Colleoni, Igor Bondarenko, Sherene Loi, Sunil Verma, H Iwata, Nadia HarbeckAbstract:Abstract Background In an earlier analysis of this phase 3 trial, ribociclib plus Fulvestrant showed a greater benefit with regard to progression-free survival than Fulvestrant alone in postmenopau...
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phase iii randomized study of ribociclib and Fulvestrant in hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer monaleesa 3
Journal of Clinical Oncology, 2018Co-Authors: Dennis J Slamon, Patrick Neven, S Chia, Peter A Fasching, Michelino De Laurentiis, Seockah Im, K Petrakova, G V Bianchi, Francisco J Esteva, Miguel MartinAbstract:PurposeThis phase III study evaluated ribociclib plus Fulvestrant in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer who were treatment naive or had received up to one line of prior endocrine therapy in the advanced setting.Patients and MethodsPatients were randomly assigned at a two-to-one ratio to ribociclib plus Fulvestrant or placebo plus Fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety.ResultsA total of 484 postmenopausal women were randomly assigned to ribociclib plus Fulvestrant, and 242 were assigned to placebo plus Fulvestrant. Median progression-free survival was significantly improved with ribociclib plus Fulvestrant versus placebo plus Fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consiste...
Miguel Martin - One of the best experts on this subject based on the ideXlab platform.
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Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.
The New England journal of medicine, 2019Co-Authors: Dennis J Slamon, Patrick Neven, Peter A Fasching, Michelino De Laurentiis, Francisco J Esteva, Stephen Chia, Katarina Petrakova, Giulia V Bianchi, Miguel MartinAbstract:In an earlier analysis of this phase 3 trial, ribociclib plus Fulvestrant showed a greater benefit with regard to progression-free survival than Fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to Fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus Fulvestrant showed a significant overall survival benefit over placebo plus Fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. Ribociclib plus Fulvestrant showed a significant overall survival benefit over placebo plus Fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.). Copyright © 2019 Massachusetts Medical Society.
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phase iii randomized study of ribociclib and Fulvestrant in hormone receptor positive human epidermal growth factor receptor 2 negative advanced breast cancer monaleesa 3
Journal of Clinical Oncology, 2018Co-Authors: Dennis J Slamon, Patrick Neven, S Chia, Peter A Fasching, Michelino De Laurentiis, Seockah Im, K Petrakova, G V Bianchi, Francisco J Esteva, Miguel MartinAbstract:PurposeThis phase III study evaluated ribociclib plus Fulvestrant in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer who were treatment naive or had received up to one line of prior endocrine therapy in the advanced setting.Patients and MethodsPatients were randomly assigned at a two-to-one ratio to ribociclib plus Fulvestrant or placebo plus Fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety.ResultsA total of 484 postmenopausal women were randomly assigned to ribociclib plus Fulvestrant, and 242 were assigned to placebo plus Fulvestrant. Median progression-free survival was significantly improved with ribociclib plus Fulvestrant versus placebo plus Fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consiste...
S Jones - One of the best experts on this subject based on the ideXlab platform.
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Effectiveness and tolerability of Fulvestrant in postmenopausal women with hormone receptor-positive breast cancer.
Clinical Breast Cancer, 2005Co-Authors: S Jones, J. PippenAbstract:Fulvestrant, an estrogen receptor antagonist that downregulates the estrogen receptor but has no known agonist effects, has been evaluated in 2 randomized trials involving postmenopausal women with hormone receptor-positive, progressive advanced-stage breast cancer after disease progression with antiestrogen therapy. These phase III studies, from which data were reported separately and in a planned combined analysis, showed that Fulvestrant 250 mg per month intramuscularly was at least as effective as anastrozole 1 mg per day orally with respect to the primary endpoint of time to progression as well as secondary efficacy endpoints, which included objective response, clinical benefit, and survival. Both trials showed that patients treated with Fulvestrant had a significantly longer duration of response, and a retrospective analysis found that pretreatment with Fulvestrant did not preclude response to third-line hormonal therapy. More recently, Fulvestrant was shown to be active as first-line hormonal therapy for advanced-stage breast cancer, with overall efficacy similar to that of tamoxifen in patients with hormone receptor-positive disease. Fulvestrant has been well tolerated in comparative trials published to date, translating into low study withdrawal rates and maintenance of quality of life. The incidence of adverse events was similar between the treatment arms in both trials of Fulvestrant versus anastrozole, but it was notably lower for Fulvestrant relative to tamoxifen in the first-line setting. In light of the results of comparative phase III trials, Fulvestrant is effective and well tolerated in the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer.
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Fulvestrant an estrogen receptor antagonist that downregulates the estrogen receptor
Seminars in Oncology, 2003Co-Authors: S JonesAbstract:Fulvestrant, a novel antiestrogen classified as an estrogen receptor antagonist without known agonist effects, was recently approved in the United States for the treatment of postmenopausal, hormone receptor-positive women with progressive metastatic breast cancer after antiestrogen therapy. In a phase II trial, monthly administration of Fulvestrant, 250 mg intramuscularly, conferred clinical benefit (partial response or stable disease for >or= 24 weeks) in 69% of patients with tamoxifen-resistant advanced breast cancer. Furthermore, the median duration of response and survival for this population (26 and 54 months, respectively) was twice as high as those documented for a megestrol acetate-treated historical cohort (14 months and 30 months, respectively). Comparative phase III trials conducted in North America and internationally, which used time to progression as the primary endpoint, demonstrated Fulvestrant's tolerability and equivalence to anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer, which led to its approval in this setting. Vasodilation and nausea were the principal treatment-related adverse events in the Fulvestrant arms, and mild injection-site reactions occurred in 4.6% and 1.1% of monthly Fulvestrant courses given in the North American and international trials, respectively. Recent subanalyses of the pivotal phase III data have found that Fulvestrant produces a 30% longer mean duration of response compared with anastrozole and that Fulvestrant-induced estrogen receptor downregulation does not preclude response to subsequent hormonal therapy. Ongoing trials in patients with advanced breast cancer will provide further insight into the relative merits of Fulvestrant versus tamoxifen as first-line therapy for metastatic disease, the use of Fulvestrant within combination and sequential regimens, and the efficacy of Fulvestrant specifically in premenopausal women. Research efforts focusing on alternate administration schedules for Fulvestrant and its potential as an adjuvant hormonal therapy are also anticipated.
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Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women a prospective combined analysis of two multicenter trials
Cancer, 2003Co-Authors: John F.r. Robertson, Anthony Howell, Kent C Osborne, S Jones, L Mauriac, Matthew J Ellis, Ulrich R Kleeberg, Steven E Come, Ignace Vergote, Stan GertlerAbstract:BACKGROUND Fulvestrant (ICI 182,780) is a new type of estrogen receptor (ER) antagonist that down-regulates the ER and has no known agonist effects. The authors report the prospectively planned combined analysis of data from 2 Phase III trials comparing Fulvestrant 250 mg monthly (n = 428) and anastrozole 1 mg daily (n = 423) in postmenopausal women with advanced breast carcinoma (ABC) who previously had progressed after receiving endocrine treatment. METHODS The primary endpoint was time to progression (TTP). Secondary endpoints included objective response (OR), duration of response (DOR), and tolerability. The trials were designed to demonstrate superiority of Fulvestrant over anastrozole. Noninferiority of Fulvestrant versus anastrozole was determined using a retrospectively applied statistical test. RESULTS At a median follow-up of 15.1 months, ≈ 83% of patients in each treatment arm had progressed. The median TTP was 5.5 months in the Fulvestrant group and 4.1 months in the anastrozole group, and the OR rates were 19.2% and 16.5% for Fulvestrant and anastrozole, respectively (although the difference between treatments was not statistically significant). In patients who responded, further follow-up (median, 22.1 months) was performed to obtain more complete information on DOR; the median DOR (from randomization to disease progression) in patients who responded to treatment was 16.7 months in the Fulvestrant group and 13.7 months in the anastrozole group. In a statistical analysis of DOR (using all randomized patients; from the start of response to disease progression), DOR was significantly longer for patients in the Fulvestrant group compared with patients in the anastrozole group. Both drugs were tolerated well; withdrawals due to drug-related adverse events were 0.9% and 1.2% in the Fulvestrant group and the anastrozole group, respectively. The incidence of joint disorders was significantly lower in the Fulvestrant group (P = 0.0036). CONCLUSIONS Fulvestrant was tolerated well and was at least as effective as anastrozole in the second-line treatment of patients with ABC. This new hormonaltherapy may provide a valuable treatment option for ABC in postmenopausal women. Cancer 2003;98:229–38. © 2003 American Cancer Society.
