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Chris Twelves - One of the best experts on this subject based on the ideXlab platform.

  • A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of Eribulin mesilate in combination with capecitabine
    British Journal of Cancer, 2019
    Co-Authors: Chris Twelves, Ishtiaq Zubairi, Larisa Reyderman, Alan Anthoney, Claudio I. Savulsky, Matthew Guo, Nicola Cresti, Vladimir Semiglazov, Constanta Timcheva, Rosemary Morrison
    Abstract:

    Background Capecitabine and Eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities. Methods In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received Eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m^2 days 1–14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received Eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics. Results DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of Eribulin was 1.6 mg/m^2 day 1 for schedule 1 and 1.4 mg/m^2 days 1 and 8 for schedule 2. ORR in phase 2 (Eribulin 1.4 mg/m^2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy. Conclusions The combination of capecitabine and Eribulin showed promising efficacy with manageable tolerability in patients with MBC.

  • Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer
    'SAGE Publications', 2016
    Co-Authors: Chris Twelves, Javier Cortes, Ahmad Awada, Louise Yelle, Corina E Dutcus, Galina Velikova, Martin S. Olivo, James Song, Peter A Kaufman
    Abstract:

    Purpose and Methods Our secondary analyses compared survival with Eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous Eribulin mesylate 1.4 mg/m 2 on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m 2 on days 1–14 (21-day cycles). Results In the intent-to-treat population (Eribulin 554 and capecitabine 548), overall survival appeared longer with Eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from Eribulin as first-, second-, and third-line chemotherapies. Trial Registration (Primary Study) This study reports the subgroup analyses of Eribulin versus capecitabine from a phase 3, open-label, randomized study ( www.clinicaltrials.gov ; ClinicalTrials.gov identifier: NCT00337103)

  • phase iii open label randomized study of Eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane
    Journal of Clinical Oncology, 2015
    Co-Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, E A Perez, Corina E Dutcus, Galina Velikova, Martin Olivo, Javier Cortes
    Abstract:

    Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared Eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive Eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for Eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for Eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for Eribulin and 11.5% for capecitabine. Global health sta...

  • abstract s6 6 a phase iii open label randomized multicenter study of Eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes
    Cancer Research, 2012
    Co-Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, E A Perez, J Wanders, Corina E Dutcus
    Abstract:

    Background: Eribulin is a non-taxane microtubule dynamics inhibitor. In a previous Phase III trial, Eribulin demonstrated a statistically significant improvement in overall survival (OS) versus current treatments and a manageable toxicity profile, in heavily pre-treated patients (pts) with metastatic breast cancer (MBC). Here we report results from a Phase III trial of Eribulin compared with capecitabine in earlier-line pts with MBC (NCT00337103). Patients and methods: Pts were randomized 1:1 to Eribulin mesylate 1.4 mg/m 2 given on Days 1 and 8 of a 21 day cycle or capecitabine 2.5 g/m 2 /day administered orally BID on Days 1 to 14 of a 21 day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1 st , 2 nd , or 3 rd line therapy for advanced disease. The co-primary endpoints of this study were OS and progression free survival (PFS): pre-specified statistical significance at final analysis for Eribulin versus capecitabine were p ≤ 0.0372 for OS and p Results: Of 1102 pts, 554 were randomized to Eribulin and 548 capecitabine (375 and 380 pts were HER2[−], respectively). The median age was 54.0 years (range 24–80). Pts received study treatment as their 1 st (27.2%), 2 nd (57.4%) or 3 rd -line (14.7%) chemotherapeutic regimen in the setting of metastatic disease. The median number of treatment cycles was 6 for Eribulin and 5 for capecitabine. Median OS was 15.9 and 14.5 months (hazard ratio [HR] 0.879; 95% confidence intervals [CI] 0.770–1.003; p = 0.056), and PFS (independent review) was 4.1 and 4.2 months (HR 1.079; 95% CI 0.932–1.250; p = 0.305) for Eribulin and capecitabine, respectively. ORR (independent review) were 11.0% (95% CI 8.5–13.9) and 11.5% (95% CI 8.9–14.5; p = 0.849), respectively. OS for HER2(−) pts was 15.9 months for Eribulin and 13.5 months for capecitabine (HR 0.838; 95% CI 0.715–0.983; p = 0.030). AEs were consistent with the known side-effect profiles of both drugs. The most common AEs for Eribulin and capecitabine (>20% all grades) were neutropenia (54.2% vs 15.9%), hand-foot syndrome (0.2% vs 45.1%) alopecia (34.6% vs 4.0%), leukopenia (31.4% vs 10.4%), diarrhea (14.3% vs 28.8%), and nausea (22.2% vs 24.4%), respectively. Conclusion: In this Phase III trial, Eribulin demonstrated a trend favoring improved OS, compared with capecitabine, although this improvement does not meet the pre-defined criteria for statistical significance. This study confirms Eribulin as an active drug in pts with MBC, and exploratory analyses suggest possible benefits of Eribulin in specific subsets of pts, sufficient to warrant further study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-6.

  • abstract p6 13 02 survival outcomes with Eribulin mesylate vs treatment of the physician s choice tpc in heavily pretreated subjects with locally recurrent or metastatic breast cancer in north america western europe and australia results of the phase iii embrace study
    Cancer Research, 2010
    Co-Authors: Linda T. Vahdat, Chris Twelves, J Wanders, S Seegobin, C Akerele, Jorge E Cortes
    Abstract:

    Background: Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor. We conducted a randomized, controlled, open-label, phase III study to compare the efficacy and safety of Eribulin vs. TPC in heavily pretreated subjects with locally recurrent or metastatic breast cancer. This report focuses on outcomes for participants enrolled in North America, Western Europe, and Australia (Region 1). Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment. They were randomized 2:1 to receive Eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. The primary endpoint was overall survival (OS); progression-free survival (PFS) was a secondary endpoint. Results: A total of 762 subjects in 135 centers worldwide were enrolled. Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81% had taxane-refractory disease. The median time since original diagnosis was 6.7 years. The majority of subjects (488 [64%]) were from Region 1, of whom 325 received Eribulin and 163 received TPC. The most common treatments received by subjects from Region 1 in the TPC arm were vinorelbine (28%), gemcitabine (17%), capecitabine (13%), taxanes (20%), and anthracyclines (12%). 9% of subjects in this region received other therapies. Among the intent-to-treat population in Region 1, median OS was significantly prolonged with Eribulin (13.3 months) vs. TPC (10.2 months) (HR: 0.724; 95% CI: 0.568-0.924; p=0.009). Median PFS was also prolonged with Eribulin (3.3 months) vs. TPC (2.2 months; HR: 0.843; 95% CI: 0.666-1.066; p=0.153) in this population, as assessed by independent reviewers. Conclusion: OS was significantly prolonged in Eribulin-treated patients participating in the EMBRACE trial in the North America, Western Europe, and Australia region. When assessed by independent review, PFS was also prolonged with Eribulin, although this difference did not reach statistical significance for this geographic region. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-02.

Javier Cortes - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of single agent chemotherapy for patients with advanced invasive lobular carcinoma a pooled analysis from three clinical trials
    Oncologist, 2019
    Co-Authors: Jose Perezgarcia, Javier Cortes, Otto Metzger Filho
    Abstract:

    BACKGROUND Data on the efficacy of chemotherapy regimens in patients with advanced invasive lobular carcinoma (ILC) of the breast are limited. We investigated the efficacy of single-agent Eribulin for the treatment of advanced ILC when compared with invasive ductal carcinoma (IDC). PATIENTS AND METHODS Results from the Eribulin arms of two phase III studies (305 [EMBRACE] and 301) and a single-arm, phase II study were pooled. The studies involved patients with metastatic breast cancer who had previously received treatment with an anthracycline and a taxane. In all three studies, the dose of Eribulin mesylate was 1.4 mg/m2 given on days 1 and 8 of a 21-day cycle. Overall survival (OS), progression-free survival (PFS), and response rates in patients with ILC were assessed and compared with data from patients with IDC. RESULTS In total, 1,152 patients were included in this analysis (118 patients with ILC and 1,034 patients with IDC). Median OS was similar in patients with ILC and IDC (13.4 vs. 13.5 months; hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.87-1.38); as was median PFS (4.1 vs. 3.6 months; HR, 0.91; 95% CI, 0.72-1.14). There were no major differences in response rates between the two groups. CONCLUSION This retrospective analysis suggests that Eribulin demonstrates similar efficacy in patients with ILC and IDC with metastatic disease who have previously received an anthracycline and a taxane. IMPLICATIONS FOR PRACTICE Data on the efficacy of chemotherapy regimens in patients with advanced invasive lobular carcinoma (ILC) of the breast are limited. This pooled retrospective analysis of three clinical studies demonstrates that the magnitude of benefit of Eribulin in the metastatic setting did not differ between patients with ILC versus invasive ductal carcinoma (IDC), even when restricting for patients with estrogen receptor-positive/HER2-negative IDC.

  • Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer
    'SAGE Publications', 2016
    Co-Authors: Chris Twelves, Javier Cortes, Ahmad Awada, Louise Yelle, Corina E Dutcus, Galina Velikova, Martin S. Olivo, James Song, Peter A Kaufman
    Abstract:

    Purpose and Methods Our secondary analyses compared survival with Eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous Eribulin mesylate 1.4 mg/m 2 on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m 2 on days 1–14 (21-day cycles). Results In the intent-to-treat population (Eribulin 554 and capecitabine 548), overall survival appeared longer with Eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from Eribulin as first-, second-, and third-line chemotherapies. Trial Registration (Primary Study) This study reports the subgroup analyses of Eribulin versus capecitabine from a phase 3, open-label, randomized study ( www.clinicaltrials.gov ; ClinicalTrials.gov identifier: NCT00337103)

  • abstract p3 13 06 efficacy of Eribulin in patients with invasive lobular carcinoma of the breast data from a pooled analysis
    Cancer Research, 2015
    Co-Authors: Javier Cortes, J F Perez, Otto Metzgerfilho
    Abstract:

    Background: Invasive lobular carcinoma (ILC) represents the second most common breast cancer (BC) subtype and is usually characterized as hormone-receptor positive, low-to-intermediate histologic grade, and human epidermal growth factor receptor (HER) 2-negative. In the early-stage setting, ILCs are associated with lower rates of pathological response to preoperative chemotherapy compared with invasive ductal carcinoma (IDC). This exploratory analysis investigated the magnitude of benefit of single-agent Eribulin for the treatment of advanced ILC using data from three clinical trials in women with advanced BC. We also describe the patterns of response and survival outcomes compared with IDC. Methods: Individual patient (pt) data from the experimental arms of two phase III studies (305 and 301) and a single-arm, phase II study were pooled for the present analysis. Study 305 (EMBRACE) randomized pts treated with ≥2 lines of chemotherapy for advanced BC to receive Eribulin or treatment of physician9s choice. In study 301, pts treated with ≤2 lines of chemotherapy for advanced BC were randomized to receive Eribulin or capecitabine. In the phase II study, pts who had received ≥3 lines of chemotherapy were treated with Eribulin. Overall survival (OS) and progression-free survival (PFS) analyses were adjusted by study, estrogen receptor (ER) and HER2 status, and number of lines of therapy for advanced disease. Results: The three studies included 1353 Eribulin-treated pts. Of the 1152 pts included in the present analysis, 118 were classified as ILC and 1034 as IDC. Median age of ILC and IDC pts was 58 years and 55 years, respectively. ER and/or progesterone receptor (PgR) positivity was more common in ILC (ER = 69%, PgR = 55%) than IDC (ER = 60%, PgR = 48%), while HER2 positivity was less frequent in ILC than IDC (9% vs 16%). A total of 52.5% of ILC and 61.4% of IDC pts received ≥3 lines of chemotherapy (for any stage BC) prior to Eribulin. Pts with ILC and IDC had similar median OS (13.4 vs 13.5 months; hazard ratio [HR] = 1.10; 95% confidence intervals [CIs] 0.87, 1.38) and PFS (4.1 vs 3.6 months; HR = 0.91; 95% CIs 0.72, 1.14). Investigator-evaluated tumor response rates are shown in the table. Conclusions: In this exploratory, pooled analysis, magnitude of benefit from single-agent Eribulin did not differ between the ILC and IDC cohorts. While there was a limited numbers of pts with ILC, response rates, PFS, and OS were similar for the two pt groups. The results with Eribulin for advanced ILC contrast with data for other agents in early-stage settings, where ILC is generally less responsive to chemotherapy than IDC. These findings may, however, underline changes in the disease biology after exposure to previous therapies or changes inherent to disease progression. Citation Format: Javier Cortes, Jose Perez, Yi He, Otto Metzger-Filho. Efficacy of Eribulin in patients with invasive lobular carcinoma of the breast: data from a pooled analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-06.

  • phase iii open label randomized study of Eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane
    Journal of Clinical Oncology, 2015
    Co-Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, E A Perez, Corina E Dutcus, Galina Velikova, Martin Olivo, Javier Cortes
    Abstract:

    Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared Eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive Eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for Eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for Eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for Eribulin and 11.5% for capecitabine. Global health sta...

  • Eribulin monotherapy versus treatment of physician s choice in patients with metastatic breast cancer embrace a phase 3 open label randomised study
    The Lancet, 2011
    Co-Authors: Javier Cortes, Linda T. Vahdat, Joyce Oshaughnessy, David Loesch, Joanne L Blum, Katarina Petrakova, Philippe Chollet, Alexey Manikas, V Dieras, Thierry Delozier
    Abstract:

    Summary Background Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving Eribulin versus currently available treatments. Methods In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to Eribulin mesilate (1·4 mg/m 2 administered intravenously during 2–5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726. Findings 762 women were randomly allocated to treatment groups (508 Eribulin, 254 TPC). Overall survival was significantly improved in women assigned to Eribulin (median 13·1 months, 95% CI 11·8–14·3) compared with TPC (10·6 months, 9·3–12·5; hazard ratio 0·81, 95% CI 0·66–0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on Eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving Eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from Eribulin, occurring in 24 (5%) of 503 patients. Interpretation Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting. Funding Eisai.

Linda T. Vahdat - One of the best experts on this subject based on the ideXlab platform.

  • Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer a randomized phase ii study comparing the incidence of peripheral neuropathy
    Breast Cancer Research and Treatment, 2013
    Co-Authors: Linda T. Vahdat, Agustin A Garcia, Charles L Vogel, Christine M Pellegrino, Deborah Lindquist, Nicholas Iannotti, Prashanth Gopalakrishna, Joseph A Sparano
    Abstract:

    Peripheral neuropathy is a common toxicity associated with tubulin-targeted chemotherapeutic agents. This Phase II study compares the incidence and severity of neuropathy associated with Eribulin mesylate or ixabepilone in metastatic breast cancer (MBC). The primary objective was to assess the incidence of neuropathy; the study was designed to detect a difference in neuropathy rate of 35 % for Eribulin versus 63 % for ixabepilone (odds ratio 0.316, 80 % power, 0.05 two-sided significance level). Eligibility criteria included: MBC; prior taxane therapy; at least one chemotherapy for advanced disease; no or minimal pre-existing neuropathy (Grade 0 or 1). The intent-to-treat population comprised 104 patients randomized (1:1) to Eribulin mesylate (1.4 mg/m2, 2–5 min intravenous on days 1 and 8) or ixabepilone (40 mg/m2, 3 h intravenous on day 1) on a 21-day cycle. 101 patients in the safety population received a median of 5.0 Eribulin and 3.5 ixabepilone cycles. Incidence of neuropathy (any grade) was 33.3 and 48.0 %, and peripheral neuropathy was 31.4 and 44.0 % for Eribulin and ixabepilone, respectively. After controlling for pre-existing neuropathy and number of prior chemotherapies, these differences were not significant. Compared with ixabepilone, fewer patients receiving Eribulin discontinued treatment due to neuropathy (3.9 vs. 18.0 %) or adverse events (AEs) in general (11.8 vs. 32.0 %). Time to onset of neuropathy was 35.9 weeks for Eribulin and 11.6 weeks for ixabepilone, and time to resolution was 48 versus 10 weeks, respectively; other AEs were comparable. Objective responses were 15.4 versus 5.8 % and clinical benefit rates were 26.9 versus 19.2 %. In conclusion, after controlling for pre-existing neuropathy and number of prior chemotherapies, the differences in the incidence of neuropathy with Eribulin and ixabepilone were not statistically significant. Onset of neuropathy tended to occur later with Eribulin and resolve later.

  • Eribulin monotherapy versus treatment of physician s choice in patients with metastatic breast cancer embrace a phase 3 open label randomised study
    The Lancet, 2011
    Co-Authors: Javier Cortes, Linda T. Vahdat, Joyce Oshaughnessy, David Loesch, Joanne L Blum, Katarina Petrakova, Philippe Chollet, Alexey Manikas, V Dieras, Thierry Delozier
    Abstract:

    Summary Background Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving Eribulin versus currently available treatments. Methods In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to Eribulin mesilate (1·4 mg/m 2 administered intravenously during 2–5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726. Findings 762 women were randomly allocated to treatment groups (508 Eribulin, 254 TPC). Overall survival was significantly improved in women assigned to Eribulin (median 13·1 months, 95% CI 11·8–14·3) compared with TPC (10·6 months, 9·3–12·5; hazard ratio 0·81, 95% CI 0·66–0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on Eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving Eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from Eribulin, occurring in 24 (5%) of 503 patients. Interpretation Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting. Funding Eisai.

  • abstract p6 13 02 survival outcomes with Eribulin mesylate vs treatment of the physician s choice tpc in heavily pretreated subjects with locally recurrent or metastatic breast cancer in north america western europe and australia results of the phase iii embrace study
    Cancer Research, 2010
    Co-Authors: Linda T. Vahdat, Chris Twelves, J Wanders, S Seegobin, C Akerele, Jorge E Cortes
    Abstract:

    Background: Eribulin mesylate (E7389) is a nontaxane microtubule dynamics inhibitor. We conducted a randomized, controlled, open-label, phase III study to compare the efficacy and safety of Eribulin vs. TPC in heavily pretreated subjects with locally recurrent or metastatic breast cancer. This report focuses on outcomes for participants enrolled in North America, Western Europe, and Australia (Region 1). Methods: Eligible subjects had locally recurrent or metastatic breast cancer and had received 2-5 prior chemotherapy regimens, including an anthracycline and a taxane, with ≥2 of the regimens given for locally recurrent or metastatic disease. Subjects were stratified by geographic region, HER2/neu status, and prior capecitabine treatment. They were randomized 2:1 to receive Eribulin 1.4 mg/m2 intravenously over 2-5 minutes on Days 1 and 8 every 21 days or an approved TPC. The primary endpoint was overall survival (OS); progression-free survival (PFS) was a secondary endpoint. Results: A total of 762 subjects in 135 centers worldwide were enrolled. Subjects had a median age of 55 years, 92% were white, 76% were postmenopausal, and 81% had taxane-refractory disease. The median time since original diagnosis was 6.7 years. The majority of subjects (488 [64%]) were from Region 1, of whom 325 received Eribulin and 163 received TPC. The most common treatments received by subjects from Region 1 in the TPC arm were vinorelbine (28%), gemcitabine (17%), capecitabine (13%), taxanes (20%), and anthracyclines (12%). 9% of subjects in this region received other therapies. Among the intent-to-treat population in Region 1, median OS was significantly prolonged with Eribulin (13.3 months) vs. TPC (10.2 months) (HR: 0.724; 95% CI: 0.568-0.924; p=0.009). Median PFS was also prolonged with Eribulin (3.3 months) vs. TPC (2.2 months; HR: 0.843; 95% CI: 0.666-1.066; p=0.153) in this population, as assessed by independent reviewers. Conclusion: OS was significantly prolonged in Eribulin-treated patients participating in the EMBRACE trial in the North America, Western Europe, and Australia region. When assessed by independent review, PFS was also prolonged with Eribulin, although this difference did not reach statistical significance for this geographic region. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-13-02.

  • abstract p6 14 18 updated survival analysis of a phase iii study embrace of Eribulin mesylate versus treatment of physician s choice in subjects with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane
    Cancer Research, 2010
    Co-Authors: Chris Twelves, Linda T. Vahdat, J Wanders, Joanne L Blum, S Seegobin, C Akerele, D Loesch, K Petrakova, X Durando, Jorge E Cortes
    Abstract:

    Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mode of action. EMBRACE was the first trial to compare overall survival (OS) of this new chemotherapeutic agent to real-life treatment choices (treatment of physician9s choice; TPC) in heavily pretreated subjects with advanced breast cancer. TPC was any monotherapy (cytotoxic, hormonal, biologic) or supportive care only. It was previously reported that the study met its primary endpoint with a significant improvement in OS by a median of 2.5 months with Eribulin vs. TPC. That primary analysis was based on 422 of 762 events that occurred by May 12, 2009; here we present an updated survival analysis requested by the FDA of the pivotal Phase 3 study through March 3, 2010. Methods: This report is an updated survival analysis based on 589 of 762 (77.3%) events that occurred by March 3, 2010. Data were censored for subjects who were still alive, lost to follow-up, or withdrew consent on or before the date of data cut-off (March 3, 2010). A treatment arm comparison of OS was performed (with geographic region, HER2/neu status and prior capecitabine use as stratification factors for randomization) using a stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to assess the magnitude of the treatment benefit. Results: Seven hundred sixty two women were randomized in the study; 508 to the Eribulin arm and 254 to the TPC arm. 386 (76.0%) events occurred in the Eribulin-treated arm while 203 (79.9%) events were recorded in the TPC-treated group. Nine (1. 8%) Eribulin and 5 (2.0%) TPC patients were lost to follow-up or withdrew consent. OS was significantly longer in the Eribulin treatment arm as compared with the TPC treated arm. (p=0.014; HR 0.805; 95% CI 0.677, 0.958). Median OS was 403 days (13.2 months) compared with 321 days (10.5 months) for TPC. A sensitivity analysis in the following 3 populations showed that the HR was similar to the primary (intent to treat) analysis and the treatment difference was statistically different: population of subjects treated (p = 0.016; HR 0.806; 95% CI 0.676, 0.960), at the cut-off of 572 (75%) deaths (p=0.008; HR 0.787; 95% CI 0.660, 0.939) and with no stratification terms (p=0.024; HR 0.822; 95% CI 0.694, 0.975). Based on the Kaplan-Meier analysis, Eribulin-treated subjects had a 1-yr and 2-yr survival rate estimate of 54.5 and 21.9% compared with 42.8 and 19.2% for TPC, respectively. Conclusions: The OS advantage associated with Eribulin treatment reported in the primary analysis was maintained throughout the observation period. The results of this OS-updated analysis support the initial OS analysis of the pivotal trial EMBRACE, demonstrating the superiority of Eribulin over TPC in heavily pretreated women with advanced breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-18.

  • phase ii study of Eribulin mesylate a halichondrin b analog in patients with metastatic breast cancer previously treated with an anthracycline and a taxane
    Journal of Clinical Oncology, 2009
    Co-Authors: Linda T. Vahdat, B. Pruitt, Carol J. Fabian, Ragene Rivera, David Smith, Elizabeth Tanchiu, Jonathan L Wright, Antoinette R Tan, Noshir Dacosta, Ellen Chuang
    Abstract:

    Purpose Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of Eribulin in heavily pretreated patients with metastatic breast cancer (MBC). Methods MBC patients who were previously treated with an anthracycline and a taxane received Eribulin mesylate (1.4 mg/m2) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of Eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate. Results Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), Eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinica...

Corina E Dutcus - One of the best experts on this subject based on the ideXlab platform.

  • Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer
    'SAGE Publications', 2016
    Co-Authors: Chris Twelves, Javier Cortes, Ahmad Awada, Louise Yelle, Corina E Dutcus, Galina Velikova, Martin S. Olivo, James Song, Peter A Kaufman
    Abstract:

    Purpose and Methods Our secondary analyses compared survival with Eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous Eribulin mesylate 1.4 mg/m 2 on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m 2 on days 1–14 (21-day cycles). Results In the intent-to-treat population (Eribulin 554 and capecitabine 548), overall survival appeared longer with Eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from Eribulin as first-, second-, and third-line chemotherapies. Trial Registration (Primary Study) This study reports the subgroup analyses of Eribulin versus capecitabine from a phase 3, open-label, randomized study ( www.clinicaltrials.gov ; ClinicalTrials.gov identifier: NCT00337103)

  • Subgroup analyses from a phase 3, open-label, randomized study of Eribulin mesylate versus capecitabine in pretreated patients with advanced or metastatic breast cancer
    'SAGE Publications', 2016
    Co-Authors: Twelves C, Cortes J, Corina E Dutcus, Awada A, Yelle L, Velikova G, Olivo Ms, Song J, Pa Kaufman
    Abstract:

    Purpose and methods: Our secondary analyses compared survival with Eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous Eribulin mesylate 1.4 mg/m² on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m² on days 1–14 (21-day cycles). Results: In the intent-to-treat population (Eribulin 554 and capecitabine 548), overall survival appeared longer with Eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions: Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from Eribulin as first-, second-, and third-line chemotherapies

  • phase iii open label randomized study of Eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane
    Journal of Clinical Oncology, 2015
    Co-Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, E A Perez, Corina E Dutcus, Galina Velikova, Martin Olivo, Javier Cortes
    Abstract:

    Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared Eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive Eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for Eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for Eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for Eribulin and 11.5% for capecitabine. Global health sta...

  • abstract s6 6 a phase iii open label randomized multicenter study of Eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes
    Cancer Research, 2012
    Co-Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, E A Perez, J Wanders, Corina E Dutcus
    Abstract:

    Background: Eribulin is a non-taxane microtubule dynamics inhibitor. In a previous Phase III trial, Eribulin demonstrated a statistically significant improvement in overall survival (OS) versus current treatments and a manageable toxicity profile, in heavily pre-treated patients (pts) with metastatic breast cancer (MBC). Here we report results from a Phase III trial of Eribulin compared with capecitabine in earlier-line pts with MBC (NCT00337103). Patients and methods: Pts were randomized 1:1 to Eribulin mesylate 1.4 mg/m 2 given on Days 1 and 8 of a 21 day cycle or capecitabine 2.5 g/m 2 /day administered orally BID on Days 1 to 14 of a 21 day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1 st , 2 nd , or 3 rd line therapy for advanced disease. The co-primary endpoints of this study were OS and progression free survival (PFS): pre-specified statistical significance at final analysis for Eribulin versus capecitabine were p ≤ 0.0372 for OS and p Results: Of 1102 pts, 554 were randomized to Eribulin and 548 capecitabine (375 and 380 pts were HER2[−], respectively). The median age was 54.0 years (range 24–80). Pts received study treatment as their 1 st (27.2%), 2 nd (57.4%) or 3 rd -line (14.7%) chemotherapeutic regimen in the setting of metastatic disease. The median number of treatment cycles was 6 for Eribulin and 5 for capecitabine. Median OS was 15.9 and 14.5 months (hazard ratio [HR] 0.879; 95% confidence intervals [CI] 0.770–1.003; p = 0.056), and PFS (independent review) was 4.1 and 4.2 months (HR 1.079; 95% CI 0.932–1.250; p = 0.305) for Eribulin and capecitabine, respectively. ORR (independent review) were 11.0% (95% CI 8.5–13.9) and 11.5% (95% CI 8.9–14.5; p = 0.849), respectively. OS for HER2(−) pts was 15.9 months for Eribulin and 13.5 months for capecitabine (HR 0.838; 95% CI 0.715–0.983; p = 0.030). AEs were consistent with the known side-effect profiles of both drugs. The most common AEs for Eribulin and capecitabine (>20% all grades) were neutropenia (54.2% vs 15.9%), hand-foot syndrome (0.2% vs 45.1%) alopecia (34.6% vs 4.0%), leukopenia (31.4% vs 10.4%), diarrhea (14.3% vs 28.8%), and nausea (22.2% vs 24.4%), respectively. Conclusion: In this Phase III trial, Eribulin demonstrated a trend favoring improved OS, compared with capecitabine, although this improvement does not meet the pre-defined criteria for statistical significance. This study confirms Eribulin as an active drug in pts with MBC, and exploratory analyses suggest possible benefits of Eribulin in specific subsets of pts, sufficient to warrant further study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-6.

Peter A Kaufman - One of the best experts on this subject based on the ideXlab platform.

  • Subgroup Analyses from a Phase 3, Open-Label, Randomized Study of Eribulin Mesylate versus Capecitabine in Pretreated Patients with Advanced or Metastatic Breast Cancer
    'SAGE Publications', 2016
    Co-Authors: Chris Twelves, Javier Cortes, Ahmad Awada, Louise Yelle, Corina E Dutcus, Galina Velikova, Martin S. Olivo, James Song, Peter A Kaufman
    Abstract:

    Purpose and Methods Our secondary analyses compared survival with Eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous Eribulin mesylate 1.4 mg/m 2 on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m 2 on days 1–14 (21-day cycles). Results In the intent-to-treat population (Eribulin 554 and capecitabine 548), overall survival appeared longer with Eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. Conclusions Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from Eribulin as first-, second-, and third-line chemotherapies. Trial Registration (Primary Study) This study reports the subgroup analyses of Eribulin versus capecitabine from a phase 3, open-label, randomized study ( www.clinicaltrials.gov ; ClinicalTrials.gov identifier: NCT00337103)

  • phase iii open label randomized study of Eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane
    Journal of Clinical Oncology, 2015
    Co-Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, E A Perez, Corina E Dutcus, Galina Velikova, Martin Olivo, Javier Cortes
    Abstract:

    Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared Eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive Eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for Eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for Eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for Eribulin and 11.5% for capecitabine. Global health sta...

  • abstract s6 6 a phase iii open label randomized multicenter study of Eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes
    Cancer Research, 2012
    Co-Authors: Peter A Kaufman, Ahmad Awada, Chris Twelves, Louise Yelle, E A Perez, J Wanders, Corina E Dutcus
    Abstract:

    Background: Eribulin is a non-taxane microtubule dynamics inhibitor. In a previous Phase III trial, Eribulin demonstrated a statistically significant improvement in overall survival (OS) versus current treatments and a manageable toxicity profile, in heavily pre-treated patients (pts) with metastatic breast cancer (MBC). Here we report results from a Phase III trial of Eribulin compared with capecitabine in earlier-line pts with MBC (NCT00337103). Patients and methods: Pts were randomized 1:1 to Eribulin mesylate 1.4 mg/m 2 given on Days 1 and 8 of a 21 day cycle or capecitabine 2.5 g/m 2 /day administered orally BID on Days 1 to 14 of a 21 day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1 st , 2 nd , or 3 rd line therapy for advanced disease. The co-primary endpoints of this study were OS and progression free survival (PFS): pre-specified statistical significance at final analysis for Eribulin versus capecitabine were p ≤ 0.0372 for OS and p Results: Of 1102 pts, 554 were randomized to Eribulin and 548 capecitabine (375 and 380 pts were HER2[−], respectively). The median age was 54.0 years (range 24–80). Pts received study treatment as their 1 st (27.2%), 2 nd (57.4%) or 3 rd -line (14.7%) chemotherapeutic regimen in the setting of metastatic disease. The median number of treatment cycles was 6 for Eribulin and 5 for capecitabine. Median OS was 15.9 and 14.5 months (hazard ratio [HR] 0.879; 95% confidence intervals [CI] 0.770–1.003; p = 0.056), and PFS (independent review) was 4.1 and 4.2 months (HR 1.079; 95% CI 0.932–1.250; p = 0.305) for Eribulin and capecitabine, respectively. ORR (independent review) were 11.0% (95% CI 8.5–13.9) and 11.5% (95% CI 8.9–14.5; p = 0.849), respectively. OS for HER2(−) pts was 15.9 months for Eribulin and 13.5 months for capecitabine (HR 0.838; 95% CI 0.715–0.983; p = 0.030). AEs were consistent with the known side-effect profiles of both drugs. The most common AEs for Eribulin and capecitabine (>20% all grades) were neutropenia (54.2% vs 15.9%), hand-foot syndrome (0.2% vs 45.1%) alopecia (34.6% vs 4.0%), leukopenia (31.4% vs 10.4%), diarrhea (14.3% vs 28.8%), and nausea (22.2% vs 24.4%), respectively. Conclusion: In this Phase III trial, Eribulin demonstrated a trend favoring improved OS, compared with capecitabine, although this improvement does not meet the pre-defined criteria for statistical significance. This study confirms Eribulin as an active drug in pts with MBC, and exploratory analyses suggest possible benefits of Eribulin in specific subsets of pts, sufficient to warrant further study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-6.