Feasibility and Efficacy of Eribulin Mesilate in Korean Patients with Metastatic Breast Cancer: Korean Multi-center Phase IV Clinical Study Results.
ABSTRACT: Eribulin mesilate was approved for the treatment of patients with locally advanced or metastatic breast cancer (MBC), who had received at least two chemotherapeutic regimens, including anthracycline and taxane. On the other hand, the efficacy and safety information of eribulin in Korean patients is limited by the lack of clinical trials.In this multicenter, open-label, single-arm, phase IV study, locally advanced or MBC patients were enrolled between June 2013 and April 2014 from 14 centers in Korea. One point four mg/m2 dose of eribulin was administered on days 1 and 8 of every 21 days. The primary endpoint was the frequency and intensity of the treatment emergent adverse event. The secondary endpoint was the disease control rate, which included the rate of complete responses, partial responses, and stable disease.A total of 101 patients received at least one dose of eribulin and were included in the safety set. The patients received a total of 543 treatment cycles, with a median of three cycles (range, 1 to 31 cycles). The most common adverse event was neutropenia (91.1% of patients, 48.3% of cycles). The frequent non-hematological adverse events included alopecia, decrease in appetite, fatigue/asthenia, and myalgia/arthralgia. The peripheral neuropathy of any grade occurred in 27 patients (26.7%), including grade 3 in two patients. Disease control rate was 52.7% and 51.3% of patients in the full analysis set and per-protocol set, respectively.This study demonstrated the feasible safety profile and activity of eribulin in Korean patients with MBC.
Project description: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/m2 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/m2 day 1 for schedule 1 and 1.4?mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4?mg/m2 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.
Project description:PURPOSE:Approval of eribulin for metastatic breast cancer was based on data primarily from Western patients, and there is a paucity of data on the effectiveness and safety of eribulin for Asian patients. To determine the effectiveness and safety of eribulin in Korean women with breast cancer in a real-world setting, we conducted a nationwide, multicenter, retrospective study. METHODS:Patients with locally advanced or metastatic breast cancer who were treated with eribulin in 14 centers throughout Korea were included in this study. Eribulin was generally administered at a dose of 1.23 mg/m2 (equivalent to 1.4 mg/m2 eribulin mesylate) by intravenous infusion for 2-5 min, or as a diluted solution, on Days 1 and 8 of every 21-day cycle. The primary endpoint was progression-free survival (PFS) rate at 6 months. Secondary endpoints included median PFS, overall survival (OS), time-to-treatment failure (TTF), tumor response rate, and incidence of hematologic treatment-emergent adverse events (TEAEs). RESULTS:The safety and full analysis populations included 398 and 360 (38 had no efficacy data) patients, respectively. The PFS rate at 6 months was 37.8%. Median PFS, OS, and TTF were 134, 631, and 120 days, respectively. Objective response rate, clinical benefit rate, and disease control rate were 18.1%, 50.6%, and 49.4%, respectively. Hematologic TEAEs were reported in 65.1% of patients; neutropenia (56.8%) and anemia (11.3%) were most common. CONCLUSION:Real-world effectiveness and safety of eribulin in Korean breast cancer patients were consistent with previous reports; no new safety concerns were identified.
Project description:BACKGROUND:A phase II clinical trial of the comparison between eribulin plus gemcitabine (EG) and paclitaxel plus gemcitabine (PG) as first-line chemotherapy for patients with metastatic breast cancer (MBC) found that the EG regimen was less neurotoxic, but was similar in efficacy to the PG regimen. In the present study, we analyzed functional assessment of cancer therapy-taxane (FACT-Taxane) questionnaires from patients in this clinical trial to determine their quality of life (QoL). METHODS:QoL was assessed using the Korean version of the FACT-Taxane questionnaires. After baseline assessment, QoL was assessed every 2 cycles for 12 cycles and every 3 cycles thereafter. The linear mixed model was used to evaluate the difference in QoL between the EG and PG arms. RESULTS:Of the 118 enrolled patients, 117 responded to the FACT-Taxane questionnaires at baseline, 1 in the PG arm did not. Baseline QoL scores were not different between the EG and PG arms. During treatment, taxane subscale scores were significantly higher in the PG arm than in the EG arm after 2-13 cycles of chemotherapy (all P < 0.05), except for the 11th cycle. Neuropathy-specific analysis showed that patients in the PG arm had earlier and more severe neuropathic symptoms than those in the EG arm (P < 0.001). CONCLUSIONS:In our QoL analysis, the EG regimen delayed and decreased neuropathy as compared with the PG regimen. Therefore, eribulin would be a reasonable substitute for paclitaxel as first-line chemotherapy for MBC.
Project description:This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC).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).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 status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2.In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.
Project description:Background:In real-world practice, eribulin mesylate provides significant survival benefit, with a manageable safety profile in heavily pretreated patients with metastatic breast cancer (MBC). Methods:In this prospective, open-label, multicentre, observational study we evaluated the effectiveness and tolerability of eribulin as third-line treatment in a homogeneous population. The primary endpoints were the safety profile and response in metastatic sites; secondary endpoints included the response in different subtypes, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results:From 2013 to 2016, 118 women were treated in 21 Sicilian institutions; the median age was 58?years (range 29-79), with 69% of patients under 65. The median cycles of eribulin were 5.5 (range 1-26). The most common adverse event was neutropenia (9.3%, 3 cases of grade 3, 4 of grade 4); only 1 case of QT prolongation was reported. Eribulin was effective in controlling metastatic disease in all sites, and it achieved the highest ORR in brain (16%) and liver (14.9%). Median OS was 31.8?months (95% CI 27.9-34.4) and median PFS 5.5?months (95% CI 4.2-6.6). PFS was 5.2?months (95% CI 2.8-8.4) in patients with triple-negative subtype. Median PFS was longer in patients over 65?years (6.1?months, 95% CI 4.4-8.3). In patients who had visceral metastases PFS was 5.5?months (95% CI 95% 3.5-6.6) and OS 33.9?months (95% CI 29.8-40.8). Conclusions:Eribulin as third-line treatment shows an acceptable safety profile and a substantial antitumour activity in the treatment of MBC, even in elderly patients and in those with visceral disease.
Project description:BACKGROUND:This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. METHODS:Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ? 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. RESULTS:Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. CONCLUSION:This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. CLINICAL TRIAL REGISTRATION:University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491).
Project description:Background: Previous prospective studies have shown that eribulin improves the survival in patients with metastatic breast cancer (MBC). However, the optimal timing of its administration to achieve the longest extended survival and the efficacy of using eribulin monotherapy as earlier-line chemotherapy are yet unclear. Methods: We identified all consecutive female patients with MBC who received any chemotherapeutic intervention for metastatic disease at our institution between July 2012 and December 2017, excluding patients with HER2-positive disease. Those who received eribulin monotherapy for MBC were classified under the eribulin cohort, whereas those who never received eribulin were included in the non-eribulin (Non-E) cohort. Among the patients in the eribulin cohort, those who received eribulin as the first- or second-line chemotherapy for MBC were further classified under the earlier-line eribulin (EE), and otherwise classified under the later-line eribulin (LE) cohorts. The survival of patients was assessed using the log-rank test. A multivariable Cox proportional hazards model was used to assess the independent efficacy and timing of eribulin monotherapy. The inverse probability of treatment weighting (IPTW) estimate was utilized to compare the EE and LE cohorts. Results: Of the 507 patients who were initially screened, 226 were included after an intensive chart review: 93, 49, and 84 patients were included in the Non-E, EE, and LE cohorts, respectively. The eribulin cohort showed significantly longer overall survival than the Non-E cohort (30.3 vs. 22.2 months, p = 0.0217). No significant difference was observed in the progression-free survival of the EE and LE cohorts (3.4 vs. 4.4 months, p = 0.1337) after adjusting for clinically relevant factors using IPTW estimates. LE cohort showed good overall survival (OS) compared with patient group of Non-E and EE by log-rank testing (p = 0.0398), although multivariate analysis did not demonstrate eribulin administration timing as an independent prognostic factor of OS. OS was defined from the initiation of first-line chemotherapy date. Conclusions: Our data provided additional insights regarding the use of eribulin monotherapy as earlier-line chemotherapy. However, the optimal timing of eribulin monotherapy for MBC was not determined in the current study.
Project description:PURPOSE:Dose-dense chemotherapy (DD-CT) is a preferred (neo)adjuvant regimen in early breast cancer (BC). Although the results of reported randomized trials are conflicting, a recent metaanalysis showed improved overall and disease-free survival with DD-CT compared to conventional schedules. However, no DD-CT safety data for Korean BC patients are available. This phase II study was conducted to evaluate the safety and efficacy of pegteograstim in Korean BC patients receiving DD-CT. Materials and Methods:Patients with operable (stage I-III), histologically confirmed BC received four cycles of intravenous doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 every 2 weeks as neoadjuvant or adjuvant therapy. Pegteograstim (6.0 mg) was administered subcutaneously on day 2 of each cycle. The primary endpoint was the incidence of febrile neutropenia (FN). The secondary endpoints were safety and tolerability. RESULTS:Of 63 patients, one (1.6%) developed FN during all cycles of DD-CT. Dose delay was observed in four patients (6.3%) and dose reduction in two (3.2%) during DD-CT. Frequent adverse events (AEs) were nausea, alopecia, generalized muscle weakness, myalgia, mucositis, anorexia, dyspepsia, and diarrhea; most AEs were related to chemotherapy. Grade 3-4 AEs were reported in five of 63 patients (7.9%), and all grade 3 and 4 AEs were related to chemotherapy. Adverse drug reactions possibly linked to pegteograstim were abdominal pain, bone pain, myalgia, generalized muscle weakness, and headache in five of 63 patients (7.9%). CONCLUSION:Dose-dense AC (doxorubicin/cyclophosphamide) chemotherapywith pegteograstim support is a tolerable and safe regimen in Korean early BC patients.
Project description:BACKGROUND:Eribulin has significantly improved overall survival for patients with metastatic breast cancer who received ? 2 prior chemotherapy regimens for advanced disease. This trial assessed eribulin as adjuvant therapy for patients with early-stage breast cancer. PATIENTS AND METHODS:Patients with human epidermal growth factor receptor 2-negative, stage I to III breast cancer received doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 provided intravenously on day 1 of each 14-day cycle for 4 cycles, with pegfilgrastim on day 2, followed by 4 cycles of eribulin mesylate 1.4 mg/m2 provided intravenously on days 1 and 8 every 21 days. There were 2 cohorts, as follows: cohort 1: no prophylactic growth factor with eribulin (allowed at physician's discretion only); cohort 2: prophylactic filgrastim with eribulin. The primary end point was feasibility, defined as the percentage of patients who completed the eribulin portion of the regimen without a dose omission, delay, or reduction due to an eribulin-related adverse event. Relative dose intensity of eribulin and toxicities are summarized by cohort. Exploratory end points included 3-year disease-free survival and overall survival. RESULTS:Eighty-one patients (cohort 1, n = 55; cohort 2, n = 26) entered the treatment phase; 88% completed treatment. Feasibility was 72.9 % (90% confidence interval, 60.4, 83.2) in cohort 1 and 60.0% (90% confidence interval, 41.7, 76.4) in cohort 2. The most frequent eribulin-related adverse events (all grades) were fatigue (75.9%), peripheral neuropathy (54.4%), nausea (39.2%), neutropenia (35.4% [31.5% of patients in cohort 1; 44.0% in cohort 2]), and arthralgia (26.6%). CONCLUSION:The primary end point of > 80% feasibility was not met. No unexpected adverse events were observed, and 62% of patients received full dosing with no dose delay or reduction. Further investigation of this regimen with alternative dosing schedules or use of growth factors could be considered.
Project description:Eribulin, an antimicrotubule chemotherapeutic agent, is approved for the treatment of pretreated metastatic breast cancer (mBC) based on the positive outcomes of phase II and phase III clinical trials, which enrolled mainly Western patients. Eribulin has recently been approved in an increasing number of Asian countries; however, there is limited clinical experience in using the drug in certain countries. Therefore, we established an Asian working group to provide practical guidance for eribulin use based on our clinical experience. This paper summarizes the key clinical trials, and the management recommendations for the reported adverse events (AEs) of eribulin in mBC treatment, with an emphasis on those that are relevant to Asian patients, followed by further elaboration of our eribulin clinical experience. It is anticipated that this clinical practice guide will improve the management of AEs resulting from eribulin treatment, which will ensure that patients receive the maximum treatment benefit.