Key inclusion criteria included: female patients with histologically confirmed HER2-negative MBC (including patients with unresectable advanced disease); aged ≥20 and <75 years; no history of chemotherapy for MBC other than peri-operative therapy (patients who received hormone therapy, immunotherapy, or local radiotherapy for MBC could be included in this trial); at least 6 months since the last administration of neoadjuvant or adjuvant chemotherapy; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; having measurable lesion(s) based on the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 (New response evaluation criteria in solid tumours 2009); and adequate bone marrow, liver, renal, and lung functions. Key exclusion criteria included: hypersensitivity to eribulin; systemic infection; uncontrolled pleural effusion/ascites or pericardial effusion; symptomatic brain tumor; serious complications, active concomitant malignancy; pregnancy (including possible pregnancy) of premenopausal women. Patients who were considered ineligible by the investigator were also excluded.
This was a phase II, open-label, single-arm, multicenter trial conducted at eight sites in Japan. The study protocol and all amendments were approved by local ethics committees or the institutional review board at each study site. This trial was conducted in accordance with the Japanese Guidelines for Clinical Research of the Ministry of Health, Labor and Welfare and the Declaration of Helsinki, as well as other applicable regulatory requirements. All participants provided written informed consent prior to study entry. The present trial has been registered with the University Hospital Medical Information Network (UMIN) Center (ID: UMIN000006086). This was an investigator-initiated clinical trial that was not supported by any industry funding, nor requested by any organization.
Eribulin was administered intravenously, without any premedication, at a dose of 1.4 mg/m2 over 2–5 min on days 1 and 8 of a 21-day cycle (2-weeks-on, 1-week-off). For patients who were not eligible for administration of eribulin on day 8 (i.e., neutrophil count <1000/mm3, platelet count <75,000/mm3, ≤grade 2 non-hematological adverse events), the next cycle started on day 22. The dose was reduced to 1.1 mg/m2 if one of the following had occurred during the previous cycle: neutrophil count <500/mm3 for more than 7 days; presence of febrile neutropenia; grade 4 thrombocytopenia; and grade 3 or higher non-hematological toxicity. The dose was further reduced to 0.7 mg/m2 if there was a toxicity as described above despite dose reduction to 1.1 mg/m2. Patients who were refractory to eribulin were able to continue treatment based on the choice of the investigator. Concomitant use of other anticancer therapy (e.g., hormone therapy, targeted therapy, immune therapy, and chemotherapy other than eribulin) and any local therapy was prohibited. Concomitant use of bone modifying agents was permitted if the agents had been used since prior to the study entry. Use of granulocyte colony-stimulating factor was permitted, but not for prophylactic administration, by decision of the investigator based on the clinical practice guideline (Smith et al. 2006).
The primary efficacy outcome was overall response rate (ORR), defined as the proportion of patients who achieved a complete response (CR) plus those who achieved a partial response (PR). The secondary endpoints included progression-free survival (PFS), OS, time to treatment failure (TTF), and safety. Time to response and duration of response were also assessed.
The information on patients’ characteristics at baseline was collected within 28 days prior to the initiation of eribulin administration. Baseline tumor assessments by radiographic evaluation (e.g., computerized tomography or magnetic resonance imaging scans) were also performed within 28 days prior to the initiation of eribulin administration, and tumor assessments were performed by the same methods every 2 cycles thereafter. Tumor assessments were analyzed based on the RECIST ver. 1.1 and classified as CR, PR, stable disease (SD), progressive disease, or not evaluable. Tumor response was confirmed at least 4 weeks after the criteria for response were met. PFS was defined as the time from initiation of eribulin to disease progression or death from any cause, OS was defined as the time from initiation of eribulin to death from any cause, and TTF was defined as the time from initiation of eribulin to treatment discontinuation for any reason (e.g., disease progression, treatment toxicity, patient preference, or death). Time to response was the time from initiation of eribulin to documentation of tumor response and duration of response was defined as the time from documentation of tumor response to disease progression, which was assessed among patients who reached ORR. For safety, adverse events, physical examination, vital signs, laboratory tests, and tumor markers (i.e., carcinoembryonic antigen and breast cancer antigen 15-3) were assessed during the study. All adverse events were graded according to the Common Terminology Criteria for Adverse Events ver. 4.0 (CTEP 2015).
The following assumptions were made to determine target enrollment. In the EMBRACE study (Cortes et al. 2011), ORR for patients who received eribulin after a median of four previously administered regimens was 12 %. In addition, ORR of nanoparticle albumin-bound paclitaxel and paclitaxel for MBC was reported as 33 and 19 %, respectively, in all patients and 42 and 27 %, respectively, in the subgroup (40 % of the full cohort) who received those agents as first-line therapy in the phase III trial (Gradishar et al. 2005). Based on those results, we set threshold and expected values of ORR as 20 and 40 %, respectively. To meet the threshold and expected values of ORR with 80 % power and one-sided alpha error of 0.05, at least 32 patients were needed. Thus, we aimed to enroll 35 patients with the expectation of approximately 10 % ineligible patients.
Primary efficacy outcome (proportion of patients who achieved CR or PR for at least 4 weeks) was assessed in the full analysis set, which included all patients who received at least one dose of eribulin. In addition, clinical benefit rate (CBR) was defined as the proportion of patients who achieved CR, PR, or SD for at least 24 weeks. The median values with 95 % confidence interval (CI) for PFS, and OS curves were estimated with the Kaplan–Meier method. TTF, time to response, and duration of response were presented as median values with ranges. The safety analysis was also conducted in the full analysis set. All statistical analyses were one-sided, and probability values of <0.05 were considered to indicate a statistically significant difference.