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Objective: The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy.Methods: We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL.Results: Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia.Conclusions: We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses.Trial Registration Number: C000000416. [ABSTRACT FROM AUTHOR]

Purpose: This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC).Methods: In this open-label, nonrandomized, two-cohort, dose-escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (≈1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day -5 (fasting state) and day -2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide.Results: Of 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced ≥1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug-related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade ≥4 DR-TEAEs or new safety signals were observed. C max and AUC (0-t last) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean C max increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0-t last) increased 2.5-fold after both doses under fed conditions.Conclusions: Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients. [ABSTRACT FROM AUTHOR]

Background: Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting.Methods: We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416).Findings: Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9-44·4). Median overall survival was 35·0 months (95% CI 31·1-39·0) in the S-1 group and 37·2 months (33·0-40·1) in the taxane group (HR 1·05 [95% CI 0·86-1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group.Interpretation: S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer.Funding: Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho. [ABSTRACT FROM AUTHOR]

Purpose: This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment.Methods: Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m(2) weekly.Results: Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m(2)) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m(2) and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m(2) allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug-drug interactions.Conclusions: Afatinib 40 mg QD plus vinorelbine 25 mg/m(2) weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients. [ABSTRACT FROM AUTHOR]

Background: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer.Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969.Findings: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis.Interpretation: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer.Funding: Public Health Research Foundation (Japan), Taiho Pharmaceutical. [ABSTRACT FROM AUTHOR]