title: Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial.
abstract: Utidelone, a genetically engineered epothilone analogue, has shown promise as a potential treatment for breast cancer in phase 1 and 2 trials. The aim of this phase 3 trial was to compare the efficacy and safety of utidelone plus capecitabine versus capecitabine alone in patients with metastatic breast cancer.
  
  
  
  We did a multicentre, open-label, superiority, phase 3, randomised controlled trial in 26 hospitals in China. Eligible participants were female patients with metastatic breast cancer refractory to anthracycline and taxane chemotherapy regimens. We randomly assigned participants (2:1) using computer based randomisation and block sizes of 6 to a 21-day cycle of either utidelone (30 mg/m2intravenously once per day on days 1-5) plus capecitabine (1000 mg/m2orally twice per day on days 1-14), or capecitabine alone (1250 mg/m2orally twice per day on days 1-14), until disease progression or unacceptable toxicity occurred. Patients, physicians, and assessors were not masked to treatment allocation; however, an independent radiology review committee used to additionally assess response was masked to allocation. The primary endpoint was centrally assessed (by an independent radiology review committee) progression-free survival, and analysed using the Kaplan-Meier product-limit method in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. Follow-up is ongoing. This study is registered at ClinicalTrials.gov, number NCT02253459.
  
  
  
  Between Aug 8, 2014, and Dec 14, 2015, we enrolled and randomly assigned 270 patients to treatment with utidelone plus capecitabine, and 135 to capecitabine alone. Median follow-up for progression-free survival was 6·77 months (IQR 3·81-10·32) for the utidelone plus capecitabine group and 4·55 months (2·55-9·39) for the capecitabine alone group. Median progression-free survival by central review in the utidelone plus capecitabine group was 8·44 months (95% CI 7·95-9·92) compared with 4·27 months (3·22-5·68) in the capecitabine alone group; hazard ratio 0·46, 95% CI 0·36-0·59; p<0·0001. Peripheral neuropathy was the most common grade 3 adverse event in the utidelone plus capecitabine group (58 [22%] of 267 patients vs 1 [<1%] of 130 patients in the capecitabine alone group). Palmar-plantar erythrodysaesthesia was the most prominent grade 3 adverse event in the capacitabine alone group (in 10 [8%] of 130 patients) and was the next most frequent grade 3 event in the utidelone plus capecitabine group (in 18 [7%] of 267 patients). 16 serious adverse events were reported in the combination therapy group (diarrhoea was the most common, in three [1%] patients) and 14 serious adverse events were reported in the monotherapy group (the most common were diarrhoea, increased blood bilirubin, and anaemia, in two [2%] patients for each event). 155 patients died (99 in the combination therapy arm, 56 in the monotherapy arm). All deaths were related to disease progression except for one in each group (attributed to pericardial effusion in the combination therapy group and dyspnoea in the monotherapy group) that were considered possibly or probably treatment-related.
  
  
  
  Despite disease progression with previous chemotherapies, utidelone plus capecitabine was more efficacious compared with capecitabine alone for the outcome of progression-free survival, with mild toxicity except for peripheral sensory neuropathy, which was manageable. The findings from this study support the use of utidelone plus capecitabine as an effective option for patients with metastatic breast cancer.
  
  
  
  Beijing Biostar Technologies, Beijing, China.
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Pin
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Liaoning Cancer Hospital and Institute, Shenyang, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: The 307th Hospital of Chinese PLA, Beijing, China.
authors.forename: Zefei
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Zhejiang Cancer Hospital, Hangzhou, China.
authors.forename: Xiao Jia
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Breast Cancer Center, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Shude
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China.
authors.forename: Yuee
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Fudan University Cancer Center, Shanghai, China.
authors.forename: Xi-Chun
authors.initials: XC
authors.lastname: Hu
authors.affiliation: The 301st Hospital of Chinese PLA, Beijing, China.
authors.forename: Junlan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Breast Oncology, Tianjin Medical University Cancer Hospital, Tianjin, China.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Tong
authors.affiliation: Peking University Cancer Hospital, Beijing, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Li
authors.affiliation: Nankai University Tianjin People's Hospital, Tianjin, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Qingdao University Yantai Yuhuangding Hospital, Yantai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Sun
authors.affiliation: Sichuan University West China Hospital, Chengdu, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Tongji Medical College Wuhan Union Hospital, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Shanghai Jiaotong University Renji Hospital, Shanghai, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Nantong Tumor Hospital, Nantong, China.
authors.forename: Baochun
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Hebei Medical University Tumor Hospital, Shijiazhuang, China.
authors.forename: Cuizhi
authors.initials: C
authors.lastname: Geng
authors.affiliation: Fujian Medical University Cancer Hospital, Fuzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Roujun
authors.initials: R
authors.lastname: Peng
authors.affiliation: Breast Cancer Center, Henan Cancer Hospital, Zhengzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: The 307th Hospital of Chinese PLA, Beijing, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Zhejiang Cancer Hospital, Hangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Beijing Biostar Technologies, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: Beijing Biostar Technologies, Beijing, China.
authors.forename: Rongguo
authors.initials: R
authors.lastname: Qiu
authors.affiliation: Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: bhxu@hotmail.com.
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D000069287:Capecitabine / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D034261:Epothilones / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D018943:Anthracyclines; D001952:Bridged-Ring Compounds; D034261:Epothilones; D043823:Taxoids; C080625:taxane; D000069287:Capecitabine