title: Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial.
abstract: Weekly administration of solvent-based paclitaxel is one of the standard second-line chemotherapy regimens for advanced gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed to improve the solubility of paclitaxel and does not need premedication to avoid infusion-related reactions associated with solvent-based paclitaxel. Additionally, higher doses of nab-paclitaxel can be administered over a shorter infusion time and at higher drug concentrations compared with solvent-based paclitaxel. We aimed to investigate the efficacy and safety of nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer.
  
  
  
  We did a randomised, open-label, non-inferiority, phase 3 trial at 72 institutions in Japan. Patients aged 20 years or older with advanced gastric adenocarcinoma refractory to a fluoropyrimidine-containing first-line chemotherapy regimen, with progressive disease or a relapse fewer than 24 weeks after the final dose of adjuvant chemotherapy were randomly assigned (1:1:1) to receive intravenous nab-paclitaxel (260 mg/m2) every 3 weeks (on day 1 of a 21-day cycle), weekly nab-paclitaxel (100 mg/m2, on days 1, 8, and 15 of a 28-day cycle), or weekly solvent-based paclitaxel (80 mg/m2, on days 1, 8, and 15 of a 28-day cycle). Randomisation was done with the minimisation method, with stratification for previous use of docetaxel, presence of peritoneal metastases, and Eastern Cooperative Oncology Group (ECOG) performance status. The primary endpoint was overall survival in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, with a non-inferiority margin of 1·25 for the hazard ratio. This trial is registered with Japan Pharmaceutical Information Center Clinical Trial, number JapicCTI-132059, and has been completed.
  
  
  
  Between March 13, 2013, and May 14, 2015, 741 patients were randomly assigned to nab-paclitaxel every 3 weeks (n=247), weekly nab-paclitaxel (n=246), or weekly solvent-based paclitaxel (n=248). Median follow-up for overall survival was 9·99 months (IQR 6·05-15·05). Median overall survival was 10·3 months (95% CI 8·7-11·4) in the group that received in the nab-paclitaxel every 3 weeks, 11·1 months (9·9-13·0) in the weekly nab-paclitaxel group, and 10·9 months (9·4-11·8) in the weekly solvent-based paclitaxel group. Weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel (hazard ratio 0·97, 97·5% CI 0·76-1·23; non-inferiority one-sided p=0·0085), whereas nab-paclitaxel every 3 weeks was not non-inferior to solvent-based paclitaxel (1·06, 95% CI 0·87-1·31; non-inferiority one-sided p=0·062). The main grade 3 or worse adverse drug reactions were neutropenia (158 [65%] of 244 patients in the group that received nab-paclitaxel every 3 weeks vs 99 [41%] of 241 patients in the weekly nab-paclitaxel group vs 71 [29%] of 243 patients in the weekly solvent-based paclitaxel group), peripheral sensory neuropathy (49 [20%] vs six [2%] vs six [2%]), and febrile neutropenia (30 [12%] vs seven [3%] vs two [1%]). Hypersensitivity reactions were less frequent with nab-paclitaxel every 3 weeks (two [1%] patients) and weekly nab-paclitaxel (three [1%] patients) than with weekly solvent-based paclitaxel (13 [5%] patients). Four treatment-related deaths were reported overall (pneumonia in one patient in the group that received nab-paclitaxel every 3 weeks, febrile neutropenia/pneumonia in one patient, and septic shock in one patient in the weekly nab-paclitaxel group, and respiratory disease/interstitial lung disease in one patient in the weekly solvent-based paclitaxel group).
  
  
  
  As the trial showed that weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel in terms of overall survival, the advantages of the nab-paclitaxel formulation make it a potential regimen for second-line treatment of gastric cancer.
  
  
  
  Taiho Pharmaceutical.
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address: kshitara@east.ncc.go.jp.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Takashima
authors.affiliation: Department of Surgery, Osaka General Medical Center, Osaka, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Fujitani
authors.affiliation: Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Koeda
authors.affiliation: Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Norisuke
authors.initials: N
authors.lastname: Nakayama
authors.affiliation: Clinical Trial Promotion Department, Chiba Cancer Center, Chiba, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hironaka
authors.affiliation: Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nishikawa
authors.affiliation: Department of Surgery, Sakai City Medical Center, Sakai, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Makari
authors.affiliation: Department of Gastroenterology, Ibaraki Central Hospital, Kasama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Amagai
authors.affiliation: Department of Medical Oncology, Kindai University Nara Hospital, Ikoma, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimodaira
authors.affiliation: Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishina
authors.affiliation: Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kurokawa
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, Sayama, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Institute of Molecular Oncology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000368:Aged; D000418:Albumins / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D000074099:Equivalence Trials as Topic; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D012997:Solvents; D013274:Stomach Neoplasms / Q000188:drug therapy*; D016019:Survival Analysis
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D012997:Solvents; D017239:Paclitaxel