title: Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter Phase II trial.
abstract: We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ).
  
  
  
  Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure-response analysis was undertaken.
  
  
  
  Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69-1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure-response analysis indicated that patients with higher ramucirumab exposure had longer OS.
  
  
  
  The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population.
  
  
  
  NCT01246960.
authors.affiliation: Medical Oncology, Mayo Clinic, Rochester, MN yoon.harry@mayo.edu.
authors.forename: H H
authors.initials: HH
authors.lastname: Yoon
authors.affiliation: GI Cancer Research Program, Sarah Cannon Research Institute, Tennessee Oncology, Nashville.
authors.forename: J C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas.
authors.forename: F S
authors.initials: FS
authors.lastname: Braiteh
authors.affiliation: Medical Oncology, Sarah Cannon Research Institute/Oncology Hematology Care, Inc., Cincinnati.
authors.forename: I
authors.initials: I
authors.lastname: Firdaus
authors.affiliation: Department of Oncology, Barbara Ann Karmanos Cancer Institute/Wayne State University, Detroit.
authors.forename: P A
authors.initials: PA
authors.lastname: Philip
authors.affiliation: Medical Oncology, Rocky Mountain Cancer Centers/US Oncology, Denver.
authors.forename: A L
authors.initials: AL
authors.lastname: Cohn
authors.affiliation: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia.
authors.forename: N
authors.initials: N
authors.lastname: Lewis
authors.affiliation: Department of Hematology, Oncology and Transplantation, Metro-Minnesota Community Clinical Oncology Program, St. Louis Park.
authors.forename: D M
authors.initials: DM
authors.lastname: Anderson
authors.affiliation: Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology, Chattanooga.
authors.forename: E
authors.initials: E
authors.lastname: Arrowsmith
authors.affiliation: Oncology, Eli Lilly and Company, Bridgewater.
authors.forename: J D
authors.initials: JD
authors.lastname: Schwartz
authors.affiliation: Oncology, Eli Lilly and Company, Bridgewater.
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.affiliation: Oncology, Eli Lilly and Company, Bridgewater.
authors.forename: Y
authors.initials: Y
authors.lastname: Hsu
authors.affiliation: Oncology, Eli Lilly and Company, Bridgewater.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Oncology, Eli Lilly and Company, Bridgewater.
authors.forename: D
authors.initials: D
authors.lastname: Ferry
authors.affiliation: Medical Oncology, Mayo Clinic, Rochester, MN.
authors.forename: S R
authors.initials: SR
authors.lastname: Alberts
authors.affiliation: Division of Hematology Oncology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
authors.forename: Z A
authors.initials: ZA
authors.lastname: Wainberg
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004943:Esophagogastric Junction / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D013274:Stomach Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D000096662:Ramucirumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005472:Fluorouracil; D002955:Leucovorin; D009944:Organoplatinum Compounds; D000096662:Ramucirumab
keywords: esophageal cancer; gastric cancer; gastroesophageal junction; ramucirumab; vascular endothelial growth factor