title: Sorafenib in combination with oxaliplatin, leucovorin, and fluorouracil (modified FOLFOX6) as first-line treatment of metastatic colorectal cancer: the RESPECT trial.
abstract: OBJECTIVE
  This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC).
  
  
  METHODS
  Patients were randomized to sorafenib (400 mg b.i.d.) or placebo, combined with mFOLFOX6 (oxaliplatin 85 mg/m(2); levo-leucovorin 200 mg/m(2); fluorouracil 400 mg/m(2) bolus and 2400 mg/m(2) continuous infusion) every 14 days. Primary endpoint was progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power (two-sided α = 0.20) to detect an HR = 0.65.
  
  
  RESULTS
  Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR = 0.88; 95% CI, 0.64-1.23; P = 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand-foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm.
  
  
  CONCLUSIONS
  This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC.
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. jtabernero@vhio.net
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Rocio
authors.initials: R
authors.lastname: Garcia-Carbonero
authors.forename: James
authors.initials: J
authors.lastname: Cassidy
authors.forename: Alberto
authors.initials: A
authors.lastname: Sobrero
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Oleg
authors.initials: O
authors.lastname: Gladkov
authors.forename: Irina
authors.initials: I
authors.lastname: Davidenko
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.forename: Liubov
authors.initials: L
authors.lastname: Vladimirova
authors.forename: Sergey
authors.initials: S
authors.lastname: Cheporov
authors.forename: Olga
authors.initials: O
authors.lastname: Burdaeva
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivera
authors.forename: Leslie
authors.initials: L
authors.lastname: Samuel
authors.forename: Irina
authors.initials: I
authors.lastname: Bulavina
authors.forename: Vanessa
authors.initials: V
authors.lastname: Potter
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Chang
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Lokker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010671:Phenylurea Compounds / Q000008:administration & dosage; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D000077150:Oxaliplatin; D009536:Niacinamide; D000077157:Sorafenib; D002955:Leucovorin; D005472:Fluorouracil