title: Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.
abstract: OBJECTIVE
  KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer.
  
  
  OBJECTIVE
  To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed.
  
  
  METHODS
  SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases.
  
  
  METHODS
  Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle.
  
  
  METHODS
  The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival.
  
  
  RESULTS
  There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients).
  
  
  CONCLUSIONS
  Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01658943.
authors.affiliation: City of Hope National Medical Center, Duarte, California.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chung
authors.affiliation: SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Shannon
authors.initials: S
authors.lastname: McDonough
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Philip
authors.affiliation: Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Dana
authors.initials: D
authors.lastname: Cardin
authors.affiliation: Washington University in St Louis, St Louis, Missouri.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Kaiser Permanente NCORP, Sacramento, California.
authors.forename: Laifong
authors.initials: L
authors.lastname: Hui
authors.affiliation: University of Rochester, Rochester, New York.
authors.forename: Mohamedtaki A
authors.initials: MA
authors.lastname: Tejani
authors.affiliation: University of California, Irvine, Orange.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Seery
authors.affiliation: Crossroads Cancer Center/Heartland NCORP, Effingham, Illinois.
authors.forename: Irene A
authors.initials: IA
authors.lastname: Dy
authors.affiliation: St Joseph Mercy Hospital/Michigan CRC NCORP, Ann Arbor.
authors.forename: Tareq
authors.initials: T
authors.lastname: Al Baghdadi
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Hendifar
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: University of California, San Diego, La Jolla.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.affiliation: SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Guthrie
authors.affiliation: SWOG Group Chair's Office/Knight Cancer Institute, Oregon Health and Science University, Portland.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.affiliation: Yale Cancer Center, New Haven, Connecticut.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Hochster
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D016879:Salvage Therapy / Q000379:methods*
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil