title: A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing, KRAS-Mutated Metastatic Colorectal Cancer.
abstract: BACKGROUND
  Mutations in the KRAS gene predict for resistance to anti-epidermal growth factor receptor (EGFR) therapies, including cetuximab. Upregulation of vascular endothelial growth factor (VEGF)-A has been implicated in resistance to anti-EGFR treatment. Abrogation of the VEGF and RAS/RAF/MEK/ERK pathways has the potential to restore cetuximab sensitivity.
  
  
  METHODS
  Adult patients with histologically documented, measurable, EGFR-expressing, KRAS-mutated metastatic colorectal cancer (mCRC) that had progressed after 5-fluorouracil-based regimens were treated with sorafenib 400 mg orally twice daily and intravenous cetuximab weekly in 28-day cycles. The primary endpoint was the response rate (complete response, partial response, and stable disease at 4 cycles). The secondary endpoints included plasma biomarker analysis of angiogenic cytokines and correlative imaging studies with dynamic contrast-enhanced magnetic resonance imaging and zirconium 89-panitumumab.
  
  
  RESULTS
  Of the 30 patients enrolled, 26 were evaluable for response. Of the 26 patients evaluated, 4 had stable disease at 4 cycles and 1 had stable disease at 8 cycles. The median progression-free survival was 1.84 months. The common toxicities were rash, diarrhea, and liver enzyme elevations. Of the angiogenic cytokines evaluated, only the placental growth factor increased significantly with treatment (P < .0001). No pharmacodynamic parameters were associated with the treatment response.
  
  
  CONCLUSIONS
  We report the results of a trial that combined cetuximab and sorafenib for the treatment of KRAS-mutated mCRC, with correlative imaging studies and pharmacodynamic angiogenic cytokine profiling as downstream markers of EGFR and VEGF receptor (VEGFR) signaling. No objective responses were observed. Additional development of biomarkers for patient selection is needed to evaluate combined EGFR and VEGFR blockade as a therapeutic option in KRAS-mutated CRC.
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
authors: Khanh
authors: K
authors: Do
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Liang
authors: L
authors: Cao
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Zhigang
authors: Z
authors: Kang
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Baris
authors: B
authors: Turkbey
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Maria L
authors: ML
authors: Lindenberg
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Erin
authors: E
authors: Larkins
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Beata
authors: B
authors: Holkova
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Seth M
authors: SM
authors: Steinberg
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Mark
authors: M
authors: Raffeld
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Cody J
authors: CJ
authors: Peer
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: William D
authors: WD
authors: Figg
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
authors: Michelle
authors: M
authors: Eugeni
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
authors: Paula
authors: P
authors: Jacobs
authors: Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors: Peter
authors: P
authors: Choyke
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
authors: John J
authors: JJ
authors: Wright
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
authors: James H
authors: JH
authors: Doroshow
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD. Electronic address: kummars@mail.nih.gov.
authors: Shivaani
authors: S
authors: Kummar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D018579:Patient Selection; D010671:Phenylurea Compounds / Q000008:administration & dosage; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: C117307:KRAS protein, human; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: Antiangiogenic therapy; Biomarkers; Combination Therapy; Panitumumab imaging; Pharmacodynamics