title: A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma.
abstract: OBJECTIVE
  On the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors in pancreatic ductal adenocarcinoma (PDAC), we evaluated the safety and efficacy of selumetinib, a MEK1/2 inhibitor, plus erlotinib in patients with previously treated advanced PDAC.
  
  
  METHODS
  In this single-arm phase II trial, eligible patients received the combination of erlotinib 100 mg plus selumetinib 100 mg daily in 3-week cycles. Study assessments included measurement of clinical outcomes, with a primary endpoint of overall survival, and exploration of potential molecular predictors of treatment benefit.
  
  
  RESULTS
  Forty-six patients were enrolled and received a median of two cycles (range, 1-7). Although no objective responses were observed, 19 patients (41%) showed evidence of stable disease for ≥6 weeks, and 13 of 34 patients (38%) had a CA19-9 decline ≥50%. Median progression-free survival was 1.9 months [95% confidence interval (CI), 1.4-3.3 months], with a median overall survival of 7.3 months (95% CI, 5.2-8.0 months). Common adverse events included rash, diarrhea, and nausea/vomiting. Patients with tumors exhibiting an epithelial phenotype (demonstrated by a high level of E-cadherin expression) were more likely to be sensitive to study treatment. Tumor-derived DNA was detectable in plasma from the majority of patients using next-generation digital DNA sequencing, and its relative abundance correlated with tumor burden.
  
  
  CONCLUSIONS
  A therapeutic strategy of dual targeted inhibition of the MEK and EGFR pathways shows modest antitumor activity in pancreatic cancer. Specific molecular subtypes may derive greatest benefit from this combination. Further exploration, both with more potent MEK inhibitors and in molecularly enriched patient subsets, is warranted.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. andrewko@medicine.ucsf.edu.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Ko
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California.
authors.forename: Jessica
authors.initials: J
authors.lastname: Van Ziffle
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Mirzoeva
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Joseph
authors.affiliation: Guardant Health, Inc., Redwood City, California.
authors.forename: AmirAli
authors.initials: A
authors.lastname: Talasaz
authors.affiliation: University of Southern California, Los Angeles, California.
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhn
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tempero
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: R Kate
authors.initials: RK
authors.lastname: Kelley
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dito
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Anna
authors.initials: A
authors.lastname: Ong
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Sharvina
authors.initials: S
authors.lastname: Ziyeh
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Ryan
authors.initials: R
authors.lastname: Courtin
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: Regina
authors.initials: R
authors.lastname: Linetskaya
authors.affiliation: Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Sanaa
authors.initials: S
authors.lastname: Tahiri
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Korn
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D015415:Biomarkers; D004273:DNA, Neoplasm / Q000097:blood; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D019233:Retreatment
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D015415:Biomarkers; D004273:DNA, Neoplasm; D000069347:Erlotinib Hydrochloride