title: Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results.
abstract: OBJECTIVE
  Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy.
  
  
  METHODS
  Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m(2) as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations.
  
  
  RESULTS
  The median PFS was 2.07 months (95% CI; 1.87-5.50 months) and the ORR was 11%. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23%), lymphopenia (23%), and fatigue (13%). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations.
  
  
  CONCLUSIONS
  Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA, thomas.semrad@ucdmc.ucdavis.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Semrad
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Barzi
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Irene M
authors.initials: IM
authors.lastname: Hutchins
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kim
authors.forename: I-Yeh
authors.initials: IY
authors.lastname: Gong
authors.forename: Michael
authors.initials: M
authors.lastname: Tanaka
authors.forename: Laurel
authors.initials: L
authors.lastname: Beckett
authors.forename: William
authors.initials: W
authors.lastname: Holland
authors.forename: Rebekah A
authors.initials: RA
authors.lastname: Burich
authors.forename: Leslie
authors.initials: L
authors.lastname: Snyder-Solis
authors.forename: Philip
authors.initials: P
authors.lastname: Mack
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis* / Q000235:genetics; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine
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