title: Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104).
abstract: OBJECTIVE
  AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine.
  
  
  METHODS
  281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients.
  
  
  RESULTS
  Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2-4:2.9/4.3/6.7 months, p<0.0001) and survival (3.4/7.0/9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p=0.005).
  
  
  CONCLUSIONS
  Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.
authors: Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Marchioninistr. 15, D-81377 Munich, Germany. volker.heinemann@med.uni-muenchen.de
authors: Volker
authors: V
authors: Heinemann
authors: Ursula
authors: U
authors: Vehling-Kaiser
authors: Dirk
authors: D
authors: Waldschmidt
authors: Erika
authors: E
authors: Kettner
authors: Angela
authors: A
authors: Märten
authors: Cornelia
authors: C
authors: Winkelmann
authors: Stefan
authors: S
authors: Klein
authors: Georgi
authors: G
authors: Kojouharoff
authors: Thomas C
authors: TC
authors: Gauler
authors: Ludwig Fischer
authors: LF
authors: von Weikersthal
authors: Michael R
authors: MR
authors: Clemens
authors: Michael
authors: M
authors: Geissler
authors: Tim F
authors: TF
authors: Greten
authors: Susanna
authors: S
authors: Hegewisch-Becker
authors: Oleg
authors: O
authors: Rubanov
authors: Gerold
authors: G
authors: Baake
authors: Thomas
authors: T
authors: Höhler
authors: Yon D
authors: YD
authors: Ko
authors: Andreas
authors: A
authors: Jung
authors: Sascha
authors: S
authors: Neugebauer
authors: Stefan
authors: S
authors: Boeck
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069347:Erlotinib Hydrochloride; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D011799:Quinazolines; D003841:Deoxycytidine; D000069287:Capecitabine; D000069347:Erlotinib Hydrochloride; D005472:Fluorouracil; D000093542:Gemcitabine