title: Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: a randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie.
abstract: BACKGROUND
  Human epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC.
  
  
  METHODS
  Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250mg per day 1-21 plus capecitabine (CAP) 2000mg/m(2) on days 1-14 of a 21-day cycle or LAP 1500mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ⩾20% in either of the two arms.
  
  
  RESULTS
  37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37-34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38-61) days in the LAP group and 83 (95% CI: 42-86) days in the LAP+CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP+CAP (61%; 95% CI: 35-83) compared to 26% (95% CI 9-51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]).
  
  
  CONCLUSIONS
  Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404).
authors.affiliation: 3rd Department of Internal Medicine (Hematology/Medical Oncology), Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lorenzen
authors.affiliation: Department of Hematology and Oncology, University Hospital Marburg, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Riera Knorrenschild
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Georg-Martin
authors.initials: GM
authors.lastname: Haag
authors.affiliation: Department of Medicine, Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pohl
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Virchow-Klinikum, Charité, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Thuss-Patience
authors.affiliation: 3rd Department of Internal Medicine (Hematology/Medical Oncology), Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Bassermann
authors.affiliation: 3rd Medical Department, Hematology and Oncology, Klinikum Braunschweig, Braunschweig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Helbig
authors.affiliation: Department of Medicine, Hematology, Oncology and Palliative Care, Evangelisches Krankenhaus, Bielefeld, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Weißinger
authors.affiliation: Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schnoy
authors.affiliation: Onkologische Praxis Hamburg-Lerchenfeld, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Becker
authors.affiliation: University Cancer Center Leipzig (UCCL), University Medicine Leipzig, Leipzig, Germany.
authors.forename: Gertraud
authors.initials: G
authors.lastname: Stocker
authors.affiliation: Targos Molecular Pathology, Kassel, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.affiliation: NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Eisenmenger
authors.affiliation: NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Irini
authors.initials: I
authors.lastname: Karapanagiotou-Schenkel
authors.affiliation: University Cancer Center Leipzig (UCCL), University Medicine Leipzig, Leipzig, Germany; NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany. Electronic address: florian.lordick@medizin.uni-leipzig.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Lordick
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005784:Gene Amplification; D018628:Gene Dosage; D005858:Germany; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: EGFR; Gastric cancer; HER2; Lapatinib