Sylvie Lorenzen1, Jorge Riera Knorrenschild2, Georg-Martin Haag3, Michael Pohl4, Peter Thuss-Patience5, Florian Bassermann1, Ulrike Helbig6, Florian Weißinger7, Elisabeth Schnoy8, Klaus Becker9, Gertraud Stocker10, Josef Rüschoff11, Andreas Eisenmenger12, Irini Karapanagiotou-Schenkel12, Florian Lordick13. 1. 3rd Department of Internal Medicine (Hematology/Medical Oncology), Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 2. Department of Hematology and Oncology, University Hospital Marburg, Germany. 3. Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. 4. Department of Medicine, Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, Germany. 5. Department of Hematology, Oncology and Tumor Immunology, Virchow-Klinikum, Charité, Berlin, Germany. 6. 3rd Medical Department, Hematology and Oncology, Klinikum Braunschweig, Braunschweig, Germany. 7. Department of Medicine, Hematology, Oncology and Palliative Care, Evangelisches Krankenhaus, Bielefeld, Germany. 8. Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany. 9. Onkologische Praxis Hamburg-Lerchenfeld, Hamburg, Germany. 10. University Cancer Center Leipzig (UCCL), University Medicine Leipzig, Leipzig, Germany. 11. Targos Molecular Pathology, Kassel, Germany. 12. NCT Trial Center, National Center for Tumor Diseases, Heidelberg, Germany. 13. 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.
Abstract
INTRODUCTION: 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. MATERIALS AND 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%]). DISCUSSION: 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).
RCT Entities:
INTRODUCTION: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. MATERIALS AND 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%]). DISCUSSION: 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: Vincent T Janmaat; Ewout W Steyerberg; Ate van der Gaast; Ron Hj Mathijssen; Marco J Bruno; Maikel P Peppelenbosch; Ernst J Kuipers; Manon Cw Spaander Journal: Cochrane Database Syst Rev Date: 2017-11-28
Authors: Do-Youn Oh; Kewn-Wook Lee; Jae Yong Cho; Won Ki Kang; Seock-Ah Im; Jin Won Kim; Yung-Jue Bang Journal: Gastric Cancer Date: 2015-11-18 Impact factor: 7.370