caa a22 4500 605490872 CHVBK 20210128100507.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s10147-014-0730-2 doi (NATIONALLICENCE)springer-10.1007/s10147-014-0730-2 Pharmacodynamic separation of gemcitabine and erlotinib in locally advanced or metastatic pancreatic cancer: therapeutic and biomarker results [Elektronische Daten] [Thomas Semrad, Afsaneh Barzi, Heinz-Josef Lenz, Irene Hutchins, Edward Kim, I-Yeh Gong, Michael Tanaka, Laurel Beckett, William Holland, Rebekah Burich, Leslie Snyder-Solis, Philip Mack, Primo Lara Jr.] Purpose: 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 1000mg/m2 as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150mg/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 2.07months (95% CI; 1.87-5.50months) 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. 4.6months, p=0.014) and overall survival (3.0 vs. 10.5months, 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. Japan Society of Clinical Oncology, 2014 Gemcitabine nationallicence Erlotinib nationallicence Pancreatic cancer nationallicence Pharmacodynamic separation nationallicence KRAS mutation nationallicence Semrad Thomas Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Barzi Afsaneh Medical Oncology, Keck School of Medicine, University of Southern California Norris Cancer Center, Los Angeles, CA, USA aut Lenz Heinz-Josef Medical Oncology, Keck School of Medicine, University of Southern California Norris Cancer Center, Los Angeles, CA, USA aut Hutchins Irene Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA aut Kim Edward Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Gong I-Yeh Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Tanaka Michael Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Beckett Laurel Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Davis, CA, USA aut Holland William Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Burich Rebekah Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Snyder-Solis Leslie Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Mack Philip Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut Lara Jr. Primo Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut International Journal of Clinical Oncology Springer Japan 20/3(2015-06-01), 518-524 1341-9625 20:3<518 2015 20 10147 https://doi.org/10.1007/s10147-014-0730-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10147-014-0730-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Semrad Thomas Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Barzi Afsaneh Medical Oncology, Keck School of Medicine, University of Southern California Norris Cancer Center, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Lenz Heinz-Josef Medical Oncology, Keck School of Medicine, University of Southern California Norris Cancer Center, Los Angeles, CA, USA aut NATIONALLICENCE 700 1- Hutchins Irene Department of Internal Medicine, University of California, Davis, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Kim Edward Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Gong I-Yeh Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Tanaka Michael Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Beckett Laurel Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Davis, CA, USA aut NATIONALLICENCE 700 1- Holland William Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Burich Rebekah Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Snyder-Solis Leslie Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Mack Philip Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 700 1- Lara Jr Primo Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, 4501 X Street, Suite 3016, 95817, Sacramento, CA, USA aut NATIONALLICENCE 773 0- International Journal of Clinical Oncology Springer Japan 20/3(2015-06-01), 518-524 1341-9625 20:3<518 2015 20 10147