title: Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer.
abstract: OBJECTIVE
  Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two).
  
  
  METHODS
  Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR).
  
  
  RESULTS
  In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively.
  
  
  CONCLUSIONS
  Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. csaura@vhio.net.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saura
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Garcia-Saenz
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Binghe
authors.initials: B
authors.lastname: Xu
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Wael
authors.initials: W
authors.lastname: Harb
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Moroose
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Timothy
authors.initials: T
authors.lastname: Pluard
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Corinne
authors.initials: C
authors.lastname: Kiger
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Caroline
authors.initials: C
authors.lastname: Germa
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Kongming
authors.initials: K
authors.lastname: Wang
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Cristina Saura and Javier Cortés, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Jose A. Garcia-Saenz, Hospital Clinico San Carlos; Miguel Martin, Hospital Gregorio Maranon, Universidad Complutense, Madrid, Spain; Binghe Xu, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China; Wael Harb, Horizon Medical Group, Lafayette, IN; Rebecca Moroose, University of Florida Health Cancer Center, Orlando, FL; Timothy Pluard, Washington University School of Medicine, St Louis, MO; Corinne Kiger, Pfizer Global Research and Development, Paris; Caroline Germa, Novartis Pharma, Rueil-Malmaison, France; Kongming Wang, Pfizer, Pearl River; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010292:Paresthesia / Q000139:chemically induced; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013577:Syndrome; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D000077341:Lapatinib; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C487932:neratinib