title: Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial.
abstract: OBJECTIVE
  Efficacious ERBB2 (formerly HER2 or HER2/neu)-directed treatments, in addition to trastuzumab and lapatinib, are needed.
  
  
  OBJECTIVE
  To determine whether neratinib, an irreversible pan-ERBB tyrosine kinase inhibitor, plus paclitaxel improves progression-free survival compared with trastuzumab plus paclitaxel in the first-line treatment of recurrent and/or metastatic ERBB2-positive breast cancer.
  
  
  METHODS
  In the randomized, controlled, open-label NEfERT-T trial conducted from August 2009 to December 2014 at 188 centers in 34 countries in Europe, Asia, Africa, and North America, 479 women with previously untreated recurrent and/or metastatic ERBB2-positive breast cancer were randomized to 1 of 2 treatment arms (neratinib-paclitaxel [n = 242] or trastuzumab-paclitaxel [n = 237]). Women with asymptomatic central nervous system metastases were eligible, and randomization was stratified by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region.
  
  
  METHODS
  Women received neratinib (240 mg/d orally) or trastuzumab (4 mg/kg then 2 mg/kg weekly), each combined with paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory.
  
  
  METHODS
  The primary outcome was progression-free survival. Secondary end points were response rate, clinical benefit rate, duration of response, frequency, and time to symptomatic and/or progressive central nervous system lesions, and safety.
  
  
  RESULTS
  The intent-to-treat population comprised 479 women 18 years or older (neratinib-paclitaxel, n = 242; trastuzumab-paclitaxel, n = 237) randomized and stratified in their respective treatment arms by prior trastuzumab and lapatinib exposure, hormone-receptor status, and region. Median progression-free survival was 12.9 months (95% CI, 11.1-14.9) with neratinib-paclitaxel and 12.9 months (95% CI, 11.1-14.8) with trastuzumab-paclitaxel (hazard ratio [HR], 1.02; 95% CI, 0.81-1.27; P =.89). With neratinib-paclitaxel, the incidence of central nervous system recurrences was lower (relative risk, 0.48; 95% CI, 0.29-0.79; P = .002) and time to central nervous system metastases delayed (HR, 0.45; 95% CI, 0.26-0.78; P = .004). Common grade 3 to 4 adverse events were diarrhea (73 of 240 patients [30.4%] with neratinib-paclitaxel and 9 of 234 patients [3.8%] with trastuzumab-paclitaxel), neutropenia (31 patients [12.9%] vs 34 patients [14.5%]) and leukopenia (19 patients [7.9%] vs 25 patients [10.7%]); no grade 4 diarrhea was observed.
  
  
  CONCLUSIONS
  In first-line ERBB2-positive metastatic breast cancer, neratinib-paclitaxel was not superior to trastuzumab-paclitaxel in terms of progression-free survival. In spite of similar overall efficacy, neratinib-paclitaxel may delay the onset and reduce the frequency of central nervous system progression, a finding that requires a larger study to confirm.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00915018.
authors.affiliation: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.affiliation: Division of Medical Oncology, Hospital Universitario La Princesa, Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Colomer
authors.affiliation: Division of Breast Oncology, Saitama Cancer Center, Ina, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine.
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.affiliation: Tata Memorial Centre, Parel, India.
authors.forename: Rajendra A
authors.initials: RA
authors.lastname: Badwe
authors.affiliation: University of the Witwatersrand Department of Medical Oncology and Wits Donald Gordon Medical Centre, Johannesburg, South Africa.
authors.forename: Georgia
authors.initials: G
authors.lastname: Demetriou
authors.affiliation: National University Cancer Institute, Singapore, Singapore.
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Central India Cancer Research Institute, Nagpur, India.
authors.forename: Ajay O
authors.initials: AO
authors.lastname: Mehta
authors.affiliation: Asan Medical Center, University of Ulsan, Seoul, South Korea.
authors.forename: Sung-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Centre Léon Bérard, Lyon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: B.P. Poddar Hospital and Medical Research Ltd, Kolkata, India.
authors.forename: Chanchal
authors.initials: C
authors.lastname: Goswami
authors.affiliation: Institute Rotary Cancer Hospital, AIIMS, New Delhi, India.
authors.forename: Suryanarayan
authors.initials: S
authors.lastname: Deo
authors.affiliation: Washington University School of Medicine, St Louis, Missouri.
authors.forename: Ron
authors.initials: R
authors.lastname: Bose
authors.affiliation: Puma Biotechnology Inc, Los Angeles, California.
authors.forename: Alvin
authors.initials: A
authors.lastname: Wong
authors.affiliation: Puma Biotechnology Inc, Los Angeles, California.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Puma Biotechnology Inc, Los Angeles, California.
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.affiliation: Puma Biotechnology Inc, Los Angeles, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Bryce
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D017239:Paclitaxel; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C487932:neratinib