Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial

A. Awada, R. Colomer, K. Inoue, I. Bondarenko, Rajendra A. Badwe, G. Demetriou, C. S. Lee, A.O. Mehta, Sung Bae Kim, T. Bachelot, C. Goswami, S. Deo, Ron Bose, A. Wong, Fei Xu, Bing Yao, R. Bryce, L.A. Carey, Lorenzo Pavesi

Research output: Contribution to journalArticle

Abstract

Importance: 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. Design, Setting, and Participants: 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. Interventions: 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. Main Outcome and Measures: 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 and Relevance: 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. Trial Registration: clinicaltrials.gov Identifier: NCT00915018.
Original languageEnglish
Pages (from-to)1557-1564
Number of pages8
JournalJAMA oncology
Volume2
Issue number12
DOIs
Publication statusPublished - 2016

Keywords

  • antineoplastic agent
  • epidermal growth factor receptor 2
  • ERBB2 protein, human
  • N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide
  • paclitaxel
  • quinoline derivative
  • trastuzumab
  • adolescent
  • adult
  • adverse drug reaction
  • aged
  • Breast Neoplasms
  • Central Nervous System Neoplasms
  • controlled study
  • disease free survival
  • female
  • genetics
  • human
  • Kaplan Meier method
  • middle aged
  • pathology
  • randomized controlled trial
  • secondary
  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols
  • Disease-Free Survival
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Middle Aged
  • Paclitaxel
  • Quinolines
  • Receptor, ErbB-2
  • Trastuzumab

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    Awada, A., Colomer, R., Inoue, K., Bondarenko, I., Badwe, R. A., Demetriou, G., Lee, C. S., Mehta, A. O., Kim, S. B., Bachelot, T., Goswami, C., Deo, S., Bose, R., Wong, A., Xu, F., Yao, B., Bryce, R., Carey, L. A., & Pavesi, L. (2016). Neratinib Plus Paclitaxel vs Trastuzumab Plus Paclitaxel in Previously Untreated Metastatic ERBB2-Positive Breast Cancer: The NEfERT-T Randomized Clinical Trial. JAMA oncology, 2(12), 1557-1564. https://doi.org/10.1001/jamaoncol.2016.0237