Awada, Ahmad; Colomer, Ramon; Inoue, Kenichi; Bondarenko, Igor; Badwe, Rajendra A; Demetriou, Georgia; Lee, Soo-Chin; Mehta, Ajay O; Kim, Sung-Bae; Bachelot, Thomas; Goswami, Chanchal; Deo, Suryanarayan; Bose, Ron; Wong, Alvin; Xu, Feng; Yao, Bin; Bryce, Richard; Carey, Lisa A
JAMA oncology
2016Apr ; 90 ( 9 ) :.
PMID : 27078022
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Awada, Ahmad - Medical Oncology Clinic, Institut Jules Bordet, Universite Libre de Bruxelles, Bruxelles, Belgium.
Colomer, Ramon - Division of Medical Oncology, Hospital Universitario La Princesa, Madrid, Spain.
Inoue, Kenichi - Division of Breast Oncology, Saitama Cancer Center, Ina, Japan.
Bondarenko, Igor - Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine.
Badwe, Rajendra A - Tata Memorial Centre, Parel, India.
Demetriou, Georgia - University of the Witwatersrand Department of Medical Oncology and Wits Donald Gordon Medical Centre, Johannesburg, South Africa.
Lee, Soo-Chin - National University Cancer Institute, Singapore, Singapore.
Mehta, Ajay O - Central India Cancer Research Institute, Nagpur, India.
Kim, Sung-Bae - Asan Medical Center, University of Ulsan, Seoul, South Korea.
Bachelot, Thomas - Centre Leon Berard, Lyon, France.
Goswami, Chanchal - B.P. Poddar Hospital and Medical Research Ltd, Kolkata, India.
Deo, Suryanarayan - Institute Rotary Cancer Hospital, AIIMS, New Delhi, India.
Bose, Ron - Washington University School of Medicine, St Louis, Missouri.
Wong, Alvin - Puma Biotechnology Inc, Los Angeles, California.
Xu, Feng - Puma Biotechnology Inc, Los Angeles, California.
Yao, Bin - Puma Biotechnology Inc, Los Angeles, California.
Bryce, Richard - Puma Biotechnology Inc, Los Angeles, California.
Carey, Lisa A - Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill.
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.
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