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/ormetastatic 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 (240mg/d orally) or trastuzumab (4mg/kg then 2mg/kg weekly), each combined with paclitaxel (80mg/m2 on days 1, 8, and 15 every 28 days). Primary prophylaxis for diarrhea was not mandatory. MAIN OUTCOME AND MEASURES The primary outcomewas progression-free survival. Secondary end pointswere 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-positivemetastatic 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.