Abstract
IMPORTANCE: The BRIGHT-2 interim analysis demonstrated the efficacy of bireociclib plus fulvestrant in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (ERBB2; previously HER2)-negative advanced breast cancer (ABC) after endocrine therapy progression. This final analysis includes an additional 11-month follow-up. OBJECTIVE: To evaluate the efficacy and safety of bireociclib plus fulvestrant in HR-positive, ERBB2-negative ABC. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled phase 3 randomized clinical trial was conducted at 64 hospitals in China between December 8, 2021, and October 24, 2022. Patients were enrolled and randomly assigned in a 2:1 to receive bireociclib plus fulvestrant or placebo plus fulvestrant. Data were analyzed from April 2024 to December 2025. INTERVENTIONS: Patients received bireociclib, 360 mg, or placebo orally every 12 hours in combination with fulvestrant, 500 mg, intramuscularly (days 1 and 15 of cycle 1, then day 1 of each 28-day cycle). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate, duration of response, and safety. RESULTS: Of 305 included patients, the mean (SD) age was 54.1 (10.2) years, and the median (IQR) follow-up at data cutoff was 19 (18.5-19.6) months. Patients were randomized to bireociclib plus fulvestrant (n = 204) or placebo plus fulvestrant (n = 101); 275 (90.2%) had measurable disease and 268 (87.9%) had received prior systemic chemotherapy. Bireociclib plus fulvestrant significantly prolonged PFS vs placebo (median PFS, 14.7 months [95% CI, 11.1-20.2] vs 7.3 months [95% CI, 5.5-11.0]; hazard ratio, 0.54; 95% CI, 0.40-0.74; P < .001). The objective response rate was higher (45.6% [95% CI, 38.6-52.7] vs 14.9% [95% CI, 8.6-23.3]) in the bireociclib group, with a prolonged median duration compared with placebo (not reached [95% CI, 11.1 to not reached] vs 13.1 months [95% CI, 10.2 to not reached]). Safety was consistent with the interim findings and the profiles of known cyclin-dependent kinase 4/6 inhibitors. Subgroup analyses across multiple patient characteristics (menopausal status, metastatic sites, prior treatment, disease-free interval, ESR1/PIK3CA/TP53 alterations and others) showed consistent PFS improvements with bireociclib vs placebo. Patients with early-onset diarrhea appeared to derive more benefit from bireociclib (hazard ratio, 0.49; 95% CI, 0.36-0.68). CONCLUSIONS AND RELEVANCE: The final analysis of the BRIGHT-2 randomized clinical trial confirms improved PFS with the addition of bireociclib to fulvestrant, with manageable safety as a treatment option for patients with HR-positive, ERBB2-negative ABC with progression after prior endocrine therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05077449.