Abstract CT099: BRIGHT-2 final analysis: A phase III trial of bireociclib plus fulvestrant as second-line endocrine therapy for patients with advanced HR+/HER2-breast cancer

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Abstract Background: At the BRIGHT-2 (NCT05077449) interim analysis, bireociclib (a novel selective CDK4/6 inhibitor) plus fulvestrant significantly improved progression-free survival (PFS) with a tolerable safety profile as second-line therapy for HR+/HER2- advanced breast cancer (ABC) patients (pts). Herein, we report the final analysis after 11-month of additional follow-up. Method: Eligible pts with HR+/HER2- ABC who have progressed on or after previous endocrine therapy were randomized 2:1 to receive bireociclib (360 mg po bid) or placebo with fulvestrant (500 mg im, d1, d15 for cycle1, d1 for the subquent cycles) on each 28-day cycle. Pts were stratified by endocrine resistance (primary vs secondary) and visceral metastases (yes vs no). The primary endpoint was investigator-assessed PFS per RECIST v1.1. A post hoc analysis was conducted to assess the impact of protocol-allowed dose reductions (120 mg decrements) on PFS in bireociclib plus fulvestrant (BF) group. Results: 305 eligible female pts were enrolled to receive BF (n = 204) or placebo plus fulvestrant (F, n = 101). 209 (68.5%) pts had visceral metastases, 78 (25.6%) pts with primary endocrine resistance and 73 (23.9%) pts had received chemotherapy for advanced disease. At data cutoff (Feb. 22, 2024), with a median follow-up of 18.99 months (mo), the investigator-assessed stratified median PFS (mPFS) was 14.69 mo (95% CI, 11.07-20.21) in BF group vs 7.33 mo (95% CI, 5.49-11.04) in F group (HR, 0.542; 95% CI, 0.399-0.735; p<0.0001). The mPFS assessed by blinded independent central review (BICR) was 17.51 mo (95% CI, 13.83-23.06) in BF group vs 7.29 mo (95% CI, 5.49-9.46) in F group (HR, 0.462; 95% CI, 0.333-0.642; p<0.0001). Improvement in PFS with BF treatment was consistent across all prespecified subgroups. HR for pts with bone-only metastases was 0.184; 95% CI, 0.063-0.541. For pts who didn't receive chemotherapy in advanced disease, the mPFS for the BF group and F group were 17.28 mo and 7.69 mo, respectively (HR, 0.559; 95% CI, 0.387-0.807). The overall survival data was yet immature, with a trend of survival benefit in BF group (HR, 0.762; 95% CI, 0.476-1.218; p=0.5221). The most common treatment-emergent adverse events (TEAEs) were hematologic toxicity and diarrhea and comparable to previously reported profiles. No new safety signal was observed. 86 pts (42.2%) received bireociclib dose reduction due to TEAEs in BF group. The mPFS was 14.52 mo (95% CI, 11.07 to NR) vs 14.75 mo (95% CI, 10.87 to NR) for pts with or without bireociclib dose reduction respectively, p=0.5758. Conclusions: Bireociclib plus fulvestrant exhibited superior efficacy and manageable tolerability as second-line endocrine therapy for HR+/HER2- ABC after prolonged follow-up, with benefits across different subgroups and clinically appropriate dose reductions not compromising efficacy. Citation Format: Jiayu Wang, Qingyuan Zhang, Huiping Li, Zhongsheng Tong, Quchang Ouyang, Huihui Li, Yuee Teng, Biyun Wang, Tao Sun, Jingfen Wang, Wei Li, Zhaofeng Niu, Hongsheng Li, Chang Gong, Li Wang, Fei Liu, Xianghui Duan, Qiuli Wang, Binghe Xu. BRIGHT-2 final analysis: A phase III trial of bireociclib plus fulvestrant as second-line endocrine therapy for patients with advanced HR+/HER2-breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT099.

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