Bireociclib plus fulvestrant for advanced HR+/HER2- breast cancer progressing after endocrine therapy: Interim analysis of a phase 3 trial (BRIGHT-2).

1058 Background: Bireociclib is a new selective inhibitor of CDK4/6 which showed promising clinical activity and manageable tolerability both as monotherapy and in combination with endocrine therapy (ET). This phase III study (BRIGHT-2, NCT05077449) was to evaluate the efficacy and safety of Bireociclib plus fulvestrant in HR + /HER2 - advanced breast cancer (ABC) that progressed on or after previous ET. Methods: BRIGHT-2 study was a multicenter, randomized, double-blinded, phase 3 trial in patients with HR + /HER2 - ABC who had progressed on or after prior ET. Eligible patients were randomized 2:1 to receive Bireociclib (360 mg po bid) or placebo with fulvestrant (500 mg im, cycle1 d1, d15, then d1) on each 28-day cycle. The primary endpoint was PFS based on investigator’s assessment per RECIST v1.1. The interim analysis was conducted when 70% PFS events occurred. Results: A total of 305 Chinese female patients were randomly allocated to receive Bireociclib plus fulvestrant (BF, n = 204) or placebo plus fulvestrant (F, n = 101). 208 (68.2%) patients had visceral metastases, 78 (25.6%) patients with primary resistance to ET and 73 (23.9%) patients had received chemotherapy in metastatic setting. As of March 28, 2023, with a median follow-up of 8.7 mo, BF significantly prolonged the PFS per investigator with 12.94 (95%CI, 11.07-NR) mo compared to 7.29 (95%CI, 5.45-11.04) mo in the F group (HR, 0.561; 95%CI, 0.393-0.799; P= 0.0012). The median PFS assessed by blinded independent central review (BICR) were no-reached (95%CI, NR-NR) in BF group and 7.46 (95%CI, 5.49-NR) mo in F group (HR, 0.461; 95%CI, 0.312-0.683; P<0.0001) which were consistent with the investigator’s assessment. The subgroup analyses revealed that in BF group, PFS was improved compared across all subgroups with HRs < 1. For patients with primary resistance to ET, with liver metastases and with bone-only metastases, the HRs were 0.254 (95%CI: 0.128-0.503), 0.381 (95%CI: 0.226-0.644) and 0.234 (95%CI: 0.070-0.787) respectively. In BF group, the most common TEAEs were diarrhea 92.6% (all grades); 5.4% (≥grade 3), neutropenia 87.3%; 31.4%, leukocytopenia 83.3%; 18.6% and anemia 66.7%; 10.8%. Most of AEs were grade 1 or grade 2 and could be alleviated or cured by dose adjustment or symptomatic treatment. Treatment discontinuation due to TEAE was reported in 3 (1.5%) patients with BF. As of March 28, 2023, 120(58.8%) patients in BF were receiving treatment and the trail were ongoing. Conclusions: Bireociclib plus fulvestrant showed superior efficacy for pretreated HR+/HER2- ABC, especially in patients with primary resistance to ET, liver metastases or bone-only metastases. The toxicity of Bireociclib plus fulvestrant were well tolerated and manageable with no new safety signal. Clinical trial information: NCT05077449 .