Abstract
PURPOSE: Several cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Despite the side effects that affect patients' quality of life, most patients still opt for CDK4/6 inhibitors due to their significant benefits. However, to further enhance treatment efficacy and safety, new approaches are still needed. PATIENTS AND METHODS: This multicentre, open-label, Phase 1 trial enrolled Chinese patients with HR+, HER2-advanced breast cancers. The primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD). Secondary endpoints included the objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and pharmacokinetic parameters. RESULTS: During the dose-escalation phase, a DLT was observed in the 150 mg bid dose cohort, specifically, 2 patients experienced grade 4 neutropenia. MTD of BEBT-209 was 100 mg bid, and the most common adverse event (AE) was neutropenia. In Phase 1b, the median PFS of patients with BEBT-209 alone, BEBT-209 plus letrozole, and BEBT-209 plus fulvestrant was 10.38 months, 24.94 months, and not reached, respectively. At doses of 25 mg qd-150 mg bid, steady state areas under the concentration-time curve and peak concentration increased proportionally with dose. The most common grade 3 or 4 AEs were neutropenia (65.4 %), lymphocytopenia (7.4 %), and anaemia (4.9 %). CONCLUSION: BEBT-209 was a primary CDK4 selective inhibitor and showed an acceptable safety profile and dose-dependent plasma exposure. The results highlight the potential of combination treatments as compelling options, particularly in combination with fulvestrant.