BEBT-209, a primary CDK4 selective inhibitor, for the treatment of HR+/HER2- advanced breast cancer (BECTOP1): a phase 1, multicentre, open-label study

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.