The objective of the study was to evaluate the safety, preliminary antitumor activity, and pharmacodynamics of BGB-43395, an investigational selective cyclin-dependent kinase 4 inhibitor, in combination with letrozole as first-line treatment.

This was an open-label Phase 1a/1b study with a safety expansion cohort in which patients with advanced or metastatic hormone receptor–positive/human epidermal growth factor receptor 2–negative breast cancer who had not previously received CDK4/6 inhibitor therapy were randomized to receive 1 of 3 dose levels of BGB-43395 plus letrozole. Patients received oral BGB-43395 at doses of 240 mg, 400 mg, or 600 mg administered twice daily in combination with letrozole to determine the recommended dose for further development. Endpoints included safety, preliminary antitumor activity assessed by investigator per RECIST version 1.1, and pharmacodynamic readouts including thymidine kinase 1 and circulating tumor DNA.

As of November 11, 2025, a total of 58 patients had received study treatment (240 mg, n=19; 400 mg, n=19; 600 mg, n=20). Treatment‑emergent adverse events were reported in 98.0% of patients overall. Grade ≥3 adverse events occurred in 32.0%, 37.0%, and 65.0% of patients receiving 240 mg, 400 mg, and 600 mg, respectively. The most common treatment‑emergent adverse events, which were predominantly Grade 1 or 2, were diarrhea (240 mg/400 mg/600 mg: 79%/95%/90%; Grade 3: 5%/11%/30%), nausea (53%/68%/85%; Grade 3: 0%/5%/0%), and vomiting (26%/47%/60%; Grade 3: 0% across all doses). Hematologic toxicities were generally low grade, and no treatment‑related deaths were reported.

Objective response rates were 58.0%, 68.0%, and 40.0% in the 240 mg, 400 mg, and 600 mg cohorts, respectively, with disease control rates ranging from 95.0% to 100.0%. Median time to response was 3.6 months, and median progression-free survival was not reached at the time of analysis. Pharmacodynamic assessments showed reductions in thymidine kinase 1 and circulating tumor DNA during treatment.