Phase 3 Randomized Study of BGB‑43395 + Letrozole versus CDK4/6 Inhibitor Combination + Letrozole in Treatment‑Naïve Advanced HR+/HER2‑ Breast Cancer

The primary objective is to compare progression‑free survival for BGB‑43395 plus letrozole versus a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) plus letrozole in patients with advanced or metastatic HR+/HER2‑negative breast cancer who are treatment‑naïve in the advanced setting.

Secondary objectives include:

• Comparison of overall survival between the two treatment arms.
• Evaluation of anticancer activity of BGB‑43395 plus letrozole relative to CDK4/6 inhibitor plus letrozole.
• Assessment of safety and tolerability of the study regimens.
• Analysis of patient‑reported disease‑ and treatment‑related symptoms.

A total of 823 participants were enrolled. The trial included adult patients of both sexes with histologically confirmed advanced or metastatic HR+/HER2- breast cancer who had not received prior systemic therapy for advanced disease. Eligible individuals were required to be at least 18 years old, have an Eastern Cooperative Oncology Group performance status of ≤ 1, and demonstrate adequate organ function. The population comprised both female and male subjects and included vulnerable individuals as defined by regulatory criteria. Age distribution corresponded to adult age codes 3 and 4, representing the typical adult age spectrum. No specific lifestyle restrictions such as diet or physical activity were stipulated in the provided information.

The study is an open-label, randomized, multicenter phase 3 trial evaluating BGB‑43395 plus letrozole versus a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) plus letrozole in patients with advanced or metastatic HR+/HER2- breast cancer who have not received prior systemic therapy for advanced disease. After an initial screening visit to confirm eligibility, eligible participants are randomized 1:1 to Arm A (BGB‑43395 + letrozole) or Arm B (selected CDK4/6 inhibitor + letrozole). Treatment continues until documented disease progression, occurrence of an unacceptable adverse event, withdrawal of consent, or study termination. Follow‑up visits are scheduled to collect safety data, laboratory results, and imaging for tumor assessment; the final end‑of‑study visit occurs after treatment discontinuation to capture final efficacy and safety outcomes. The primary endpoint is progression-free survival as assessed by blinded independent central review per RECIST v1.1, with secondary endpoints including overall survival, overall response rate, duration of response, and quality‑of‑life measures. Participant involvement may extend for several years, limited by the time to progression or the overall study end date of 2037‑08‑07.

The experimental regimen consists of BGB-43395 administered orally as a film‑coated tablet in combination with letrozole 2.5 mg taken by mouth.

The comparator regimens include oral administration of each CDK4/6 inhibitor together with letrozole 2.5 mg: palbociclib 125 mg, ribociclib 600 mg, and abemaciclib 300 mg, all provided as oral tablets.

Efficacy will be assessed primarily by measuring progression‑free survival as determined by a Blinded Independent Central Review using RECIST v1.1 criteria, defined as the interval from randomization to the first documented disease progression or death, whichever occurs first.

Secondary efficacy evaluations will include overall survival, overall response rate, duration of response, investigator‑determined progression‑free survival, clinical benefit rate, time to response, and progression‑free survival 2, all based on RECIST v1.1 assessments. Patient‑reported outcomes will be captured with the EORTC‑IL454 questionnaire to evaluate changes from baseline in global health status/quality of life, physical and role functioning, nausea/vomiting, diarrhea, breast and arm symptoms, and systemic therapy side effects.