Phase 2 Trial of Fulvestrant and Combination Therapy for Second-Line HR+/HER2- Metastatic Breast Cancer Guided by Liquid Biopsy Algorithm

The primary objective is to evaluate a biomarker-driven workflow designed to guide clinical decision-making for second-line treatment in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. This therapy study aims to assess the utility of an integrated liquid biopsy algorithm for personalizing treatment intensity and targeting. Secondary objectives include:

• Description of progression-free survival and overall survival within each study arm.
• Evaluation of the somatic mutational profile identified through plasma next-generation sequencing.
• Assessment of the prognostic impact of identified somatic alterations on survival outcomes.
• Measurement of circulating tumor cells count using the CellSearch platform.
• Evaluation of the prognostic significance of specific circulating tumor cell thresholds on survival outcomes.

The sponsor did not provide information regarding the total number of participants. The study population consists of female patients, including both pre- and postmenopausal individuals, aged 18 years or older, diagnosed with metastatic breast cancer. Eligible participants must have histologically confirmed adenocarcinoma of the breast with radiological evidence of metastasis. The disease must be hormone receptor-positive (HR+), specifically demonstrating estrogen receptor (ER) or progesterone receptor (PgR) expression ≥ 1% via immunohistochemistry, and HER2-negative as determined by fluorescence in situ hybridization (FISH) or immunohistochemistry. Participants must have experienced disease progression following at least 6 months of first-line endocrine therapy involving CDK 4/6 inhibitors. Required clinical characteristics include an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate kidney, bone marrow, and liver function. Women of childbearing potential are required to maintain effective contraception or abstinence during the study period.

This multicenter, multicohort, phase 2 platform trial is designed to evaluate a biomarker-driven workflow for guiding clinical decision-making in patients with metastatic breast cancer that is hormone receptor-positive and HER2-negative. The research methodology utilizes an integrated liquid biopsy algorithm to personalize second-line treatment intensity and targeting. The study involves several therapeutic options, including fulvestrant, trastuzumab deruxtecan, capecitabine, capivasertib, and elacestrant. The primary endpoint is the clinical benefit rate, while secondary endpoints include progression-free survival, overall survival, and the prognostic impact of somatic alterations detected via next-generation sequencing and circulating tumor cells. The trial is expected to occur between June 2026 and June 2033. Participants undergo a screening process to confirm eligibility based on histological diagnosis, molecular assessment, and performance status. Following recruitment, participants proceed through scheduled study visits to receive treatment and undergo follow-up assessments. Early termination from the study may occur based on protocol-defined conditions.

Fulvestrant is administered as a solution for injection via an intramuscular route at a dose of 500 mg.

Trastuzumab deruxtecan is provided as a powder for concentrate for solution for infusion and is administered via intravenous infusion at a dosage of 5.4 mg/kg.

Capecitabine is administered as a film-coated tablet through an oral route at a dose of 2500 mg/m2.

Capivasertib is administered as a film-coated tablet through an oral route at a dose of 800 mg.

Elacestrant is administered as a film-coated tablet through an oral route at a dose of 345 mg.

The primary efficacy endpoint for this study is the Clinical Benefit Rate (CBR). This is defined as the proportion of patients achieving a Complete response (CR), Partial response (PR), or Stable disease (SD) lasting for a minimum of 6 months, as determined by RECIST 1.1 criteria.

Secondary efficacy parameters include:

• Progression Free Survival (PFS), measured as the time from the initiation of second-line treatment until disease progression or death from any cause.
• Overall Survival (OS), measured as the time from the initiation of second-line treatment until death from any cause.
• The prevalence of somatic alterations identified through plasma NGS in patients eligible for second-line therapy in HR+/HER2- metastatic breast cancer.
• The prognostic impact of somatic alterations detected via plasma NGS on PFS and OS.
• The proportion of patients exhibiting a CTCs count ≥ 5/7.5 mL compared to those with a count <5/7.5 mL at the baseline of second-line therapy.
• The prognostic impact of a CTCs count ≥ 5/7.5 mL on PFS and OS relative to a count <5/7.5 mL.