Evaluating Biomarker Driven Early Therapeutic Selection in Patients With HR + HER2 - Metastatic or Unresectable Breast Cancer

PRIMARY OBJECTIVE:

I. Evaluate progression free survival (PFS) and clinical benefit rate (CBR) in patients who remain on CDK4/6 inhibitor (i) (patients with suppressed TKa levels at cycle [C]1 day [D]15) as well as PFS2 and CBR in patients who switch to an alternate therapy (patients with unsuppressed TKa levels at C1D15).

SECONDARY OBJECTIVES:

I. Evaluate the feasibility of early therapeutic switching in patients with metastatic estrogen receptor positive (ER+) HER2- breast cancer on first-line CDK4/6 inhibitors with unsuppressed TKa levels at C1D15 and delayed imaging in patients with suppressed TKa levels.

II. Evaluate C1D15 and C2D1 TKa level to predict overall survival (OS) on first-line CDK4/6 inhibitors and later lines of therapy.

III. In patients with TKa suppressed at C1D15, evaluate if subsequent suppressed TKa levels would have a high likelihood predicting stable disease on subsequent staging scans within the 2 years of study period.

TERTIARY/EXPLORATORY OBJECTIVES:

I. Changes in TKa between baseline and C1D15 in patients with HR positive, HER2 negative metastatic or unresectable breast cancer receiving first-line treatment with CDK4/6 inhibitor (CDK4/6i) and endocrine therapy.

II. TKa at disease progression.

III. TKa dynamics on C1D15, C2D1 and disease progression, compared to circulating tumor deoxyribonucleic acid (ctDNA) profiles.

IV. ctDNA profiles at pre-treatment (baseline) versus (vs) progression on CDK4/6 inhibitor for potential resistance mechanisms.

V. Analysis of serum or plasma for potential circulating biomarkers of CDK4/6 inhibitor response.

VI. Analysis of peripheral blood mononuclear cell (PBMC) for immune cell subset composition on CDK4/6 inhibitor.

VII. Genomic profiling of circulating tumor cells in relation to response to CDK4/6 inhibitor response.

VIII. Tumor genomic and transcriptomic studies on tumor samples collected (baseline archival required, optional biopsy at progression) for potential predictors of response.

IX. Analysis of TKa at progression to examine correlation between the TKa level at the time of progression and outcome on subsequent therapy.

OUTLINE: Patients are assigned to 1 of 2 arms. Physicians are assigned to Arm III.

ARM I: Patients receive standard of care (SOC) endocrine therapy and ribociclib or other CDK4/6 inhibitor and undergo blood sample collections on C1D15. Patients with a lack of suppressed TKa levels at C1D15 receive a recommendation to switch to an alternative therapy. Patients then undergo blood sample collections at initiation of this second-line therapy and on the first day of subsequent cycles until clinical progression. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scans on study. Patients may also undergo bone scan or positron emission tomography (PET) scans on study.

ARM II: Patients receive SOC endocrine therapy and ribociclib or other CDK4/6 inhibitor and undergo blood sample collections on C1D15. Patients with suppressed TKa levels at C1D15 or those that remain on first line treatment with lack of suppressed TKa levels at C1D15 continue SOC therapy until clinical progression in the absence of unacceptable toxicity. Patients undergo blood sample collections at C2D1, C4D1, every 3 months thereafter, and at the time of clinical progression. Patients also undergo CT or MRI scans on study. Patients may also undergo bone scan or PET scans on study.

ARM III: Physicians complete surveys on study.

After completion of study intervention, patients are followed up every 6 months for 5 years.