FDA-Approved CDK4/6 Inhibitors for Early and Metastatic Breast Cancer

FDA-Approved CDK4/6 Inhibitors for Early and Metastatic Breast Cancer

Clinical Context and Available Therapies

This educational discussion focuses on CDK4/6 inhibitors approved for hormone receptor-positive, HER2-negative breast cancer treatment. In the early breast cancer setting, two agents have received FDA approval: abemaciclib (approved based on the monarchE trial) and ribociclib (approved based on the NATALEE trial). These approvals were based on distinct study populations and cannot be directly compared due to significantly different trial designs, inclusion criteria, and treatment protocols.

Early Breast Cancer Applications

The monarchE trial evaluated abemaciclib in patients with 4 or more positive lymph nodes, or 1 to 3 positive nodes with tumors ≥5 centimeters or grade 3 histology. Treatment duration was 2 years with standard dosing (150 mg twice daily), and tamoxifen was permitted as adjuvant endocrine therapy. In contrast, the NATALEE trial studied ribociclib in patients with any nodal involvement or high-risk node-negative disease (defined by tumor size ≥5 cm, or 2- to 5-cm tumors with high genomic risk, grade 3, or Ki-67 >20%). Ribociclib was administered for 3 years at a reduced dose (400mg daily for 3 weeks, one week off), with tamoxifen contraindicated due to drug interactions.

Metastatic Disease Treatment Options

Three CDK4/6 inhibitors are approved for metastatic breast cancer: palbociclib, ribociclib, and abemaciclib. Multiple pivotal trials (PALOMA, MONALEESA, and MONARCH studies) demonstrated approximately 2-year progression-free survival advantages when combined with aromatase inhibitors, compared to 16 months with letrozole alone. These agents are also approved with fulvestrant, and abemaciclib has single-agent indication at higher dosing (200vmg twice daily). Ribociclib notably has Category 1 overall survival data in the metastatic setting, with both ribociclib and abemaciclib having Category 1 NCCN recommendations when combined with fulvestrant.