Efficacy and Safety Evaluation of Ribociclib Plus Endocrine Therapy in HR-Positive, HER2-Negative Early Breast Cancer: A Phase IIIb Study

The primary objective of this study is to evaluate the **invasive Breast Cancer Free Survival (iBCFS)** rate at 3 years for the combination of ribociclib and endocrine therapy (ET) in patients with hormone receptor-positive (HR-positive), HER2-negative early breast cancer. This objective is clinically relevant as it aims to determine the efficacy of this treatment regimen in preventing the recurrence of breast cancer, which is crucial for improving long-term patient outcomes.

Secondary objectives include: - Evaluating the **safety** of ribociclib combined with ET. - Assessing **invasive Disease Free Survival (iDFS)** for the combination therapy. - Determining **Distant Relapse-Free Survival (DRFS)**. - Evaluating **Recurrence-Free Interval (RFI)**. - Assessing the **relative dose intensity** of ribociclib. - Evaluating **Overall Survival (OS)**. - Determining the **discontinuation rates** of ribociclib. - Evaluating **Quality of Life (QoL)** through patient-reported outcomes (PROs). - Assessing **Distant Disease-Free Survival (DDFS)** for the combination therapy.

The clinical trial involves a total of **1363 participants** diagnosed with **HR-positive HER-2-negative Breast Cancer**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on a confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer, with HER2-negative status verified through local laboratory testing. The trial includes individuals who have undergone surgical resection with complete tumor removal and have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2, indicating they are in generally good health. Participants may have previously received standard neoadjuvant and/or adjuvant endocrine therapy, provided enrollment occurs within 36 months of the prior therapy start date, and they have at least three years remaining of endocrine adjuvant therapy. The trial population is diverse, including vulnerable populations, and does not impose a cap on the number of Black or African American participants with prior endocrine therapy. Adequate bone marrow and organ function are required, and specific ECG values must be met. The trial aims to evaluate the invasive Breast Cancer Free Survival (iBCFS) rate at three years for ribociclib combined with endocrine therapy in this patient group.

The clinical trial is designed to evaluate the efficacy and safety of **ribociclib** in combination with endocrine therapy in patients with HR-positive, HER2-negative early breast cancer. This is a phase IIIb, randomized, double-blind, controlled trial. The trial aims to assess the invasive Breast Cancer Free Survival (iBCFS) rate at three years. The study is expected to commence recruitment on July 30, 2025, and conclude by October 16, 2031, with an estimated duration of 36 months for each participant's involvement.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and prior treatment history. The inclusion criteria require participants to have a histologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer, with no contraindications to receive adjuvant endocrine therapy. Following the screening, participants will be randomized to receive either the investigational treatment or a control. Subsequent follow-up visits will be scheduled to monitor treatment efficacy and safety, assess adverse events, and ensure compliance with the study protocol. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the occurrence of severe adverse events, disease progression, or withdrawal of consent. The primary endpoint of the trial is the iBCFS rate, assessed using the STEEP Version 2.0 criteria. Secondary endpoints include the incidence and severity of adverse events, overall survival, and changes in quality of life measures. The trial will employ standardized definitions for efficacy endpoints in adjuvant breast cancer clinical trials, ensuring rigorous assessment of outcomes.

The clinical trial involves the administration of several experimental and non-experimental medications. **Leuprorelin Acetate** is provided in the form of a powder and solvent for suspension for injection. It is administered subcutaneously with a maximum daily dose of 11.25 mg and a total maximum dose of 135 mg over a treatment period of up to 36 months. The formulation is relabeled for clinical use in certain cases.

**Goserelin** is utilized in the form of an implant in a pre-filled syringe, also administered subcutaneously. The maximum daily dose is 10.8 mg, with a total maximum dose of 129.6 mg over a 36-month period. This product is similarly relabeled for clinical use when applicable.

**Exemestane** is administered orally in tablet form, with a maximum daily dose of 25 mg and a total maximum dose of 27,300 mg over the course of 36 months. The tablets are relabeled for clinical use in specific instances.

**Ribociclib** is provided as a film-coated tablet for oral use. The maximum daily dose is 400 mg, with a total maximum dose of 302,400 mg over a 36-month treatment period. This medication is relabeled for clinical use.

**Letrozole** is administered orally in tablet form, with a maximum daily dose of 2.5 mg and a total maximum dose of 2,730 mg over 36 months. The tablets are relabeled for clinical use in certain cases.

**Anastrozole** is also provided in tablet form for oral administration. The maximum daily dose is 1 mg, with a total maximum dose of 1,092 mg over a 36-month period. This product is relabeled for clinical use when necessary.

All medications are used in accordance with the trial protocol, and participant compliance is monitored throughout the study. The relabeling of these products is applicable only in specific cases, ensuring their suitability for clinical trial use. The trial aims to evaluate the efficacy and safety of these treatments in patients with hormone receptor-positive, HER2-negative early breast cancer.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **invasive Breast Cancer Free Survival (iBCFS)** rate at 3 years. This will be measured using the STEEP Version 2.0 criteria, which are standardized definitions for efficacy endpoints in adjuvant breast cancer clinical trials. The assessment will be conducted by the investigator. Secondary endpoints include the incidence and severity of adverse events using CTCAE v4.03, invasive Disease-Free Survival (iDFS), Distant Recurrence-Free Survival (DRFS), Recurrence-Free Interval (RFI), Relative Dose Intensity (RDI), overall survival, time to discontinuation of ribociclib, and changes from baseline in patient-reported outcomes using FACT-B, FACT-ES, FACIT-F, EQ-5D-5L, and WPAI-GH questionnaires. Additionally, Distant Disease-Free Survival (DDFS) will be evaluated using the STEEP Version 2.0 criteria.