Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer

A Phase II, Multicenter, Randomized, Open-label Study to Evaluate the Safety and Efficacy of 400 mg of Ribociclib in Combination With Non-steroidal Aromatase Inhibitors for the Treatment of Pre- and Postmenopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease

The purpose of the study was to evaluate the safety and efficacy of a reduced ribociclib starting dose of 400 mg in combination with a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) for the treatment of pre- and postmenopausal women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer (aBC) who have received no prior therapy for advanced disease. Premenopausal women were required to receive goserelin in both treatment arms.

Patients were assigned at visit Cycle 1 Day 1 to one of the following two treatment arms in a ratio of 1:1:

• Experimental arm: Ribociclib 400 mg (2 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of:

  • For postmenopausal women:

  • Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously

    • For premenopausal women:

  • Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.

• Control arm: Ribociclib 600 mg (3 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of:

  • For postmenopausal women:

    ~ Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously.

  • For premenopausal women:

    • Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.

Participants received study treatment until disease progression (radiologically documented according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

For participants who discontinued treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor assessments continued to be performed until disease progression, death, lost to follow-up, or withdrawal of consent (post-treatment efficacy follow-up).

Key inclusion criteria:

• Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable to curative therapy.

• Patient has a histologically and/or cytologically confirmed diagnosis of ER-positive and/or PgR-positive breast cancer based on the most recently analyzed tissue sample, and all tested by local laboratory.

• Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample.

• Patient must have measurable disease, i.e., at least one measurable lesion according to RECIST version 1.1. (a lesion in a previously irradiated site may only be counted as a target lesion if there is clear evidence of progression since the irradiation).

• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

• Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory:

  • QTcF interval at screening < 450 ms (QT interval using Fridericia's correction)
  • Mean resting heart rate 50 to 90 bpm (determined from the ECG)

• Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant, must have confirmed negative serum pregnancy test (for β-hCG) within 14 days prior to randomization.

• Women of CBP must be willing to use highly effective methods of contraception.

Key Exclusion Criteria:

• Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's judgment.
• Patient who received any prior systemic anti-cancer therapy(including endocrine therapy, chemotherapy, prior CDK4/6 inhibitors) for aBC. Patients who received neo-/adjuvant therapy for breast cancer are eligible.
• Patient is concurrently using other anti-cancer therapy.
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major toxicities.
• Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to randomization, and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patients in whom ≥
• 25% of the bone marrow has been previously irradiated are also excluded.
• Patient has a concurrent malignancy or malignancy within 3 years of the randomization date, with the exception of adequately treated basal or squamous cell skin carcinoma, or curatively resected cervical carcinoma in situ.
• Patients with central nervous system (CNS) involvement unless they meet specific stability criteria.
• Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality.
• Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, and has not fully recovered from side effects of such treatment.

Other protocol-defined Inclusion/Exclusion may apply.