Efficacy and Safety of Ribociclib in Pre- and Postmenopausal Chinese Women With HR Positive, HER2-negative, Advanced Breast Cancer.

Phase II Randomized, Double-blind, Placebo-controlled Study of LEE011(Ribociclib) or Placebo in Combination With Endocrine Therapy for the Treatment of Pre- and Postmenopausal Chinese Women With HR Positive, HER2-negative, Advanced Breast Cancer, Including a Subset With Pharmacokinetic Analysis.

This was a randomized, double-blind, placebo-controlled study conducted in Chinese women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer, plus an open-label, single-arm pharmacokinetic (PK) subset in postmenopausal Chinese women with HR+, HER2- advanced breast cancer.

The study included three cohorts of subjects: a premenopausal cohort and a postmenopausal cohort, both randomized and double-blind, and an open-label, single-arm pharmacokinetic (PK) cohort of postmenopausal women.

The premenopausal cohort assessed the efficacy and safety of treatment with a non-steroidal aromatase inhibitor (NSAI; letrozole or anastrozole) combined with goserelin and ribociclib, compared with NSAI plus goserelin and placebo. The postmenopausal cohort assessed the efficacy and safety of ribociclib plus letrozole versus placebo plus letrozole.

The study consisted of three periods: screening, treatment, and follow-up.

1. Screening phase: The study began with a 28-day screening period during which potential participants were evaluated against inclusion and exclusion criteria before initiating treatment on Day 1.

2. Treatment phase: Eligible participants in the premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to one of two treatment arms, while participants in the PK cohort were not randomized. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Following a statistically significant progression-free survival (PFS) benefit observed at the primary analysis and implementation of Protocol Amendment 5 (dated 18-Oct-2022), participants and investigators were unblinded. Participants still receiving placebo were offered the option to cross over to ribociclib, at the investigator's discretion and with participant consent.

3. Follow-up phase:

   • Safety follow-up: All participants were followed for safety for up to 30 days after the last dose of study treatment, except in cases of death, loss to follow-up, or withdrawal of consent.
   • Efficacy follow-up: Tumor assessments were performed at baseline and every 8 weeks (±1 week) from randomization for the first 18 months, then every 12 weeks (±1 week) until 36 months, and thereafter as clinically indicated until progression. Participants who discontinued treatment for reasons other than disease progression continued tumor assessments according to the same schedule until progression, death, withdrawal of consent, or loss to follow-up.
   • Survival follow-up: Survival status was assessed every 12 weeks (±1 week) for all participants, regardless of treatment discontinuation reason, unless consent was withdrawn.

The end of the study was defined as the earliest occurrence of one of the following: all participants had discontinued or died; a new clinical study offering ribociclib became available and all ongoing participants were eligible for transfer; or participants still benefiting from treatment could continue receiving it through an alternative setting.

Inclusion Criteria:

• Patient has a histologically and/or cytologically confirmed diagnosis of estrogen receptor (ER) positive and/or progesterone receptor positive breast cancer by local laboratory (based on most recently analyzed biopsy).

• Patient has HER2-negative breast cancer (based on most recently analyzed biopsy) defined as a negative in situ hybridization test or an Immunohistochemistry (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.

• Patient must have either:

  • Measurable disease, i.e., at least 1 measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation). OR
  • If no measurable disease is present, then at least 1 predominantly lytic bone lesion must be present (patients with no measurable disease and only 1 predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).

• Patient has ECOG performance status 0 or 1.

For premenopausal cohort:

• Patient is an adult, female ≥ 18 years old and < 60 years old at the time of informed consent and has signed informed consent before any trial related activities are conducted and according to local guidelines.
• Confirmed negative serum pregnancy test before starting study treatment or patient has had a hysterectomy.
• Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer not amenable to curative therapy (e.g.

surgery and/or radiotherapy).

• Patients who received ≤ 14 days of a NSAI (letrozole or anastrozole) with or without goserelin or goserelin ≤ 28 days for advanced breast cancer prior to randomization are eligible. Patients must continue treatment with the same hormonal agent + goserelin during the study. No treatment interruption is required for these patients prior to randomization.
• Patients who have received up to 1 line of chemotherapy for advanced breast cancer and have been discontinued 28 days before randomization are eligible.

For postmenopausal cohort:

• Patient is an adult, female ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.
• Women with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.

Exclusion Criteria:

• Patient who has received a prior CDK4/6 inhibitor.
• Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment
• Patient with CNS metastases.
• Patient who has not had resolution of clinical and laboratory acute toxicities related to prior anti-cancer therapy to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade ≤1.
• Patient has a known history of Human immunodeficiency Virus (HIV) infection (testing not mandatory).
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality
• Patient is currently receiving any of the substances as defined in the protocol that cannot be discontinued 7 days prior to the start of the treatment:

For premenopausal cohort:

• Pregnant or nursing (lactating) women.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment and for 21 days after stopping study medication.

Note: Use of oral (estrogen and progesterone), transdermal, injected or implanted hormonal methods of contraception as well as hormonal replacement therapy is not allowed in this study.

For postmenopausal cohort:

- Patient who received any prior systemic anti-cancer therapy (including hormonal therapy and chemotherapy) for advanced breast cancer.

Note: Patients who received neo (adjuvant) therapy for breast cancer are eligible. If the prior neo (adjuvant) therapy included letrozole or anastrozole, the disease free interval must be greater than 12 months from the completion of treatment until randomization.

- Patients who received ≤ 14 days of letrozole or anastrozole for advanced disease prior to randomization are eligible.

Other protocol-defined inclusion/exclusion may apply.