Study for Women and Men With Hormone-receptor Positive Locally Advanced or Metastatic Breast Cancer

This was a national, multi-center, open-label, phase IIIb trial to determine the efficacy and safety of treatment with ribociclib (LEE011) plus letrozole in patients with HR+, HER2-negative advanced (recurrent or metastatic) breast cancer. Patients were treated with daily doses of 600 mg ribociclib (3-weeks-on/1-week-off schedule) in combination with 2.5 mg letrozole daily (continuous dosing). Dose adjustments (dose reduction or interruption) according to safety findings were allowed.

The main purpose of this study was to collect additional efficacy and safety data for the combination of ribociclib and letrozole in a patient population broader than the MONALEESA-2 study (NCT01958021 / CLEE011A2301), and to provide access to ribociclib to patients for which available treatment options are unsatisfactory treatment alternatives until the drug is approved for this indication. Furthermore, this trial aimed to collect data for the combination of ribociclib and letrozole in the context of current local routine therapy algorithms for the treatment of metastatic and advanced breast cancer.

This multi-center, open-label, single-arm study aimed to evaluate the efficacy, safety, and quality of life for the combination of ribociclib and letrozole in a patient population than in the MONALEESA-2 study, i.e. in patients pretreated with one line of chemotherapy and/or a maximum of two lines of endocrine therapy as well as premenopausal patients, without limitations regarding the disease free interval after adjuvant therapy.

For ethical reasons no endocrine comparator drugs were investigated in this study. The duration of study treatment of 80 weeks was adequate to determine the primary, secondary and exploratory study parameters. The sample size was suitable to estimate the clinical benefit rate (CBR) in this patient population with reasonable precision.

Goserelin was used in premenopausal patients, since it was shown that ovarian suppression of estrogen release with luteinizing hormone-releasing hormone agonists (LHRHa) (such as goserelin) is effective in preventing relapse in premenopausal women with early stage ER+ breast cancer (Klijn et al. 2001).

The efficacy and safety of ribociclib in combination with letrozole for the treatment of postmenopausal women with advanced or metastatic breast cancer vs. placebo (i.e., letrozole alone) was already demonstrated in the preceding, pivotal MONALESSA-2 study. Thus, for ethical reasons no endocrine comparator drugs were investigated in the present RIBECCA study.

Generally, the single-arm, open-label design and the broadening of the study population (compared to the pivotal MONALESSA-2 study) in the RIBECCA study was deemed appropriate to further evaluate the efficacy and safety of ribociclib plus letrozole among breast cancer patients in a treatment setting closer to routine care. The duration of study treatment of up to 80 weeks was considered adequate to determine the primary, secondary and exploratory study parameters. Moreover, the sample size was suitable to estimate the CBR in this patient population with reasonable precision.

Eligibility Criteria:
Inclusion Criteria:

* Patient is an adult, ≥ 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 and men with advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
* Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive and HER2-negative breast cancer by local laboratory. Local pathology is sufficient for assessment.
* Patient must have either:

  1. Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1 criteria ).
  2. Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease
  3. Non-measurable disease
* Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤2

Exclusion Criteria

* Patient who received any CDK4/6 inhibitor or any mTOR inhibitor.
* Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole
* Patients with current inflammatory breast cancer.
* Patient has received \> 1 chemotherapy for the treatment of advanced/metastatic breast cancer
* Patient has received \> 2 endocrine therapies for the treatment of advanced/metastatic breast cancer
* Patient has central nervous system (CNS) involvement. If patient is fulfilling the following 3 criteria she/he is eligible for the trial.

  1. completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study and
  2. CNS tumor is clinically stable at the time of screening and
  3. Patient is not receiving steroids and enzyme inducing anti-epileptic medications for brain metastases
* Patient has active cardiac disease or a history of cardiac dysfunction