The Use of Ribociclib plus Letrozole in Patients with CNS Metastases

Approximately 10% to 30% of patients with metastatic breast cancer are diagnosed with central nervous system (CNS) metastases, which are associated with a poor prognosis and are a major cause of morbidity and mortality. Due to improving diagnostics and treatments for breast cancer, leading to longer patient survival, more CNS metastases in patients with breast cancer are being detected. However, patients with CNS metastases are often excluded from clinical trials.

Ribociclib (Kisqali), an oral, selective cyclin-dependent kinase 4/6 inhibitor, is approved for use in combination with endocrine therapy in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.

Paul Cottu, MD, MSc, Medical Oncologist, Curie Institute, Paris, France, and colleagues presented a subgroup analysis of patients with CNS metastases at baseline from the Core Phase of CompLEEment-1, a phase 3b clinical trial of ribociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer. The eligibility criteria for this study allowed a broader and more diverse patient population than those of previous phase 3 trials of ribociclib plus letrozole, to reflect a typical real-world clinical setting.

The CompLEEment-1 study included women of any menopausal status and men with HR-positive, HER2-negative advanced breast cancer treated with up to 1 line of previous chemotherapy and no previous hormonal therapy for advanced disease. Patients received ribociclib at a dose of 600 mg every day for 3 weeks on then 1 week off, combined with letrozole 2.5 mg daily. Men and premenopausal women received a luteinizing hormone-releasing hormone agonist at a dose of 3.6 mg goserelin or 7.5 mg leuprolide, every 28 days.

This subgroup analysis assessed the primary outcomes of safety and tolerability and secondary outcomes of time to progression, overall response rate, and clinical benefit rate in patients with CNS metastases.

Fifty-one patients with CNS metastases, reflecting 1.57% of the total patient population (N = 3246), were evaluated. The median age was 56.0 years. Approximately 59% of the patients were postmenopausal. An Eastern Cooperative Oncology Group performance status of <2 was observed in 96.1% of patients. Approximately 17 months was the median duration of exposure to ribociclib.

Three-quarters (74.5%) of patients reported grade ≥3 adverse effects. Eight patients reported serious adverse effects, including 1 fatal case of sepsis. Neutropenia was reported in 66.7% of patients, the most common of the all-grade adverse effects, followed by nausea in 39.2% and vomiting in 29.4% of patients. The most common grade ≥3 adverse effect was neutropenia reported by more than half (51.0%) of patients, followed by leukopenia (13.7%).

Overall, 37.3% of patients had ≥1 dose reductions of ribociclib, 23.5% due to side effects, and nearly two-thirds (62.7%) permanently discontinued treatment, of which 11.8% was due to side effects. The overall response rate was 42.9%, and the clinical benefit rate was 62.9%.

The investigators concluded that the use of ribociclib plus letrozole in patients with CNS metastases is supported by the subgroup analysis from CompLEEment-1. These patients typically have poor outcomes and are frequently excluded from clinical trials. Yet in this close to real-world setting, the efficacy results in this study highlight the potential benefit of using ribociclib plus letrozole in HR-positive, HER2-negative advanced breast cancer. With few patients discontinuing treatment due to side effects, the safety profile associated with ribociclib plus letrozole was manageable, and the outcomes were consistent with previous phase 3 trials.