ANTI-HORMONAL MAINTENANCE TREATMENT WITH THE CDK4/6 INHIBITOR RIBOCICLIB AFTER 1ST LINE CHEMOTHERAPY IN HORMONE RECEPTOR POSITIVE / HER2 NEGATIVE METASTATIC BREAST CANCER: A PHASE II TRIAL
Dysregulation of the cell cycle is one of the hallmarks of cancer. The cycline dependent kinases are a large family of serine / threonine kinases that have a crucial role in regulating cell cycle progression. Once they are activated by
their catalytic partners, the cyclines, they promote cell cycle progression in normal and malignant cells. The cycline dependent kinases 4 and 6 (CDK4/6) and their partner d-type cyclines control transition from G1 to S phase of the cell cycle by phosphorylating the retinoblastoma protein.
Strong preclinical evidence has been demonstrated for a synergistic growth inhibitory effect of CDK4/6 inhibition with antiestrogens in hormone-receptor (HR) positive breast cancer cell lines. Palbociclib, an oral small molecule inhibitor of CDK4/6 has been shown to significantly prolong progression free survival (from 10.2 to 20.2 months) in postmenopausal women with metastatic HR-positive / HER2-negative breast cancer when added to letrozole in a randomized phase II and the subsequent phase III study (from 14.5 to 24.8 months; HR=0.58). Treatment was well tolerated with mostly grade 1-2
adverse events with the exception of grade 3 neutropenia, which rarely leads to febrile neutropenia.
Ribociclib another CDK4/6 inhibitor is currently evaluated in various disease settings including phase III trials in metastatic breast cancer. The phase III MONALEESA-2 trial has reported a significant improvement in PFS in 1st line
metastatic breast cancer when ribociclib was added to letrozole (25.3 vs. 16.0 months; HR=0.57).
Albeit the guidelines recommend to use endocrine therapy as the first step in HR-positive/HER2-negative metastatic breast cancer about 30% will receive chemotherapy. At present, no evidence is available about the optimum duration of first-line chemotherapy in metastatic breast cancer. Although, a meta-analysis of 11 randomized trials has shown that longer duration of therapy is associated with longer progression-free survival (PFS) and overall survival (OS), the duration of chemotherapy is usually determined by toxicities and patients and physicians´ preferences, resulting in treatment periods of less than 6 months. In contrast, maintenance treatment strategies are standard of care not only in breast but also in lung cancer, colorectal cancer, lymphoma and myeloma.
Longer OS and PFS have been demonstrated recently in patients treated with capecitabine and bevacizumab as compared to bevacizumab alone as maintenance treatment after 1st line therapy with a taxane and bevacizumab.
Maintenance treatment with anti-hormonal drugs is also an accepted treatment strategy in everyday clinical practice although prospective data are lacking. However, data were presented recently, demonstrating that maintenance treatment with bevacizumab and exemestane was as effective as prolonged therapy with paclitaxel and bevacizumab with better tolerability.
This is a multicenter, prospective, randomized, open-label, controlled phase II study to test the addition of the CDK4/6 inhibitor ribociclib to anti-hormonal treatment as maintenance therapy in patients with disease control (at least stable disease) after 1st line chemotherapy.
Treatment will be given until disease progression, unacceptable toxicity, or withdrawal of consent of the patient.
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