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Ribociclib approved as the first-line agent for metastatic breast cancer

Breast cancer is the second leading cause of cancer-related mortality in women, after lung cancer.1 The American Cancer Society estimates that more than 250,000 women will be diagnosed with invasive breast cancer in the US in the year 2017 .1 In spite of advances in breast cancer treatment, up to one-third of patients diagnosed with early-stages of breast cancer eventually develop advanced or metastatic disease.2

Studies have revealed that approximately 80% of breast cancers are hormone receptor-positive (HR+) (either estrogen receptor {ER+}- positive or progesterone receptor {PR+}-positive)3. Approximately 75% of postmenopausal cancers are HR+, while the percentage of premenopausal cancers is about 50%.4  

 As a systemic treatment option for advanced breast cancer, endocrine therapy is very effective and important.5-7 In postmenopausal women with advanced breast cancer, third-generation aromatase inhibitors (e.g. letrozole, anastrozole, and exemestane) are used as first-line treatment.8 The development of resistance, however, restricts the long-term efficacy of endocrine therapies.9 Cyclin-dependent kinases (CDK) are found to be useful targets for overcoming resistance to hormonal therapy. CDK inhibitors target two proteins—CDK 4 and CDK 6; both are responsible for driving the growth of tumor cells. Targeting CDK 4/6 with accuracy may play an important role in control of frenzied replication of cancer cells.10

The US Food and Drug Administration (FDA), recently granted approval to ribociclib, formerly known as LEE011 (Kisqali, Novartis), a CDK4/6 inhibitor for use in combination with an aromatase inhibitor as first line therapy in postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer. Kisqali® was developed by the Novartis Institutes for Biomedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.11,12

The expedited approval was based on results of phase III MONALEESA-2 trial, comprising 668 postmenopausal women with HR+/HER2 advanced or metastatic cancer. Patients received either combination of letrozole (AI) and ribociclib or letrozole with placebo, with no prior systemic therapy. Progression free survival (PFS) .i.e., the length of time tumors did not grow after treatment, was the primarily measured parameter along with other parameters such as overall survival (OS), overall response rate and safety.  The median duration of PFS was not reached in the ribociclib group versus 14.7 months in the placebo group. This represents a 44% improvement which favours the combination therapy, which was highly statistically significant (P=.00000329). After 18 months, the PFS rate was 63% for combination therapy vs. 42.2% for letrozole with placebo. Hazard ratio based on independent review was found to be .59, in favour of the ribociclib arm (P=.002)13.

The overall response rate observed in patients with measurable disease was 53% with ribociclib plus letrozole vs. 37% with letrozole and placebo (P = .00028). The clinical benefit rate (.i.e., overall response plus stable disease that lasts 24 weeks or more) was also higher with the combination therapy: 80% vs. 72%, respectively (P = .02).Overall survival data were not mature till the time of interim analysis.13

The most common side effects (observed in 20% or more patients) associated with ribociclib treatment were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, back pain and prolonged QT interval.13

Ribociclib was granted breakthrough therapy designation by the FDA in August 2016. The results of this trial affirm that combination therapy with a CDK 4/6 inhibitor such as ribociclib and an aromatase inhibitor should be a new standard of care for initial treatment of HR+ advanced breast cancer.

Credit: Dr. Neha on behalf of Borderless Access

Copyright © 2017 BorderlessAccess



  1. American Cancer Society. How Common Is Breast Cancer?
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  5. Campone M, Bachelot T, Gnant M, et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study.
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  10. O’Sullivan C. Overcoming endocrine resistance in hormone-receptor positive advanced breast cancer-the emerging role of CDK4/6 inhibitors.
  13. Hortobagyi GN et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer.
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