Ribociclib for HR-Positive Breast Cancer

Posted by • November 3rd, 2016


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Hortobagyi et al. conducted the Mammary Oncology Assessment of LEE011’s (Ribociclib’s) Efficacy and Safety (MONALEESA-2) trial, which evaluated the efficacy and safety of the combination of ribociclib and letrozole as initial therapy in postmenopausal women with hormone-receptor (HR)–positive, human epidermal growth factor 2 (HER2)–negative advanced breast cancer. In patients with advanced HR-positive, HER2-negative breast cancer, the addition of the cyclin-dependent kinase inhibitor ribociclib to letrozole was associated with a significantly higher rate of progression-free survival than placebo. A new Original Article explains.

Clinical Pearl

What percentage of breast cancers are HR-positive?

Up to 75% of breast cancers express the estrogen receptor or progesterone receptor (HR-positive). Endocrine therapy is the standard of care for postmenopausal women with advanced breast cancer that is HR-positive and HER2-negative, with aromatase inhibitors being the preferred first-line treatment option. However, in the majority of patients, resistance to currently available options eventually develops, which requires the administration of sequential therapy with alternative endocrine regimens.

Clinical Pearl

What is ribociclib?

Ribociclib (LEE011) is an orally bioavailable, selective, small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) that blocks the phosphorylation of retinoblastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. CDK4/6 in conjunction with their protein regulator, cyclin D1 (encoded by CCND1), a direct transcriptional target of estrogen-receptor signaling, are mediators of cell-cycle progression. CDK4/6 overexpression and CCND1 amplification are frequently encountered in HR-positive breast cancers and are key mediators of endocrine resistance. The inhibition of a pathway consisting of cyclin D, CDK4/6, inhibitor of CDK4 (INK4), and retinoblastoma protein is an effective therapeutic strategy for HR-positive advanced breast cancer, both as a first-line option and in patients in whom disease has progressed while they were receiving endocrine therapy.

Morning Report Questions

Q: Does the combination of ribociclib and letrozole increase progression-free survival as compared to letrozole plus placebo when used as first-line therapy for HR-positive advanced breast cancer? 

A: At the prospectively planned interim analysis, the authors of the MONALEESA-2 trial found that postmenopausal women with HR-positive, HER2-negative advanced breast cancer who were receiving first-line treatment with ribociclib plus letrozole had a significantly longer duration of progression-free survival than did those receiving placebo plus letrozole, with a 44% lower relative risk of progression. The duration of progression-free survival was longer in all preplanned patient subgroups receiving ribociclib, including those with newly diagnosed or pretreated metastatic disease and those with or without liver or lung metastases. Further analyses of these subgroups are ongoing. Ribociclib plus letrozole was also associated with significantly higher rates of overall response and clinical benefit than was placebo plus letrozole, a finding that was consistent with observations from an earlier phase 1 trial.


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Q: What are some of the adverse events associated CDK4/6 inhibitors?

A: In the MONALEESA-2 trial, the most common grade 3 or 4 adverse events (≥5% of the patients in either group) were neutropenia (59.3% in the ribociclib group and 0.9% in the placebo group), leukopenia (21.0% and 0.6%, respectively), hypertension (9.9% and 10.9%), increased alanine aminotransferase level (9.3% and 1.2%), lymphopenia (6.9% and 0.9%), and increased aspartate aminotransferase level (5.7% and 1.2%). Hematologic adverse events in the ribociclib group reflected on-target CDK4/6 inhibition, which resulted in reversible bone marrow stem-cell quiescence. Elevations in alanine and aspartate aminotransferase levels have also been observed with other CDK4/6 inhibitors in combination with aromatase inhibitors.

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