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Ribociclib

Oral agent that is an inhibitor of cyclin D1/CDK4 and CDK6, and is a treatment for drug-resistant cancers.

During the cell cycle, CDKs enable transition of cells from G1 to S phase and from G2 to M phase by phosphorylating specific substrates.

CDKs interact with multiple cyclins, CDK4/6 partner with D type cyclins.

A selective CDK4/6 inhibitor preventing progression of dysregulated cancer cells.

Approved for use in combination with an aromatase inhibitor to treat some metastatic breast cancers.

Approved in combination with aromatase inhibitor for initial treatment of post menopausal women with hormone receptor positive HER receptor negative advanced or metastatic breast cancer.

Marketed as Kisqali.

Cyclin-dependent kinases (CDKs) 4 and 6 are enzymes that have been shown to promote cell division and multiplication in both normal and cancer cells.

Many cancer cells have shown abnormalities that increase the activity of CDK, leading to the inactivation of certain tumor suppressor genes.

Inhibiting CDK4 will slow the growth of tumors by reactivating these tumor suppressors.

When used in combination with other drugs such as an ALK or an MEK inhibitor, ribociclib has been shown to have a synergistic effect, resulting in improved responses.

The development of drug resistance can be mitigated with the addition of ribociclib to a therapeutic regime.

Its best response as a single agent thus far has been stable disease.

Increased progression-free survival has reported from the MONALEESA-2 trial, in combination with letrozole, in metastatic breast cancer.

In the MONALEESA-7 trial patients received ribociclib in combination with either tamoxifen or an aromatase inhibitor, and goserelin, a luteinizing hormone release hormone analog: median survival was 23.8 months for ribiciclib vs. standard endocrine therapy plus placebo at 13.0 months.

A trial with ribociclib plus endocrine therapy versus endocrine therapy alone among patients with ER receptor positive, HER2 negative breast cancer showed significantly longer overall survival (MONALEESMA-7).

In the above study the overall response rate was 51% vs 36% in favor of the experimental arm.

Updated analysis of the MonaLEESA-7 trial estimate overall survival at 42 months was 70.2% in the ribociclib group at 46% in the placebo group, with the median overall survival that was not reached in the ribociclib group and was 40.9 months in the placebo group.

MONALEESA-3 extended follow-up showed an overall survival was greater than 12 months longer in patients with HR responsive positive HET2 negative advanced breast cancer treatment with ribociclib plus fulvestrant compared to fulvestrant monotherapy.

Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone receptor positive, HER2 negative advanced breast cancer.

Palbociclib has similar mechanisms and effectiveness.

600 mg oral dose every day for 21 days followed by 7 days off with daily aromatase inhibitor.

Side effects include: fatigue, headache, back pain, alopecia, nausea, diarrhea, vomiting, constipation, impaired appetite, neutropenia, leukemia, elevated liver function tests.

Can cause QT prolongation and can increase the risk for arrhythmias and patients should have monitoring with EKGs, early during treatment.

The drug has been associated with a low risk of prolongation of QT interval and reversible elevation of liver enzymes.

First line therapy with ribociclib plus letrozole shows significant overall survival benefit as compared with placebo plus letrozole in patients with hormone receptor positive HER2  negative advanced breast cancer: median over survival overall survival was more than 12 months longer with ribociclib than with placebo.

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