What is ribociclib?
Ribociclib is an oral kinase inhibitor targeting cyclin-dependent kinases (CDK), specifically CDK4 and CDK6.
How does ribociclib work?
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 (cyclin types A, B, D, and E). CDK4/6 partner with D-type cyclins. Ribociclib is a selective CDK4/6 inhibitor preventing progression of dysregulated cancer cells.
What is this approved for?
Ribociclib is approved in combination with an aromatase inhibitor for initial treatment in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
What is the basis for this approval?
The FDA approval for ribociclib was based on the results of the MONALEESA-2 trial. This phase III, placebo-controlled, randomized trial compared ribociclib or placebo in combination with letrozole for front-line treatment in 668 postmenopausal patients with advanced or metastatic breast cancer found to be HR-positive and HER2-negative. The primary endpoint was progression-free survival (PFS) and secondary endpoint of overall survival (OS). At the time of the pre-planned interim analysis, the median PFS had not been reached by the ribociclib arm while the placebo arm was 14.7 months (HR 0.56; p < 0.0001). OS had not matured at the time of the interim analysis, with 23 deaths observed in the ribociclib arm compared to 20 deaths in the placebo arm (N Engl J Med 2016;375:1738-1748).
How do you administer this drug?
Ribociclib is administered as a 600 mg oral dose every day for 21 days, followed by 7 days off in combination with an aromatase inhibitor taken daily on a continuous basis. It is recommended to take ribociclib along with an aromatase inhibitor at approximately the same time each day, preferably in the morning without regard to food. Dose reductions occur by decreasing in 200 mg/day increments. Therapy should be discontinued if dosing below 200 mg/day is required.
Are there any premedications needed for ribociclib?
No routine premedications are needed with ribociclib.
What are the common side effects associated with ribociclib (> or =10%)?
* General: fatigue, headache, back pain
* Dermatologic: alopecia
* GI: nausea, diarrhea, vomiting, constipation, decreased appetite
* Hematologic: neutropenia, leukopenia
* Hepatic: increased ALT/AST, increased bilirubin
What are the uncommon side effects associated with ribociclib (less than 10%)?
Prolonged QT interval on EKG (concentration-dependent), febrile neutropenia, syncope, decreased serum bilirubin
Are there any important drug interactions I should be aware of?
Ribociclib is hepatically metabolized predominantly via CYP3A4. If a patient must receive a strong inhibitor of CYP3A4 (e.g., clarithromycin, ketoconazole) the dose of ribociclib should be reduced to 400 mg daily. It is recommended to avoid strong CYP3A4 inducers and monitor closely patients who may need to receive medications which are a CYP3A4 substrate and have a narrow therapeutic index.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
Ribociclib undergoes significant hepatic metabolism. Patients with moderate to severe hepatic impairment (Child-Pugh class B and C) should start with 400 mg daily. Pharmacokinetic data indicate no effect on the exposure of ribociclib in patients with mild-moderate renal impairment. No data is available in severe renal impairment.
Practical tips
Patients should be monitored for neutropenia, hepatobiliary toxicity, and QT interval prolongation. It is recommended to monitor ANC and AST/ALT/total bilirubin before initiating ribociclib followed by every 2 weeks for the first 2 cycles, then prior to the next 4 cycles and then as clinically indicated. EKGs should be assessed prior to starting treatment, at 14 days after initiation of therapy, the beginning of the second cycle, and then as clinically indicated.
What should my patients know about ribociclib?
Patients should contact their health care provider if they experience any of the following:
* Fever
* Abnormal heartbeat, dizziness, or fainting
* Yellowing of the skin, right-sided abdominal pain, bruising or bleeding easily, and loss of appetite
What else should I know about ribociclib?
* Ribociclib is dispensed in blister packs with each blister pack containing 21 tablets (200 mg per tablet) and three blister packs per package to assist in improved patient compliance. Additional packages are available for required dose reductions to 400 or 200 mg daily doses.
* Avoid eating and drinking pomegranate or grapefruit during treatment as this will lead to increased serum levels of ribociclib.
What useful links are available regarding ribociclib?
* https://www.us.kisqali.com/metastatic-breast-cancer/
* https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm546438.htm
Any recruiting clinical trials related to ribociclib?
Please refer to http://www.clinicaltrials.gov for updated information on current clinical trials involving ribociclib.
JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor. RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor.