Ribociclib is a unique cyclin-dependent kinase inhibitor that is used in combination with aromatase inhibitors in the treatment of postmenopausal women with metastatic breast cancer. Ribociclib is associated with a moderate rate of serum aminotransferase elevations during therapy, and to clinically apparent liver injury in a proportion of these.


Ribociclib (rye" boe sye' klib) is an orally available, small molecule inhibitor of cyclin-dependent kinases 4 and 6 that is used in combination with aromatase inhibitors in the therapy of postmenopausal women with metastatic breast cancer that is positive for the estrogen hormone receptor (ER+), but negative for human epidermal growth factor receptor 2 (HER2-). The cyclin kinases 4 and 6 regulate the cellular transition from the G1 to the S phase of the cell cycle acting through the retinoblastoma protein (Rb) pathway. Inhibition of this transition blocks the progression of the cell cycle and results in growth arrest in rapidly dividing cells. Components of this pathway are often mutated or overexpressed in cancer cells. In several clinical trials, the addition of ribociclib to letrozole (aromatase inhibitor) therapy of advanced or metastatic breast cancer (ER+, HER2-) in postmenopausal women was associated with a prolongation of disease-free but not overall survival. Ribociclib received accelerated approval for use in the United States in 2017. Ribociclib is under investigation as therapy of several solid tumors and lymphomas, but the initial indications were limited to advanced or metastatic ER+, HER2- breast cancer in postmenopausal women given in combination with an aromatase inhibitor. Ribociclib is available in tablets of 200 mg under the brand name Kisqali, and the initial recommended dose is 600 mg once daily in 21 day cycles every 28 days indefinitely or until there is disease progression. Common side effects include neutropenia, fatigue, nausea, diarrhea, anorexia, thrombocytopenia, headache and back pain. Less common, but potentially severe adverse reactions include prolongation of the QTc interval, severe neutropenia, fever and infections, and embryo-fetal toxicity.


In the large clinical trials, adverse events were common and led to dose reductions in 45% of patients and discontinuation in 7%. In preregistration clinical trials, ALT elevations occurred in 46% of ribociclib vs 36% of control subjects and elevations above 5 times the ULN in 10% vs 1%. In one study, 1% of recipients developed clinically apparent liver injury with jaundice, but all recovered. The liver injury arose after 3 to 5 cycles and presented with asymptomatic elevations in serum ALT followed by symptoms and jaundice. Immunoallergic and autoimmune features were not present, although liver histology sometimes showed autoimmune hepatitis-like features. Recovery was slow (3 to 5 months), but ultimately complete. Restarting ribociclib resulted in more rapid and severe recurrence. Thus, experience with ribociclib is limited, but it appears to be capable of causing significant liver injury.

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The causes of serum enzyme elevations and liver injury from ribociclib therapy are not known. Ribociclib is extensively metabolized in the liver largely through the CYP 3A4 pathway and liver injury might be caused by production of a toxic or immunogenic intermediate. On the other hand, inhibition of cyclin-dependent kinases 4 and 6 may also affect hepatocytes and have direct toxicity. Because it is a substrate for CYP 3A4, ribociclib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity.

Outcome and Management

The product label for ribociclib recommends prospective monitoring of liver tests during therapy, with values obtained before starting, at 2 week intervals during the first two cycles and at the beginning of the ensuing 4 cycles, and “as clinically indicated” thereafter. The product label also provides careful recommendations for dose interruption, reduction or discontinuation based upon toxicities (neutropenia, liver injury, QTc prolongation), with dose interruption until recovery for aminotransferase elevations above 3 times ULN, interruption until normal and subsequent dose reduction if above 5 times ULN, and permanent discontinuation if above 20 times ULN or in the presence of ALT elevations and jaundice. There is no information regarding cross reactivity in risk for adverse events, hypersensitivity or hepatic injury between ribociclib and palbociclib or other cyclin-dependent kinase inhibitors.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

Other Cyclin-Dependent Kinase Inhibitor Drugs: Palbociclib



Ribociclib – Kisqali®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 08 May 2018

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    (Review of hepatotoxicity published in 1999 before the availability of kinase inhibitors including palbociclib and ribociclib).
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    (Secondary analysis of controlled trial ribociclib and letrozole vs letrozole alone in 668 postmenopausal women with advanced or metastatic breast cancer [Hortobagyi 2016], focusing on 227 with de novo cancer found improved progression-free survival with addition of ribociclib, but higher rates of adverse events, including any AST elevation in 17% vs 4% and values above 5 times ULN in 6% vs none).
  • Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Pet al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2018 Apr 27. [Epub ahead of print] [PubMed: 29718092]
    (Further follow up of results of trial of letrozole with or without ribociclib in 668 postmenopausal women with advanced or metastatic breast cancer [Hortobagyi 2016] reported no differences in overall survival with addition of ribociclib, but higher rates of adverse events including neutropenia [77% vs 6%] and abnormal liver tests [20% vs 6%]).
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