Real-world evidence of ribociclib-induced hepatotoxicity in patients with breast cancer: a multi-center experience

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BACKGROUND: CDK4/6 inhibitors are primarily used to treat hormone-positive HER-2 negative (HR+/ HER2-) metastatic breast cancer. Although ribociclib is generally well-tolerated, there is limited real-world data on hepatotoxicity associated with its use. Therefore, we evaluated the characteristics and management of ribociclib-induced hepatotoxicity. METHODS: Patients screened in the study received ribociclib for the treatment of metastatic HR+/ HER2- breast cancer between January 2019 and December 2023 at Hacettepe University Hospital, Ankara Bilkent City Hospital, Ankara Etlik City Hospital, Gazi University Hospital, and Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital. Ribociclib-induced hepatotoxicity was evaluated using retrospective laboratory results. The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was utilized to grade the severity of the liver injury. The primary objective of our study is to consider ribociclib-induced hepatotoxicity, with a view to providing information about this less common adverse event. The secondary objective of our study is to compare survival rates between patients who developed grade 1-2 hepatotoxicity and those who developed grade 3-4 hepatotoxicity. RESULTS: 845 patients were screened, and 78 (9.2%) were found to have developed ribociclib-induced hepatotoxicity. Of these, 5 (6.4%) had grade 4 toxicity, 19 (24.4%) had grade 3, and 54 (69.2%) had grade 1-2 toxicity. In patients with grade 4 toxicity, ribociclib was discontinued in all patients (one of whom was successfully re-challenged with ribociclib). In patients with grade 3 toxicity, dose reduction was applied in 12 patients, and ribociclib was discontinued in 5 patients (one of whom was successfully re-challenged with palbociclib). For patients with grade 1-2 toxicity, dose reduction was applied in 7 patients, and only 1 patient permanently discontinued ribociclib. In our study, a total of 9 patients (11.5%) permanently discontinued ribociclib. This group comprised four patients with grade 4 toxicity, four patients with grade 3 toxicity, and one patient with grade 1-2 toxicity. No fatal case of ribociclib-induced hepatotoxicity was observed. The median time from the initiation of ribociclib to the onset of ribociclib-induced hepatotoxicity was 13 (IQR = 7-27) weeks. The median time from the initiation of ribociclib to the final follow-up was 16 months. The findings of our study indicate that the one-year overall survival rate for patients with grade 1-2 hepatotoxicity is 90%, while the rate for patients with grade 3-4 hepatotoxicity is 76%.(p = 0.044). CONCLUSIONS: Ribociclib is associated with an increased risk of hepatotoxicity, with the potential for grade 3-4 in a small number of patients. Our analysis suggested a potential association between grade 3-4 hepatotoxicity and reduced OS, warranting further investigation. Regular monitoring of liver function tests during ribociclib treatment may help clinicians identify high-risk patients requiring closer follow-up.