Abstract Background: Ribociclib, a CDK4/6 inhibitor, is widely used in hormone receptor-positive, HER2-negative breast cancer. While hepatotoxicity is a known adverse event associated with ribociclib, its real-world incidence and characteristics may differ from those observed in clinical trials. This study aimed to evaluate the incidence, severity, and clinical course of hepatotoxicity in patients receiving ribociclib in routine clinical practice. Methods: We conducted a retrospective chart review of 90 patients treated with ribociclib at our institution. Patients who received fewer than 14 days of treatment (n=25) were excluded, leaving 65 patients for analysis. We assessed liver function test abnormalities during treatment and graded hepatotoxicity according to CTCAE v5.0 criteria. Data on baseline liver disease, liver metastases, concurrent hepatotoxic medications, and CYP3A4 inhibitors were collected. Results: Among the 65 patients included, 10 (15.4%) developed grade 3-4 hepatotoxicity: 5 patients (7.7%) with grade 3 and 5 patients (7.7%) with grade 4. The observed incidence of grade 4 hepatotoxicity was approximately three-fold higher than reported in pivotal ribociclib clinical trials, including MONALEESA-2, MONALEESA-3, MONALEESA-7, and NATALEE, where incidence of grade 4 hepatotoxicity ranged from 0.9-2.5%.1-4 Notably, only 2 of the 10 patients had baseline liver metastases, and just 1 patient had known baseline liver disease (hepatic steatosis). None of the patients who experienced grade 3-4 hepatotoxicity were receiving strong CYP3A4 inhibitors or other hepatotoxic medications at the time of onset. The median time to onset of hepatotoxicity was 15 weeks (range: 2-29 weeks), and the median time to recovery was 11 weeks (range: 4-30 weeks). Among the 5 patients who developed grade 3 hepatotoxicity, 3 were rechallenged with a reduced dose of ribociclib. All three patients experienced recurrent hepatotoxicity following rechallenge. Conclusions: In this real-world cohort, the incidence of grade 4 hepatotoxicity with ribociclib was significantly higher than reported in clinical trials, underscoring the importance of vigilant hepatic monitoring beyond trial conditions. Hepatotoxicity occurred independently of baseline liver metastases, pre-existing liver disease, or concurrent use of known hepatotoxic agents. Rechallenge following grade 3 hepatotoxicity was associated with recurrence, suggesting cautious consideration before re-initiation. These findings highlight the need for personalized risk assessment and further investigation into predictors of severe hepatotoxicity in patients treated with ribociclib. References Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022;386(10):942-950. Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 2018;36:2465-2472. Lu YS, Im SA, Colleoni M, et al. Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2- Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial. Clin Canc Res 2022;28(5):851-859. Slamon DJ, Lipatov O, Nowecki Z, et al. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med 2024;390(12):1080-1091. Citation Format: J. Hill, B. Kielkowski, S. Nolfi, C. Marino, L. Thomas. Real-world evaluation of hepatotoxicity during treatment with ribociclib abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-03-24.
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