Tips for searching:
• You have to select a product and type at least 2 words to activate the search
• Use only words that are specific to the information you are looking for
• Avoid typing questions or sentences
Please do not use this field to report adverse events or product complaints. Adverse events and product complaints should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow card in the Google play or Apple app store. Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on 01256 315 000.
Verzenios ® (abemaciclib)
This information is intended for UK registered healthcare professionals only in response to your search for information. For current information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
How to manage hepatic toxicity and impairment with Verzenios® (abemaciclib) in early breast cancer
Dose interruption, reduction, discontinuation, or delay in starting treatment cycles is recommended for persistent or recurrent grade 2, 3 or 4, hepatic transaminase elevations.
Content overview
Management recommendations for hepatic impairment
No dose adjustments are necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment.1
In patients with severe (Child Pugh C) hepatic impairment, a decrease in dosing frequency to once daily is recommended.1
Management recommendations for hepatic toxicities
Hepatotoxicity in monarchE: AFU1 Safety Analysis
The most comprehensive safety analysis of the monarchE study data was conducted at the additional follow-up 1 (AFU1) analysis (median follow-up, 27 months; data cutoff date: April 1, 2021) therefore those results are described in detail in this response.3 Safety findings at the recent overall survival interim analysis (OS IA2) (median follow-up, 42.0 months; data cutoff date: July 1, 2022) with all treated patients off abemaciclib were consistent with previous analyses and are summarized in Hepatotoxicity in monarchE: OS IA2 Analysis.4
In the abemaciclib + ET arm, 11 patients had an aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3× upper limits of normal (ULN) with total bilirubin >2× ULN. None of the patients in monarchE experienced adverse events meeting the criteria for drug induced liver injury.3,5
ALT and AST
|
Abemaciclib + ET |
ET Alone |
Event |
||
Grade ≥3 ALT increase |
2.8% |
0.7% |
Grade ≥3 AST increase |
1.9% |
0.5% |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ET = endocrine therapy.
Median time to onset of grade ≥3 elevated ALT and AST was 3 months, with median time to resolution to grade <3 of 13 and 11 days, respectively. All grade ≥3 ALT central laboratory elevations were reversible with dose modifications or abemaciclib discontinuation.3,6
Overall, discontinuation of abemaciclib due to any grade ALT and AST increased was 0.6% and 0.1%, respectively.6
Elevated Aminotransferases
Elevated aminotransferanses (EAT) is a composite term. Data for individual EAT events are reported for the abemaciclib treatment arm: ALT increased (n=343), AST increased (n=330), transaminase increased (n=16), hepatic function abnormal (n=10), hepatic enzyme increased (n=2), drug-induced injury (n=3), liver function test increased (n=5), hepatoxicity (n=1), hypertransaminasemia (n=2), and liver function test abnormal (n=4).3
Discontinuations of abemaciclib +/- ET due to any grade increased transaminases was low (0.9%).3
The incidence of grade ≥3 increased transaminases was 3.5%. For grade ≥3 increased transaminase events
- most (86%) were single occurrences, while 14 patients (14.3%) had a recurrent grade ≥3 event
- mainly occurred during early months of treatment with a median onset of 117.5 days and 153 days in the abemaciclib and ET only arm, respectively, and
- 45 (45.9%) and 61 (62.2%) of abemaciclib treated patients had a dose reduction or hold, respectively.3,7
provides additional information on increased transaminases in monarchE.3
|
Abemaciclib + ET (N=2791) |
ET Alone (N=2800) |
Increased transaminases grade ≥3, na |
98 |
28 |
Patients with single occurrence, nb (%) |
84 (85.7) |
22 (78.6) |
Dose hold, n(%) |
61 (62.2) |
NA |
Dose reduction, n(%) |
45 (45.9) |
NA |
Time to onset, median (range), days |
117.5 (1.0-764) |
153 (16.0-719.0) |
Abbreviations: AFU1 = additional follow-up 1; ET = endocrine therapy; NA = not applicable.
aComposite term - please see definition of elevated aminotransferases.
bRecurrent event defined as a new Grade >3 event after resolution of the initial occurrence.
Elevated aminotransferases were managed using dose adjustments, were reversible, and did not lead to liver injury. Most patients experiencing EAT could continue abemaciclib treatment without further recurrence.3,7
For management of EAT events in monarchE, grade 3 events required dose holds until toxicity resolved and dose reduction by 1 dose level. Grade 4 events required discontinuation.7
Overall, the majority of clinically significant EAT events occurred within the first 6 months; no cumulative effect or increased risk with longer treatment duration of abemaciclib was observed.7
Elevated Blood Bilirubin
Increases in blood bilirubin were reported in patients receiving abemaciclib in monarchE and presented in .
CTCAE, % |
Any Grades |
Grade 2 |
Grade 3 |
Grade 4 |
|
Abemaciclib + ET, N=2791 |
|||
Blood bilirubin increased |
1.2 |
0.3 |
0.2 |
0.1 |
|
ET alone, N=2800 |
|||
Blood bilirubin increased |
1.0 |
0.2 |
0 |
0 |
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; TEAE = treatment emergent adverse events .
Hepatotoxicity in monarchE: OS IA2 Analysis
A subsequent analysis (OS IA2) was recently conducted on the monarchE study data. The data cutoff date was July 1, 2022. The median follow-up time for the overall population was 42 months, and all patients were off abemaciclib treatment at the time of the analysis. Safety data continue to be consistent with the known safety profile of abemaciclib and with previous analyses. Since the majority of abemaciclib toxicities occurred during the first few months of treatment, at OS IA2 there were minimal changes in the incidence of AEs and no additional discontinuations due to AEs. Thus, the safety findings presented above for AFU1 remain valid.4
When compared to the AFU1 analysis, patients who received abemaciclib at the OS IA2 analysis experienced no additional incidence of
- grade ≥3 AST or ALT increase
- grade ≥3 blood bilirubin increase, and
- SAEs due to increased transaminases.3,4
Safety monitoring in the long-term follow-up period is ongoing.4
Metabolism and elimination of abemaciclib
Hepatic metabolism is the main route of clearance for abemaciclib.1
Abemaciclib is metabolised to several metabolites primarily by cytochrome P450 (CYP) 3A4.1
The geometric mean hepatic clearance of abemaciclib was 22 L/h (40% coefficient of variation [CV]), and the mean plasma elimination half life (t1/2) for abemaciclib in patients was 25 hours (52% CV). After a single oral dose of [14C]-abemaciclib, approximately 81% of the dose was excreted in feces and 3.4% excreted in urine. The majority of the dose eliminated in feces was metabolites.8
MonarchE study
monarchE is an open-label, randomized, phase 3 trial comparing adjuvant abemaciclib 150 mg twice daily plus endocrine therapy (ET) vs ET alone for a two-year duration in 5637 patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), node-positive, early breast cancer at high risk of recurrence.
At the end of the study treatment, patients entered physician-directed ET follow up for a total of 5-10 years, as clinically indicated.9
References
1Verzenios [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) November 27, 2017. Accessed October 10, 2022. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf
3Rugo HS, O’Shaughnessy J, Boyle F, et al; monarchE Committee Members. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: safety and patient-reported outcomes from the monarchE study. Ann Oncol. 2022;33(6):616-627. https://doi.org/10.1016/j.annonc.2022.03.006
4Johnston SRD, Toi M, O'Shaughnessy J, et al; monarchE Committee Members. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24(1):77-90. https://doi.org/10.1016/S1470-2045(22)00694-5
5Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting. Council for International Organizations of Medical Sciences. 2020. Accessed November 11, 2020. https://cioms.ch/publications/product/druginduced-liver-injury
6Rugo H, O'Shaughnessy J, Song C, et al. Safety outcomes from monarchE: phase 3 study of abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER-2-, node-positive, high risk, early breast cancer. The Breast. 2021;56(suppl 1):S23-S24. St. Gallen International Breast Cancer Conference abstract P013. https://doi.org/10.1016/S0960-9776(21)00101-6
7Toi M, Harbeck N, Puig JM, et al. Characterization of venous thromboembolic events (VTE), elevated aminotransferase (EAT) and interstitial lung disease (ILD) in monarchE. Ann Oncol. 2021;32(suppl 2):S39-S40. European Society of Medical Oncology abstract 44O. https://doi.org/10.1016/j.annonc.2021.03.058
8Data on file, Eli Lilly and Company and/or one of its subsidiaries.
9Johnston SRD, Harbeck N, Hegg R, et al; monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. https://doi.org/10.1200/JCO.20.02514
Date of Last Review: 13 April 2023