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Verzenios ® (abemaciclib)
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How to manage hepatic toxicity and impairment with Verzenios® (abemaciclib)
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
Management recommendations for hepatic impairment
Abemaciclib is metabolised in the liver. The management of hepatic impairment may require dose interruptions or dose reductions or both. Below you will find information about the recommendations on dose adjustments in patients with mild (Child Pugh A), moderate (Child Pugh B) or with severe hepatic impairment (Child Pugh C). Please review the Verzenios Summary of Product Characteristics, particularly the sections:
- 4.2 Posology and method of administration
- 5.2 Pharmacokinetic properties
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
Liver function abnormalities are presented in ALT and AST Increases in monarchE.
|
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
Increased Transaminases Grade ≥3 in monarchE 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 TEAEs of Elevated Blood Bilirubin in monarchE .
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
Hepatotoxicity in the MONARCH 2 and MONARCH 3 clinical trials
For ALT
- the median time to onset of Grade 3 or 4 ALT elevation was 57 to 61 days, and
- following management recommendations the median time to resolution was 14 days.
For AST
- the median time to onset of Grade 3 or 4 AST elevation was 71 to 185 days, and
- the median time to resolution was 13 to 15 days.1
Please find ALT, AST and blood bilirubin increases in MONARCH 2 and MONARCH 3 in ALT and AST Increases in MONARCH 2 and MONARCH 3, Blood Bilirubin Increased in MONARCH 2 and Blood Bilirubin Increased in MONARCH 3.
|
Abemaciclib + NSAI |
Placebo + NSAI |
Abemaciclib + Fulvestrant |
Placebo + Fulvestrant |
Event |
MONARCH 3 |
MONARCH 2 |
||
Grade ≥3 ALT increase |
6% |
2% |
4% |
2% |
Median time to onset |
64 days |
--- |
57 days |
--- |
Median time to resolutiona |
14 days |
--- |
14 days |
--- |
Grade ≥3 AST increase |
4% |
1% |
2% |
3% |
Median time to onset |
87 days |
--- |
185 days |
--- |
Median time to resolutiona |
15 days |
--- |
13 days |
--- |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; NSAI = nonsteroidal aromatase inhibitor.
aTo normalization or grade <3.
CTCAE, % |
All Grades |
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
Grade 5 |
Abemaciclib + Fulvestrant, N=441 |
||||||
Blood bilirubin increased |
1.6 |
0 |
0.7 |
0.9 |
0 |
0 |
|
Placebo + Fulvestrant, N=223 |
|||||
Blood bilirubin increased |
0.9 |
0.4 |
0.4 |
0 |
0 |
0 |
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.
CTCAE, % |
All Grades |
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
Grade 5 |
|
Abemaciclib + NSAI, N=327 |
|||||
Blood bilirubin increased |
1.8 |
0.6 |
0.3 |
0.9 |
0 |
0 |
|
Placebo + NSAI, N=161 |
|||||
Blood bilirubin increased |
0.6 |
0.6 |
0 |
0 |
0 |
0 |
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; NSAI = nonsteroidal aromatase inhibitor.
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
In Vitro Mechanisms of Hepatotoxicity
A study investigated the potential mechanisms of hepatotoxicity with abemaciclib using a liver/macrophage (HepG2/THP-1) co-culture model. Oxidative stress, inflammatory response, and necrotic cell death were observed in HepG2 cells, suggesting that abemaciclib hepatotoxic effects are likely due to these mechanisms and not direct toxicity to mitochondria.10
An Exploratory Study on Prediction of Risk for Abemaciclib-Induced Interstitial Lung Disease or Hepatotoxicity by Specific Human Leukocyte Antigen Alleles
An exploratory study was conducted to identify whether specific human leukocyte antigen (HLA)alleles were associated with abemaciclib-induced hepatotoxicity. Alleles assessed included HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and -DPB1. There were 28 alleles that had a frequency of ≥10% in cases of grade ≥2 ALT elevation. HLA-DQA1*05:05 allele carriage was found to be significantly associated with ALT elevation (odd ratio [OR] 45.0; 95% CI: 2.23-907; P=.00147). Other suggestive associations with ALT elevation were with HLA-DPB1*05:01 (OR 11.5; 95% CI: 1.38-95.7; P=.00930) and HLA-A*31:01 carriage (OR 5.86; 95% CI: 1.46-23.4; P=.01522) The authors identified HLA-DQA1*05:05 as a promising marker candidate that can predict patients that may have a higher risk of abemaciclib-induced hepatotoxicity but further study is needed to confirm the association.11
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.
9Rugo HS, Huober J, Garcia-Saenz JA, et al. Management of abemaciclib-associated adverse events in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: safety analysis of MONARCH 2 and MONARCH 3. Oncologist. 2021;26(1):e53-e65. http://dx.doi.org/10.1002/onco.13531
10Boran T, Zengin OS, Seker Z, et al. The cyclin-dependent kinase inhibitor abemaciclib-induced hepatotoxicity: insight on the molecular mechanisms in HepG2/THP-1 co-culture model. Toxicol Lett. 2024;391:1-12. https://doi.org/10.1016/j.toxlet.2023.11.005
11Imamura C, Mushiroda T, Hosonaga M, et al. An exploratory study on prediction of risk for abemaciclib-induced interstitial lung disease or hepatotoxicity by specific human leukocyte antigen alleles [abstract]. J Clin Onc. 2024:42(16)(suppl):3087. https://doi.org/10.1200/JCO.2024.42.16_suppl.3087
Links to references and third-party websites are provided solely for your convenience and to facilitate easy access to the sources cited.
Date of Last Review: 13 April 2023