Verzenios ® ▼ (abemaciclib)

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How to manage hepatic toxicities in Verzenios® ▼ (abemaciclib) treated patients 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.

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Hepatotoxicity in monarchE

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.1

In the abemaciclib + ET arm, 9 patients had an aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3× upper limit of normal (ULN) with total bilirubin >2× ULN. None of the patients in monarchE experienced AEs meeting the criteria for drug induced liver injury.2,3

ALT and AST

Liver function abnormalities are presented in ALT and AST Increases in monarchE.

ALT and AST Increases in monarchE4

 

Abemaciclib + ET
N=2791

ET Alone
N=2800

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.2

Overall, discontinuation of abemaciclib due to any grade ALT and AST increased was 0.6% and 0.1%, respectively.2

Elevated Aminotransferases

Elevated aminotransferase (EAT) is a composite term. Data for individual EAT events are reported for the abemaciclib treatment arm: ALT increased (n=291), AST increased (n=281), transaminase increased (n=10), hepatic function abnormal (n=8), hepatic enzyme increased (n=2), drug-induced injury (n=3), liver function test increased (n=3), hepatoxicity (n=1), hypertransaminasemia (n=1), and liver function test abnormal (n=2).5

For grade ≥3 EAT events,

  • most (85%) were single occurrences, while 13 patients (15%) had a recurrent grade ≥3 event
  • most patients could continue treatment after grade ≥3 EAT, including 71.3% after dose hold and/or dose reduction
  • events mainly occurred during early months of treatment with a median onset of around 3 months and 4 months in the abemaciclib and ET only arm, respectively
  • after 6 months, grade ≥3 events were rare, ≤0.5% of treated patients in each arm, and
  • in patients with grade ≥3 EAT, 16% discontinued treatment.5

EAT in monarchE provides additional information on EAT in monarchE.5

EAT in monarchE5

EAT, n (%)

Abemaciclib + ET
n=2791

ET Alone
n=2800

 

Any Grade

Grade ≥3

Any Grade

Grade ≥3

Patients with ≥1 TEAE

356 (12.8)

87 (3.1)a

181 (6.5)

24 (0.9)b

 SAEs

11 (0.4)

2 (0.1)

Discontinuations

22 (0.8)

0

Time to onset of grade ≥3 event; median (range), days

91.0 (1.0-670.0)

131.5 (16.0-719.0)

Abbreviations: AE = adverse event; EAT = elevated aminotransferases; ET = endocrine therapy; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

aSix grade 4 events in the abemaciclib arm. No fatal AEs reported in either arm.

bOne grade 4 event in the ET-alone arm. No fatal AEs reported in either arm.

EAT 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.5

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.5

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.5

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  .

TEAEs of Elevated Blood Bilirubin in monarchE 4 

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 . 

Management Recommendations for Hepatic Toxicities

Monitor alanine aminotransferase (ALT) and aspartate aminostransferase (AST)

  • prior to the start of abemaciclib therapy
  • every two weeks for the first two months
  • monthly for the next two months, and
  • as clinically indicated.6

Please find management recommendations for increased aminotransferases in   Management recommendations for increased aminotransferases.

  Management recommendations for increased aminotransferases6

Toxicitya

Management recommendations

Grade 1 (>ULN-3.0 x ULN)

Grade 2 (>3.0-5.0 x ULN)

No dose adjustment required.

Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN)

Suspend dose until toxicity resolves to baseline or Grade 1.

Resume at next lower dose.

Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis

Discontinue abemaciclib.

Grade 4 (>20.0 x ULN)

Discontinue abemaciclib.

 Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

aNCI CTCAE

References

1Johnston 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

2Rugo HS, 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+, HER2−, node-positive, high risk, early breast cancer. Poster presented at: 17th Annual St. Gallen International Breast Cancer Conference (SGBCC Virtual); March 17-21, 2021. Accessed November 29, 2021. https://www.lillymedical.com/en-us/answers/safety-outcomes-from-monarche-phase-3-study-of-abemaciclib-combined-with-endocrine-therapy-for-the-adjuvant-treatment-of-hr-her2-node-positive-high-risk-early-breast-cancer-138624?

3Drug-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

4Data on file, Eli Lilly and Company and/or one of its subsidiaries.

5Toi M, Harbeck N, Puig JM, et al; monarchE Investigators. Characterization of venous thromboembolic events (VTE), elevated aminotransferase (EAT) and interstitial lung disease (ILD) in monarchE. Abstract presented at: 3rd Annual Meeting of the European Society of Medical Oncology Breast Cancer Congress (ESMOBCC Virtual); May 5-8, 2021. Accessed December 3, 2021. https://www.lillymedical.com/en-us/answers/characterization-of-venous-thromboembolic-events-vte-elevated-aminotransferases-eat-and-interstitial-lung-disease-ild-in-monarche-142393?

6Verzenios [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: 08 September 2021


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