Verzenios ® ▼ (abemaciclib)

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Are Verzenios® ▼ (abemaciclib) patients at an increased risk of experiencing venous thromboembolic events in early breast cancer?

Venous thromboembolic events were reported in 2.4% of patients in the abemaciclib arm of monarchE.

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Venous thromboembolism in monarchE

monarchE is an open-label, randomized, phase 3 trial comparing adjuvant abemaciclib 150 mg twice daily plus endocrine therapy (ET) versus ET alone for a two-year duration, in 5,637 patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer (EBC) 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.1 

Venous thromboembolism in monarchE

The Khorana score was utilized to determine the baseline risk of venous thromboembolism (VTE) of patients in this safety analysis.2 The Khorana scoring system assigns one point (unless otherwise noted) for each of the following characteristics

  • site of cancer 
    • high risk (1 point): lung, lymphoma, gynecologic, genitourinary (excluding prostate)
    • very high risk (2 points): stomach, pancreas
  • platelet count of 350x109/L or more
  • hemoglobin <10g/dL and/or use of erythropoiesis-stimulating agents
  • leukocyte count > 11x109/L, and
  • body mass index (BMI) >35 kg/m2.3

Patients are divided into low risk (0 points), intermediate risk (1-2 points), and high risk (>3 points) based on the scoring system.3

In monarchE, the baseline Khorana risk score was well balanced across arms. Known risk factors (increased age and BMI) were also analyzed in patients experiencing VTE.2

The data and information presented in this document are from the primary outcome (PO) analysis, which includes 19.1 months of median follow up in both arms.4 At a later data cut with a median follow-up time of 27 months (Additional Follow-up 1 [AFU1] analysis), there were minimal increases in incidence of most frequently reported treatment-emergent adverse events, including VTE, in the abemaciclib + ET arm.5

At the primary outcome analysis, in patients treated with abemaciclib, most VTEs were grade >3 and primarily pulmonary embolism (PE) events, including 6 Grade 4 VTEs.6

Of the VTEs,

  • 17 PEs had a serious outcome (e.g. hospitalization), and
  • the remaining 9 PEs did not qualify as SAEs.6

The observed rate of VTEs was higher when tamoxifen, rather than AI, was administered as the initial ET.6

Risk factors for VTE were generally well-balanced across arms and around 94% patients who experienced VTEs received anti-coagulation therapy.6

Most VTEs (88.1%) were single occurrences. There were 8 patients that reported 2 episodes of VTE, including 5 patients with simultaneous VTE and PE. Only one patient had recurrent VTE after resuming abemaciclib.2

Most patients continued abemaciclib after a VTE,

  • with 57% requiring a dose hold, and
  • 19.4% discontinuing, mainly due to Grade >3 events.2

Approximately half of the VTE events occurred early on treatment in both arms, with a median time of onset of first VTE at approximately 6 months. In the abemaciclib arm, 47% experienced a VTE within the first 180 days, and 48% of PE events occurred within first 180 days.2

VTE events at the PO analysis are summarized in VTE Events in monarchE.

VTE Events in monarchE2,4,6

 

Abemaciclib  + ET

N=2791

ET Alone

N=2800

Event Term, n (%)

Any Grade

Grade 1

Grade 2

Grade >3

Any Grade

Grade 1

Grade 2

Grade >3

VTE

67 (2.4)a

3 (0.1)

27 (1.0)

37 (1.3)

16 (0.6)b

0

9 (0.3)

7 (0.3)c

   PEd

26 (0.9)e

0

0

26 (0.9)

4 (0.1)

0

0

4 (0.1)c

Serious VTE

33 (1.2)

N/A

N/A

N/A

8 (0.3)

N/A

N/A

N/A

VTE by First ET

Abemaciclib + ET

ET Alone

Tamoxifenf

35 (4.1)

2 (0.2)

14 (1.6)

19 (2.2)

6 (0.7)

0

2 (0.2)

4 (0.4)

Aromatase Inhibitorsg

32 (1.7)

1 (0.1)

13 (0.7)

18 (0.9)

10 (0.5)

0

7 (0.4)

3 (0.2)

Time to Onset of first VTE event (days); median (range)

182 (8.0-714.0)

187.5 (9.0-716.0)

Discontinuation due to VTE

13 (0.5)

2 (0.1)

Abbreviations: CTCAE = CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; N/A = not applicable; PE = pulmonary embolism; VTE = venous thromboembolism.

aAfter 27 months of median follow-up, the incidence of any grade VTE was 2.5% in the abemaciclib+ET treatment arm.

bAfter 27 months of median follow-up, the incidence of any grade VTE was 0.6% in the ET alone treatment arm.

c1 Grade 5 event.

dCTCAE minimum severity for PE is Grade 3 for uncomplicated events.

eAfter 27 months of median follow-up, the incidence of any grade PE was 1.0% in the abemaciclib+ET treatment arm.

fNx=857 (abemaciclib + ET); Nx=898 (ET Alone).

gNx=1929 (abemaciclib + ET); Nx =1892 (ET Alone)

Other risk factors for patients reporting a VTE (abemaciclib vs. ET only, respectively) include

  • central catheter use (22% vs. 50%)
  • recent flight or recent period of immobility (25.4% vs. 18.8%), and
  • 1 patient in the abemaciclib arm with a prior history of VTE.2

There was no correlation observed with incidence of VTE/PE and increasing age, but there was a trend for higher incidence of PE and Grade 3/4 VTE with increasing BMI, as seen in VTE Events by BMI in the Abemaciclib Arm (n=2791) of the monarchE trial.2

VTE Events by BMI in the Abemaciclib Arm (n=2791) of the monarchE trial2

VTE Events, n (%)

BMI Categories


<18.5

n=49

18.5-24.9

n=1070

25.0-29.9

n=890

30+

n=721

Not Reported

n=78

VTE, Any Grade

1 (2.0)

16 (1.5)

23 (2.6)

25 (3.5)

2 (2.6)

   VTE, Grade 3 and 4

0

7 (0.7)

10 (1.1)

19 (2.6)

1 (1.3)

PE, Any Grade

0

5 (0.5)

8 (0.9)

12 (1.7)

1 (1.3)

   PE, Grade 3 and 4

0

5 (0.5)

8 (0.9)

12 (1.7)

1 (1.3)

Abbreviations: BMI = body mass index; PE = pulmonary embolism; VTE = venous thromboembolism

Overall, the majority of clinically significant VTE events occurred within the first 6 months; no cumulative effect or increased risk with longer treatment duration of abemaciclib was observed.2

Management of VTEs in Early Breast Cancer

VTE was managed per standard clinical practice and most patients experiencing VTE could continue abemaciclib treatment without further recurrence.2

For management of VTE events in monarchE, abemaciclib was held for 1-2 weeks and anticoagulation was started per local clinical practice. Patients taking tamoxifen were recommended to change ET therapy. Patients with a prior history of VTE were excluded.2

Dose reductions of abemaciclib were reported for 4 patients in the abemaciclib + ET arm and 38 patients had dose omissions in the abemaciclib + ET arm.5

Dose modification and management recommendations are summarized in Dose Modification and Management - VTEs. 

Dose Modification and Management - VTEs7

CTCAE Grade

Abemaciclib Dose Modifications

Grade 1, 2, 3, or 4

Suspend dose and treat as clinically indicated. Abemaciclib may be resumed when the patient is clinically stable.

 Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; VTE = venous thromboembolism.

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

2Toi 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. 

3Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-4907. http://dx.doi.org/10.1182/blood-2007-10-116327

4O'Shaughnessy JA, Johnston S, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. Abstract presented at: 43rd Annual San Antonio Breast Cancer Symposium (SABCS Virtual); December 8-11, 2020

5Data on file, Eli Lilly and Company and/or one of its subsidiaries.

6Rugo 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.

7Verzenios [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: 15 September 2021


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