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Verzenios ® (abemaciclib)
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What was the incidence and management of venous thromboembolic events with Verzenios® (abemaciclib) in early breast cancer?
Venous thromboembolic events were reported in 2.5% of patients in the abemaciclib arm, compared to 0.6% in the ET alone arm of monarchE, and was managed with dose reductions, dose holds and anticoagulation therapy.
How was venous thromboembolic events (VTEs) defined and risk assessed in monarchE?
For the purposes of adverse event (AE) reporting in monarchE, all reported terms included in the broad clinical category of VTE were summarized under the composite term venous thromboembolic events (VTEs), with the most frequently reported individual terms being deep vein thrombosis and pulmonary embolism.1
In monarchE, patients with a prior history of VTE were excluded from enrollment in the trial. The baseline Khorana risk score was well balanced across arms. Known risk factors (eg, increased age and body mass index [BMI]) were also analyzed in patients experiencing VTE.1
The Khorana score, summarized in The Khorana Scoring System, was utilized to determine the baseline risk of a VTE for patients enrolled in monarchE.2
Patient Characteristics |
Score |
|
1 point |
|
2 points |
|
1 point |
|
1 point |
|
1 point |
|
1 point |
|
Total combined points |
Patients are divided into low risk (0 points), intermediate risk (1-2 points), and high risk (≥3 points) based on the scoring system.3
How should venous thromboembolic events be managed in early breast cancer?
Management recommendations from the Summary of Product Characteristics
The management of venous thromboembolic events (VTEs) may require dose interruptions or dose reductions or both. Below you will find information about the recommendations on dose adjustments.
Please review the Verzenios Summary of Product Characteristics, particularly the section:
• 4.2 Posology and method of administration
Management of VTEs in monarchE for early breast cancer
VTE was managed per standard clinical practice and most patients experiencing VTE could continue abemaciclib treatment without further recurrence.1
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.1
Dose reductions and dose holds due to a VTE occurred in 4 (5.6%) and 40 (56.3%) abemaciclib-treated patients, respectively.1
Incidence of VTEs in monarchE
Venous thromboembolic events in monarchE in the additional follow-up 1 (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.1
Safety findings at 2 subsequent overall survival interim analyses (OS IA2, median follow-up 42 months and OS IA3, median follow-up 54 months) with all treated patients off abemaciclib were consistent with previous analyses and are summarized in Incidence and Severity of VTEs in monarchE at the AFU1 Analysis.4-6
At the AFU1 analysis, the number of patients experiencing a VTE in the abemaciclib + ET arm was 2.5% compared to 0.6% in the ET alone arm; most VTEs were grade ≥3 and primarily pulmonary embolism (PE) events (1.0%) (Incidence and Severity of VTEs in monarchE at the AFU1 Analysis).1
Serious VTEs were uncommon. Only 0.7% of patients who had a PE required hospitalization; the remaining cases were uncomplicated PEs.1
There were no fatal VTEs in abemaciclib-treated patients.1
|
Abemaciclib + ET |
ET Alone |
||||||
Event Term |
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
VTEa |
71 (2.5) |
2 (0.1) |
31 (1.1) |
38 (1.4)b |
17 (0.6) |
0 |
9 (0.3) |
8 (0.3) |
PEc |
28 (1.0) |
NA |
NA |
28 (1.0)d |
4 (0.1) |
NA |
NA |
4 (0.1) |
Seriouse VTE |
34 (1.2) |
NA |
NA |
NA |
8 (0.3) |
NA |
NA |
NA |
Seriouse PE |
19 (0.7) |
NA |
NA |
NA |
5 (0.2) |
NA |
NA |
NA |
Abbreviations: AFU1 = additional follow-up 1; CTCAE = Common Terminology Criteria for Adverse Events; ET = endocrine therapy; NA = not applicable; PE = pulmonary embolism; VTEs = venous thromboembolic events.
aVenous thromboembolic event is a composite term including the following preferred terms: abemaciclib arm (any grade, n)-catheter site thrombosis (1), cerebral vein thrombosis (2), cerebral venous thrombosis (0), deep vein thrombosis (36), device-related thrombosis (3), embolism (1), hepatic vein thrombosis (0), jugular vein occlusion (0), jugular vein thrombosis (3), ovarian vein thrombosis (0), portal vein thrombosis (1), pulmonary embolism (27), subclavian vein thrombosis (2), and venous thrombosis limb (1); ET arm (any grade, n)-catheter site thrombosis (0), cerebral vein thrombosis (1), cerebral venous thrombosis (0), deep vein thrombosis (7), device-related thrombosis (1), embolism (0), hepatic vein thrombosis (1), jugular vein occlusion (1), jugular vein thrombosis (0), ovarian vein thrombosis (1), portal vein thrombosis (0), pulmonary embolism (4), subclavian vein thrombosis (0), and venous thrombosis limb (0).
bSix (0.2%) grade 4 VTE events occurred in the abemaciclib arm.
cPulmonary embolism is a composite term: embolism (n=1 in the abemaciclib arm not confirmed by imaging) and PE (n=27); minimum severity grade as per CTCAE for PE is grade 3 for uncomplicated events.
dThree grade 4 PEs occurred in the abemaciclib arm.
eTreatment-emergent serious adverse events are reported as events that first occurred or worsened in severity while on therapy and within 30 days after treatment discontinuation, or serious events which occurred beyond 30 days after treatment discontinuation and were considered related to study treatment by the investigator.
Most VTEs (96%) did not recur. Only one patient had recurrent VTE after resuming abemaciclib.1
Most patients continued abemaciclib after a VTE
- with 56% requiring a dose hold, and
- 93% being managed with anticoagulation.1
Discontinuations due to VTEs in the abemaciclib arm were low (0.5%).1
The characterization and management of VTE in monarchE is summarized in Characterization and Management of VTE in monarchE.
|
Abemaciclib + ET |
ET Alone |
VTEa, n |
71 |
17 |
Patients with single occurrenceb, n (%) |
68 (96) |
14 (82.4) |
Time to onset, median (range), days |
204.0 (8.0-714.0) |
202.0 (9.0-716.0) |
Dose reduction, n (%) |
4 (5.6) |
NA |
Dose hold, n (%) |
40 (56.3) |
NA |
Anticoagulation treatment, n (%) |
66 (93.0) |
15 (88.2) |
Abbreviations: DVT = deep vein thrombosis; ET = endocrine therapy; NA = not applicable; PE = pulmonary embolism; VTE = venous thromboembolic event.
aComposite term; see footnote in Table 2 for definitions.
bIncluding 6 patients in the abemaciclib + ET arm and 1 patient in the ET alone arm who reported simultaneous PE/DVT.
As shown in VTE Events by First ET and Risk Factor, the observed rate of VTEs was higher when tamoxifen, rather than an aromatase inhibitor, was administered as the initial ET (4.3% vs 1.8%, respectively, in the abemaciclib arm).1
Frequent risk factors in patients who experienced VTEs were recent flights or periods of immobility (25%) and an indwelling catheter (27%).1
- 1 patient in the abemaciclib arm did have a prior history of VTE.2
Abemaciclib + ET |
ET Alone |
|||||||
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
Any Grade |
Grade 1 |
Grade 2 |
Grade ≥3 |
|
VTE by first ET |
71 (2.5)a |
2 (0.1) |
31 (1.1) |
38 (1.4) |
17 (0.6)b |
0 (0.0) |
9 (0.3) |
8 (0.3) |
Tamoxifenc |
37 (4.3) |
1 (0.1) |
16 (1.9) |
20 (2.3) |
6 (0.7) |
0 |
2 (0.2) |
4 (0.4) |
Aromatase Inhibitorsd |
34 (1.8) |
1 (0.1) |
15 (0.8) |
18 (0.9) |
11 (0.6) |
0 |
7 (0.4) |
3 (0.2) |
Abbreviations: ET = endocrine therapy; VTE = venous thromboembolic event.
aNineteen patients had recent flight or period of immobility; 16 patients had prior catheter.
bThree patients had recent flight or period of immobility; 8 patients had prior catheter.
cIncluding 857 patients in the abemaciclib + ET arm and 898 patients in the ET alone arm.
dIncluding 1928 patients in the abemaciclib + ET arm and 1891 patients in the ET alone arm.
There was no correlation observed with incidence of VTE and age, but patients with a high BMI had a higher risk of developing a severe (grade ≥3) VTE, as seen in VTE Events by BMI and Age in the Abemaciclib Arm of monarchE.1
|
Abemaciclib + ET |
|
VTE by BMI |
BMI <25 kg/m2 |
BMI ≥ 25 kg/m2 |
Any grade VTE Grade ≥3 VTE |
19 (1.6) 8 (0.7) |
52 (3.2) 30 (1.9) |
VTE by Age |
Age <50 Years |
Age ≥50 Years |
Any grade VTE Grade ≥3 VTE |
30 (2.4) 15 (1.2) |
41 (2.6) 23 (1.5) |
Abbreviations: BMI = body mass index; ET = endocrine therapy; VTE = venous thromboembolic event.
Overall, half of the VTEs occurred within the first 6 months; no cumulative effect or increased risk with longer treatment duration of abemaciclib was observed.1
Updated results from recent analyses
Two analyses of the monarchE study data have occurred since the AFU1 analysis.4,5
A prespecified overall survival interim analysis (OS IA2) was planned to occur 2 years after the primary outcome analysis, with a data cutoff date of July 1, 2022.
- Median follow-up time: 42 months.
- All patients were the off abemaciclib treatment at analysis time.
- Safety data consistent with known profile of abemaciclib from previous analyses.
- Minimal changes in AE incidence; no additional discontinuations due to AEs.
No new VTEs were observed beyond the AFU1 analysis. The absence of an increased risk of VTEs in the longer treatment duration of abemaciclib highlights the necessity of early intervention and risk monitoring to mitigate early-onset toxicities and improve tolerability.4
Another prespecified overall survival interim analysis (OS IA3) recently conducted on monarchE study data.
- Data cutoff: July 3, 2023.
- Median follow-up time: 54 months.
- No new safety concerns identified in long-term follow-up.
- No cumulative or persistent symptoms post-treatment.4
The 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 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.7 The trial is active but not recruiting.8
References
1Rugo 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
2Toi 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
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
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
5Rastogi P, O'Shaughnessy J, Martin M, et al. Adjuvant abemaciclib plus endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. J Clin Oncol. 2024;42(9):987-993. https://doi.org/10.1200/jco.23.01994
6Harbeck N, Rastogi P, O'Shaughnessy J, et al. Adjuvant abemaciclib plus endocrine therapy for HR+, HER2-, high-risk early breast cancer: results from a preplanned monarchE overall survival interim analysis, including 5-year efficacy outcomes. Poster presented at: 48th Annual European Society for Medical Oncology (ESMO) Congress; October 20-24, 2023; Madrid, Spain. Accessed January 5, 2024. https://oncologypro.esmo.org/meeting-resources/esmo-congress/adjuvant-abemaciclib-plus-endocrine-therapy-for-hr-her2-high-risk-early-breast-cancer-results-from-a-preplanned-monarche-overall-survival-inte
7Johnston 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
8Endocrine therapy with or without abemaciclib (LY2835219) following surgery in participants with breast cancer (monarchE). ClinicalTrials.gov identifier: NCT03155997. Updated July 14, 2023. Accessed September 5, 2023. https://clinicaltrials.gov/study/NCT03155997
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: 14 March 2024