The cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors offer new hope for the management of metastatic breast cancer (BC). Among the agents in this class are abemaciclib, palbociclib, and ribociclib. All of these drugs are indicated for advanced and/or metastatic BC. Abemaciclib is the only CDK 4/6 inhibitor with the additional indication of being available for use in early, high-risk, hormone receptor-positive, HER2-negative, node-positive BC. Abemaciclib received this expanded indication following the monarchE trial that showed mortality benefit when the CDK 4/6 inhibitor was used in conjunction with endocrine therapy in early high-risk disease.
Despite the beneficial effect of abemaciclib, clinical trials have indicated that the drug has an incidence of VTE ranging from 4.8% to 6%; the latter percentage was 10-fold higher than that seen in the placebo group. Nonetheless, this may be an underestimation of risk given the restrictions and exclusion criteria of clinical trials.
To help address these concerns about VTE in real-world clinical practice, a multicenter, observational, cohort study was conducted to determine rates and predictors of venous and arterial thrombosis in patients receiving abemaciclib for metastatic BC.
This population-based cohort study was conducted in five affiliated hospitals between November 1, 2018, and December 1, 2020; the database was locked on April 29, 2021. All symptomatic and asymptomatic venous (i.e., upper and lower extremity deep vein thrombosis [DVT], splanchnic vein thrombosis, cerebral venous sinus thrombosis, superficial thrombophlebitis, and pulmonary embolism) and arterial thrombotic (i.e., ST elevation, myocardial infarction, STEMI [ST-elevated myocardial infarction] and non-STEMI, unstable angina, ischemic stroke, transient ischemic attack, peripheral arterial thrombosis, and mesenteric artery thrombosis) events were included in the study. Patients were excluded if BC was not listed as the primary diagnosis or if abemaciclib had been received as part of a clinical trial.
Patients were assessed using the Khorana risk score, which is a score to estimate the risk of VTE in patients with cancer; 0 indicates low risk, 1 to 2 indicates intermediate risk, and 3 and above indicates high risk of embolic disease.
The data were gathered on numerous known risk factors for venous and arterial thrombosis including age, BMI, prior history of thrombosis, recent surgery, hereditary thrombophilia (e.g., presence of factor V Leiden), systemic inflammatory disease (e.g., systemic lupus erythromatosis, rheumatoid arthritis, and inflammatory bowel disease), presence of brain metastases, hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, heart failure, and known atherosclerosis.
The primary endpoint was venous and/or arterial thromboembolic events while on abemaciclib or within 30 days of discontinuation of treatment.
A total of 364 patients were included in the study, of whom 360 were female. The majority of patients (88.7%) were postmenopausal. The median age was 61 years. Most patients (87.9%) were White. Endocrine therapy was used concomitantly in 80% of patients, with fulvestrant being the most common agent (48.1%). An additional 19 patients (5.2%) received tamoxifen.
Fifty-one patients (14%) received long-term anticoagulation, 31 patients (8.5%) of whom received direct oral anticoagulants and 47 patients (12.9%) of whom were on long-term antiplatelet therapy (e.g., aspirin). Most patients (93.1%) had a low to intermittent risk of VTE as determined by the Khorana risk score. The median duration of abemaciclib therapy was 5.5 months, with a median duration of follow-up of 12.7 months.
Almost three-quarters of patients (73.4%) had invasive ductal carcinoma, and almost all (99.5%) were estrogen-receptor positive, while only 78.3% were also progesterone-receptor positive. Brain metastases were present in 19.5% of patients.
The investigators found that 7.4% of patients (n = 27) had thrombotic events, with 4.7% experiencing a VTE, 2.5% having an arterial thrombosis, and 0.3% experiencing both types. The most common VTE was a pulmonary embolism, which occurred in 1.9% of patients, and the most common arterial event, which occurred in 1.1% of patients, was stroke. The median time to either type of thromboembolic event was 2.8 months.
The rate of VTE was higher than in controlled clinical trials (i.e., 9.1 per 100 person-years vs. 4.1-4.9 per 100 person-years). Additionally, the rate of either a venous or arterial thromboembolic event was more than twice that seen in clinical trials (i.e., 13.7 events per 100 person-years vs. 4.1-4.9 events per 100 person-years). One patient had been on prophylactic enoxaparin, and two patients were receiving prophylactic aspirin therapy at the time of the thrombotic event.
The Khorana score did not predict risk of embolic events. Rather, the most significant risk factors were a prior history of a VTE or of arterial thrombosis, known thrombophilia, antiphospholipid antibody syndrome, and Factor V Leiden, whereas the most common risk factors for arterial thrombosis were hypertension and hyperlipidemia.
The occurrence of a VTE during therapy resulted in a 2.09-fold greater risk of death, and the median overall survival was reduced from 25.8 months to 9.6 months. On the other hand, the occurrence of arterial thrombosis did not affect survival. Twelve patients died following thrombosis, and for half of these patients, it was felt that thrombosis was either directly or possibly related to abemaciclib therapy, whereas the cause of death in the other half of patients was due to disease progression.
This study provides pharmacists with real-world experience of the use of abemaciclib in patients with metastatic BC and highlights the fact that the risk of thrombotic events is greater than what has been identified from clinical trials. Pharmacists need to take a proactive approach in monitoring patients with BC who are receiving this CDK 4/6 inhibitor and educating them on recognizing the signs and symptoms of embolic events. The use of prophylactic anticoagulation or antiplatelet therapy requires further evaluation.
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Published September 20, 2022