Venous and Arterial Thrombosis Following Abemaciclib Therapy for Metastatic Breast Cancer

Introduction: Over the past several years, inhibitors of cyclin-dependent kinases 4 and 6 (CDK 4/6) have revolutionized the treatment of hormone receptor (HR)-positive breast cancer. However, evidence suggests an increased risk of venous thromboembolism (VTE) with use of these agents. Recent studies additionally suggest higher VTE rates in real-world populations receiving palbociclib as compared with the highly selected population of published clinical trials. Such study in real-world patients has not been performed for abemaciclib, a newer CDK 4/6 inhibitor with unique pharmacokinetic and pharmacodynamic properties. This study evaluated rates and predictors of thrombosis in patients receiving abemaciclib for metastatic breast cancer. Methods: We conducted a multicenter observational cohort study of patients with metastatic breast cancer receiving abemaciclib at 5 affiliated hospitals. A research patient data repository was queried to identify all patients receiving abemaciclib and manual chart review was used to extract all data. Patient demographics, concurrent medications, labs, Khorana risk score, tumor characteristics, and relevant venous and arterial thrombotic risk factors (including age, BMI, prior thrombosis, recent surgery, hereditary thrombophilia, systemic inflammatory diseases, presence of brain metastases, hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, heart failure, and atherosclerosis) were collected for all patients. The primary endpoint was thrombosis during abemaciclib treatment or within 30 days of discontinuation. Multivariable logistic models assessed predictors of VTE and a multivariable Cox proportional hazards model was used to compare mortality in patients developing VTE with those who did not. Data are presented as median (IQR) or number (%). Results: Patient Cohort and Thrombosis Risk Factors. 364 patients were included in the analysis. 360 (98.9%) patients were female, with median (interquartile range) age of 61 (53-71) years. 320 (88.7%) were post-menopausal and 291 (79.9%) were concurrently on endocrine therapy (of which 19 (5.2%) were on tamoxifen). At the time of abemaciclib initiation, 51 (14.0%) were receiving long-term anticoagulation and 47 (12.9%) were receiving aspirin. Khorana scores were between 0-3 with 339 (93.1%) patients having a score of 0 or 1. 267 (73.4%) and 46 (12.6%) were diagnosed with invasive ductal and lobular carcinoma, respectfully. Brain metastases were present in 71 (19.5%) patients. Venous and arterial thrombosis risk factors for this cohort are highlighted in TABLE 1. The median duration of abemaciclib therapy was 5.5 (2.8-13.0) months and median duration of follow-up was 12.7 (6.2-22.1) months. Thrombotic Events. 27 patients (7.4%) developed one or more thrombotic event (17 VTE, 9 arterial thrombosis, 1 both). Events are described in TABLE 2. Risk Factors for VTE. In a multivariable logistic model including age, race, BMI, receipt of long-term anticoagulation, receipt of aspirin, brain metastases, Khorana risk score, receipt of tamoxifen, prior VTE, systemic autoimmune disease, and known thrombophilia, HER2 positivity was predictive of VTE during or after abemaciclib treatment (odds ratio 5.20, 95% CI 1.29-20.93, P=0.020). Association of VTE with Mortality. In a multivariable Cox model controlling for age, race, HER2 status, receipt of long-term anticoagulation, receipt of aspirin, brain metastases, Khorana risk score, receipt of tamoxifen, prior VTE, systemic autoimmune disease, and known thrombophilia, patients developing VTE during abemaciclib therapy had a significantly higher risk of death (hazard ratio, 2.04, 95% CI, 1.03-4.01, P=0.040), FIGURE 1. Median survival in patients developing a VTE vs. those who did not was 9.6 months vs. 25.8 months, respectively. Conclusions: In this study, we provide the first real-world data describing risk of venous and arterial thrombosis in a large cohort of patients with metastatic breast cancer treated with the CDK 4/6 inhibitor abemaciclib. As the role of abemaciclib continues to expand both within and beyond the metastatic disease setting, understanding the VTE risk of this agent has become critical. Thrombosis occurred in 7.4%, and in multivariable models controlling for relevant covariates, HER2 positivity predicted for development of VTE, and patients developing VTE had an approximate 2-fold risk of mortality. Figure 1 Figure 1. Disclosures Al-Samkari: Moderna: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Rigel: Consultancy; Argenx: Consultancy; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.