Abstract P1-16-04: Risk of venous thromboembolism with abemaciclib based regimen versus other CDK 4/6 inhibitor containing regimens in patients with hormone receptor-positive HER2-negative metastatic breast cancer
Authors: Thein KZ , Ball S , Zaw MH , Quirch M , Hardwicke F , Awasthi S , Oo TH , Jones C 
Published: May 2019

Background: Approximately 70% of patients with metastatic breast cancer (MBC) are hormone receptor (HR) - positive and the cyclin dependent kinases (CDK) along with their D-type cyclin catalysts, have been shown to play a role in mediating the resistance to endocrine therapy. Several CDK-targeted agents have been recently approved by FDA. Nevertheless, the risk of venous thromboembolism (VTE) with the use of different CDK 4/6 inhibitors has never been reported. We undertook a systematic review and meta-analysis of randomized controlled trials (RCT) to determine the risk of VTE with abemaciclib based regimens versus other CDK 4/6 inhibitor containing regimens in patients with HR-positive HER2-negative MBC.

Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through February 2018. The randomized controlled trials that mention deep vein thrombosis and pulmonary embolism as adverse effects of CDK 4/6 inhibitor therapy were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR) and risk difference (RD) with 95% confidence interval (CI).

Results: Five phase 3 studies and one phase 2 study with a total of 3,159 patients with HR-positive HER2-negative MBC were eligible for analysis. The study arms used palbociclib-letrozole, palbociclib-fulvestrant, ribociclib-letrozole, abemaciclib-fulvestrant, and abemaciclib-nonsteroidal aromatase inhibitors (either letrozole or anastrozole) while the control arms utilized placebo in combination with letrozole or anastrozole or fulvestrant. The randomization ratio was 2 to 1 in PALOMA-2, PALOMA-3, MONARCH-2 and MONARCH-3 studies and 1 to 1 in PALOMA-1 and MONALEESA-2 trials. CDK 4/6 inhibitors were utilized as first line treatment in PALOMA-1, PALOMA-2, MONALEESA-2 and MONARCH-3. The I2 statistic for heterogeneity was 0, and the heterogeneity X2 (Cochran's Q) was 1 (P= 0.707), suggesting homogeneity among RCTs. The VTE incidence was 25 (3.255%) in the abemaciclib group vs 2 (0.520%) in the control group. The pooled relative risk for VTE was 6.222 (95% CI: 1.481 – 26.145, P = 0.013) and the absolute RD was 0.027 (95% CI: 0.013 – 0.042, P &lt; 0.0001). In other CDK 4/6 inhibitor containing regimens, the VTE incidence was reported at 15 (1.243%) vs 2 (0.374%) in the control arm. The pooled RR for VTE was 2.312 (95% CI: 0.852 –6.272, P = 0.100) and the absolute RD was 0.008 (95% CI: - 0.000 – 0.017, P = 0.259).

Conclusion: VTE is a major cause of morbidity and mortality and is particularly common in patients with breast cancer. Our meta-analysis demonstrated that the addition of abemaciclib to endocrine therapy notably contributed to a higher incidence of VTE with a relative risk of 6.22. However, no significant increase in the risk of VTE was noted in other CDK 4/6 inhibitor-based regimen. More randomized trials are required to determine the actual relation and definitive incidence of VTE among different CDK-targeted agents when added to endocrine therapy.

Citation Format: Thein KZ, Ball S, Zaw MH, Quirch M, Hardwicke F, Awasthi S, Oo TH, Jones C. Risk of venous thromboembolism with abemaciclib based regimen versus other CDK 4/6 inhibitor containing regimens in patients with hormone receptor-positive HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-04.