Treatment with abemaciclib, an orally available inhibitor of CDK4 and 6, has been associated with venous thromboembolic events (VTE), elevated aminotransferases (EAT), and interstitial lung disease (ILD). Although more episodes of VTE, EAT, and ILD were reported in patients receiving abemaciclib plus endocrine therapy as adjuvant treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer compared to similar patients receiving only endocrine therapy, most of these events were manageable with dose interruptions or co-treatments in a large patient population. Findings from a safety analysis of data from the phase III monarchE study were presented at the ESMO Breast Cancer Virtual Congress 2021, held 5 to 8 May.

Masakazu Toi of the Breast Unit, Kyoto University-Graduate School of Medicine in Kyoto, Japan, noted that more patients in the monarchE study (NCT03155997) receiving adjuvant treatment comprising abemaciclib and endocrine therapy for HR-positive, HER2-negative high-risk early breast cancer reported these adverse events (AEs) than patients receiving only endocrine therapy. Therefore, Dr. Toi and colleagues were prompted to investigate the safety outcomes of these patients.

The monarchE study did not enroll patients with a documented history of VTE. Baseline risk factors for VTE according to the Khorana risk score and the use of adjuvant radiotherapy (95.4%) were well balanced across treatment arms.

Among the 2791 patients receiving abemaciclib plus endocrine therapy, the median duration of abemaciclib was 17 months. Endocrine therapy alone was administered to 2800 patients.

Overall, more AEs were reported in patients receiving abemaciclib plus endocrine therapy

Regarding any grade AEs, VTE was reported in 67 (2.4%) patients administered abemaciclib plus endocrine therapy compared to 16 (0.6%) patients treated with endocrine therapy alone; EAT occurred in 356 (12.8%) versus 181 (6.5%), and ILD occurred in 82 (2.9%) versus 34 (1.2%) patients in the respective treatment arms.

Grade ≥3 VTE was reported in 37 (1.3%) patients receiving abemaciclib compared to 7 (0.3%) patients receiving endocrine therapy alone; Grade ≥3 EAT occurred in 87 (3.1%) versus 24 (0.9%), and Grade ≥3 ILD occurred in 11 (0.4%) versus 1 (<0.1%) patients in the respective treatment arms.

With abemaciclib, serious VTE AEs were reported in 33 (1.2%) patients, serious EAT AEs in 11 (0.4%), and serious ILD AEs in 14 (0.5%) patients. In contrast, serious VTE, EAT, and ILD AEs were reported in 8 (0.3%), 2 (0.1%), and 1 (<0.1%) patients, respectively, in the endocrine therapy alone arm.

No deaths due to VTE or EAT and one death due to ILD occurred within the abemaciclib arm. In the endocrine therapy cohort, one death due to VTE and no deaths due to EAT or ILD were reported.

Thirteen (0.5%), 22 (0.8%), and 19 (0.8%) patients discontinued abemaciclib treatment in the abemaciclib cohort due to VTE, EAT, and ILD, respectively. In the endocrine therapy alone arm, 2 (0.15%) patients discontinued treatment due to VTE and no patients discontinued due to EAT or ILD.

The monarchE protocol included management guidance for AEs

Regarding patients experiencing VTE, 94% were treated with anti-coagulants and 19.4% discontinued either abemaciclib or all treatment due to VTE. Tamoxifen used as first endocrine therapy compared to aromatase inhibitor was associated with numerically higher incidence of VTE. Grade ≥3 VTE AEs occurred more often in patients (1.8%) with higher body mass index (BMI ≥25) as compared to 0.6% of patients with BMI <25.

The majority (85%) of Grade ≥3 EAT events were single occurrences and were reported more often within approximately 3 months of treatment start. Among these patients, 71% were treated for EAT by dose hold/reduction and 16% discontinued treatment due to EAT. All Grade ≥3 alanine aminotransferase increases, per central lab, were reversible with dose modification or discontinuation and there were no episodes of drug-induced liver injury (no Hy’s law cases).

Most (1.4%) ILD events were Grade 1. Fifty-two percent of these patients were treated with steroids and/or antibiotics and 23% discontinued abemaciclib or all treatment due to ILD. More (6.6%) Asian patients experienced ILD; among these, 4.9% were Grade 1 and 0.3% were Grade ≥3. In all, 13% of Asian patients with ILD discontinued treatment, which represented 0.9% of the population.


Dr. Toi and colleagues concluded that AEs comprising VTE, EAT, and ILD were manageable with dose adjustments and co-medications in patients with high-risk early breast cancer. Furthermore, these results were consistent with the known safety profile of abemaciclib.

They pointed out that, even though the prevalence of ILD was higher in the Asian population, clinically significant (Grade ≥2) AEs and discontinuations were similar.

These findings suggest that most patients experiencing VTE, EAT, or ILD AEs were able to continue abemaciclib treatment and support the tolerability of abemaciclib in the adjuvant setting.

The study was funded by Eli Lilly.


44O – Toi M, Harbeck N, Puig JM, et al. Characterization of venous thromboembolic events (VTE), elevated aminotransferases (EAT) and interstitial lung disease (ILD) in monarchE. ESMO Breast Cancer Virtual Congress 2021 (5-8 May 2021).