Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3

Abstract

Background: Abemaciclib demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Here we provide a comprehensive summary of the most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression-free survival (PFS), in the MONARCH 2 and 3 trials.

Materials and methods: Incidence of the most clinically relevant AEs, management, and outcomes were summarized. Time-dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia.

Results: The most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib-treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities.

Conclusion: Abemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS.

Implications for practice: Treatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any-grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.

Keywords: Abemaciclib; Advanced breast cancer; Diarrhea; Neutropenia; Safety.

Figure 1

Recommendation for management of adverse events. (A), hematological toxicities (B), nonhematologic toxicities except diarrhea, increased ALT, and ILD/pneumonitis (C), increased ALT (D), and interstitial lung disease/pneumonitis (E) management. A dose reduction corresponds to a reduction of 50 mg of abemaciclib at a time. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. For neutropenia evaluation, blood counts should be performed before starting abemaciclib treatment, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. If blood cell growth factors are administered, abemaciclib treatment must be suspended for at least 48 hours after the last administration of cell growth factors and until toxicity resolves to grade ≤2. Reduce the abemaciclib dose, unless already performed, for the toxicity that led to the use of growth factor. ^aGrade 2 toxicity that does not resolve with maximal supportive measures within 7 days to grade ≤1. ^bFor grade 4 increased aminotransferases, discontinue abemaciclib. Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ILD, interstitial lung disease; ULN, upper limit of normal.

Figure 2

Percentage of patients with clinically significant diarrhea or neutropenia, relative to exposure by cycle for MONARCH 1 and MONARCH 2. ^aAbemaciclib at 150 mg after amendment twice a day, plus fulvestrant. ^bAbemaciclib at 150 mg twice a day plus nonsteroidal aromatase inhibitor. Each light blue bar corresponds to the number of patients who received a cycle of treatment, representing total exposure by cycle. Each dark blue bar represents those with grade ≥2 diarrhea or grade ≥3 neutropenia. The number displayed above each dark blue bar is the percentage of patients with clinically significant diarrhea or neutropenia within each cycle. No grade ≥4 diarrhea was observed.

Figure 3

Time‐dependent covariate analysis of progression‐free survival among patients with reduced dose compared with those without. Abbreviations: CI, confidence interval; HR, hazard ratio; NSAI, nonsteroidal romatase inhibitor.