Abstract PS13-25: Management of abemaciclib associated diarrhea in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Analysis of the MONARCH plus study
Authors: Jiang Zefei , Hu Xichun , Zhang Qingyuan , Sun Tao , Yin Yongmei , Li Huiping , Yan Min , Tong Zhongsheng , Oppermann Christina Pimentel , Liu Yunpeng , Costa Romulo , Li Man , Chen Xi , Cheng Ying , Ouyang Quchang , Liao Ning , Wang Xiaojia , Wu Xinhong , Feng Jifeng , Hegg Roberto , Setty Govindbabu Kanaka , Agarwal Amit , Bajpai Jyoti , Cheng Jing , Girotto Gustavo , Goswami Chanchal , Hu Wenjing , Huang Jian , Portugal MA Coccia , Yang Jin , Zheng Rongsheng , Franke Fabio Andre , Liu Qiang , Liu Yunjiang , Lu Yongkui , Souza Cristiano , Yu Shiying , Kilara Nalini , Panchal Harsha , Singh Ashish , Nag Shona , Liu Jian , Rapoport Bernardo , Tabane Neonyana Keorapetse Rebecca , Wang Hongxia , Wang Ning , Han Rubing , Zhang Wanli 
Published: February 2021

Abstract
Background:
In the phase III MONARCH plus study (NCT02763566) the cyclin-dependent kinase (CDK) 4&6 inhibitor abemaciclib in combination with non-steroidal aromatase inhibitors (NSAI) or with fulvestrant compared with placebo demonstrated its efficacy and acceptable safety profile at interim analysis in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locoregionally recurrent or metastatic breast cancer. One of the most common treatment-emergent adverse event (TEAE) was diarrhea, typically low grade and of early onset. We will further characterize abemaciclib-associated diarrhea and describe its management in MONARCH plus trial.
Methods:
MONARCH plus study included two cohorts of patients. Cohort A enrolled patients with initial treatment of endocrine therapy, received abemaciclib or placebo plus NSAI (anastrozole or letrozole); Cohort B enrolled patients who progressed on prior endocrine therapy, receiving abemaciclib or placebo plus fulvestrant. The relative dose intensity was defined as the percentage of actual dose received relative to the planned dose. The severity of diarrhea was reported by investigators and graded according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). Further analysis on diarrhea included time to onset, duration, supportive medication and dose modifications. Progression-free survival (PFS) was defined as time from randomization to death or progression (RECIST v1.1), and a stratified Cox proportional hazard model was used to estimate the hazard ratio (HR) between study intervention arm and placebo arm.
Results:
The median relative dose intensity of abemaciclib in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm were 96.77% and 96.30% respectively. In abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, the median time to onset of first reported diarrhea was 7 and 6 days and majority of diarrhea events occurred early (66.3% and 71.2% of patients reported diarrhea in Cycle 1 respectively). Diarrhea was typically of low grade (3.9% and 1.9% of patients reported Grade 3 in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, no Grade 4 diarrhea was reported in either arm). Median duration of grade ≥ 3 diarrhea was 2.5 and 3.5 days. Diarrhea was managed by dose adjustments and/or supportive medication (Table 1). Dose reductions were present in 2.0% and 2.9% of patients, and anti-diarrhea therapy was received in 30.2% and 32.7% of patients with abemaciclib plus NSAI and abemaciclib plus fulvestrant arm, respectively. As data cutoff, most diarrhea events were reported as resolved, and the incidence dropped below 10% (Grade 2) and 1% (Grade 3) by Cycle 2 in both arms and kept low incidence over time. Compared to the placebo arm, patients treated with abemaciclib combination who reported diarrhea within the first 7 days (abemaciclib + NSAI, HR [95% CI]: 0.289 [0.166, 0.502]; abemaciclib + fulvestrant, HR [95% CI]: 0.371 [0.213, 0.647]) had significant improvement in PFS.
Conclusion:
Majority of diarrhea events were of low grade in severity and well managed by anti-diarrheal medications, dose omissions or/and dose reductions in MONARCH plus patients.
Table 1. Summary of dose adjustments and supportive medications in patients experiencing diarrheaCohort ACohort BAbemaciclib + NSAIAbemaciclib + FulvestrantN = 205N = 104Diarrhea (any grade), n (%)164 (80.0)82 (78.8)1105 (51.2)52 (50.0)251 (24.9)28 (26.9)38 (3.9)2 (1.9)Outcome, number of events, n796333Recovered/resolved, n (%)757 (95.1)318 (95.5)Not recovered/resolved, n (%)17 (2.1)7 (2.1)Treatment change, n (%)Dose reduction4 (2.0)3 (2.9)Dose omission3 (1.5)3 (2.9)Treatment discontinuation00Anti-diarrhea therapies, n (%)62 (30.2)34 (32.7)loperamide48 (23.4)21 (20.2)berberine6 (2.9)6 (5.8)
Citation Format: Zefei Jiang, Xichun Hu, Qingyuan Zhang, Tao Sun, Yongmei Yin, Huiping Li, Min Yan, Zhongsheng Tong, Christina Pimentel Oppermann, Yunpeng Liu, Romulo Costa, Man Li, Xi Chen, Ying Cheng, Quchang Ouyang, Ning Liao, Xiaojia Wang, Xinhong Wu, Jifeng Feng, Roberto Hegg, Govindbabu Kanaka Setty, Amit Agarwal, Jyoti Bajpai, Jing Cheng, Gustavo Girotto, Chanchal Goswami, Wenjing Hu, Jian Huang, MA Coccia Portugal, Jin Yang, Rongsheng Zheng, Fabio Andre Franke, Qiang Liu, Yunjiang Liu, Yongkui Lu, Cristiano Souza, Shiying Yu, Nalini Kilara, Harsha Panchal, Ashish Singh, Shona Nag, Jian Liu, Bernardo Rapoport, Neonyana Keorapetse Rebecca Tabane, Hongxia Wang, Ning Wang, Rubing Han, Wanli Zhang. Management of abemaciclib associated diarrhea in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Analysis of the MONARCH plus study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-25.