Safety in Japanese Advanced Breast Cancer Patients Who Received Abemaciclib in MONARCH 2 and MONARCH 3: Assessment of Treatment-Emergent Neutropenia, Diarrhea, and Increased Alanine Aminotransferase and Aspartate Aminotransferase Levels

Abstract

Our objective was to gain a better understanding of the safety of abemaciclib in Japanese patients with hormone receptorpositive, human epidermal growth factor receptor 2-negative advanced breast cancer. Patients and Methods: Treatment-emergent adverse events (TEAEs) were assessed in pooled Japanese subpopulation data from two phase 3 studies assessing abemaciclib/placebo in combination with fulvestrant (MONARCH 2; M2) or non-steroidal aromatase inhibitors (MONARCH 3; M3). For common, clinically relevant TEAEs, event characteristics and management were summarized by study. Results: In the Japanese safety subpopulation (abemaciclib: N=101; placebo: N=46), all patients experienced ≥1 TEAE (Grade ≥ 3: abemaciclib, 71.3%; placebo, 23.9%; no Grade 5). Clinically relevant TEAEs that were more frequent in abemaciclib-treated Japanese patients compared to the overall safety populations included diarrhea (any grade, 95.0%; Grade ≥ 3, 12.9%), neutropenia (any grade, 75.2%; Grade 3-4, 35.6%), increased alanine aminotransferase (ALT; any grade, 39.6%; Grade 3-4, 14.9%), and increased aspartate aminotransferase (AST; any grade, 37.6%; Grade 3-4, 8.9%). Diarrhea was Grade ≤3 and successfully managed with medications (≥87%) and dose reductions (≤25%) and/ or omissions (≤23.3%). Most Grade ≥2 diarrhea occurred in the first treatment cycle, declining thereafter. Neutropenia, the most common Grade ≥3 TEAE in abemaciclib-treated Japanese patients, was generally manageable with dose omissions (M2: 42.0%; M3: 23.1%) and/or reductions (M2: 16%; M3: 15.4%). Neutrophil counts plateaued after Cycle 2, recovering to pretreatment levels after discontinuation of abemaciclib. Hepatic events were managed with medication (≤21%) and dose adjustments (≤33.3%), with most Grade ≥2 events occurring in early treatment cycles. Discontinuation of any study treatment in Japanese patients occurred more frequently due to increased ALT/AST (M2: 9.1%/10.5%; M3: 16.7%/10.5%) compared with diarrhea (M2: 0%; M3: 2.8%) or neutropenia (M2: 0%; M3: 3.8%). Conclusion: Abemaciclib was well tolerated in Japanese patients in MONARCH 2 and MONARCH 3, with common, clinically relevant TEAEs manageable with appropriate interventions.

Patient characteristics, treatment patterns, and outcomes of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer patients prescribed cyclin-dependent kinase 4 and 6 inhibitors: large-scale data analysis using a Japanese claims database

“…The incidence of AEs of interest and use of concomitant therapies during therapies with CDK4 and 6 inhibitors were generally consistent with clinical study observations for palbociclib and abemaciclib [ 6 , 7 , 9 , 11 , 13 , 16 , 17 , 20 , 23 , 35 , 36 ]. In particular, the higher incidence of diarrhea AEs of interest and higher use of antidiarrhea agents observed in the abemaciclib subcohort are consistent with MONARCH 2 and MONARCH 3 findings and the main management strategy in these studies [ 35 ].…”

“…The incidence of AEs of interest and use of concomitant therapies during therapies with CDK4 and 6 inhibitors were generally consistent with clinical study observations for palbociclib and abemaciclib [ 6 , 7 , 9 , 11 , 13 , 16 , 17 , 20 , 23 , 35 , 36 ]. In particular, the higher incidence of diarrhea AEs of interest and higher use of antidiarrhea agents observed in the abemaciclib subcohort are consistent with MONARCH 2 and MONARCH 3 findings and the main management strategy in these studies [ 35 ]. Similarly, the higher incidence of neutropenia observed with palbociclib is consistent with previously reported clinical data [ 37 , 38 ] although only neutropenia events requiring prescription of G-CSF drugs were captured herein, per the definition of neutropenia used in this study.…”

“…The incidence of AEs of interest and use of concomitant therapies during therapies with CDK4 and 6 inhibitors were generally consistent with clinical study observations for palbociclib and abemaciclib [6,7,9,11,13,16,17,20,23,35,36]. In particular, the higher incidence of diarrhea AEs of interest and higher use of antidiarrhea agents observed in the abemaciclib subcohort are consistent with MONARCH 2 and MONARCH 3 findings and the main management n (%) shown, where % was calculated using the number of patients in the subcohorts as the denominator, unless otherwise indicated below a Standard dose is 300 mg/day for abemaciclib and 125 mg/day for palbociclib b n (%) shown where % was calculated using Nx c Median bodyweight for each subcohort was used to define cutoff (abemaciclib, 54.1 kg; palbociclib, 53.0 kg) d For dose reduction and MPR data, only patients who continued treatment for ≥ 30 days and then discontinued abemaciclib/palbociclib were eligible for the analysis e Calculation of MPR = (total days supplied of CDK4 and 6 inhibitor) / (duration of CDK4 and 6 inhibitor therapy period) * 100 wherein total days supplied was obtained by summing up "days supplied" of all the prescriptions during the abemaciclib/palbociclib therapy period.…”

“…In particular, the higher incidence of diarrhea AEs of interest and higher use of antidiarrhea agents observed in the abemaciclib subcohort are consistent with MONARCH 2 and MONARCH 3 findings and the main management n (%) shown, where % was calculated using the number of patients in the subcohorts as the denominator, unless otherwise indicated below a Standard dose is 300 mg/day for abemaciclib and 125 mg/day for palbociclib b n (%) shown where % was calculated using Nx c Median bodyweight for each subcohort was used to define cutoff (abemaciclib, 54.1 kg; palbociclib, 53.0 kg) d For dose reduction and MPR data, only patients who continued treatment for ≥ 30 days and then discontinued abemaciclib/palbociclib were eligible for the analysis e Calculation of MPR = (total days supplied of CDK4 and 6 inhibitor) / (duration of CDK4 and 6 inhibitor therapy period) * 100 wherein total days supplied was obtained by summing up "days supplied" of all the prescriptions during the abemaciclib/palbociclib therapy period. If MPR exceeded 100%, MPR was defined as 100% strategy in these studies [35]. Similarly, the higher incidence of neutropenia observed with palbociclib is consistent with previously reported clinical data [37,38] although only neutropenia events requiring prescription of G-CSF drugs were captured herein, per the definition of neutropenia used in this study.…”

Design, Synthesis and Cytotoxic Activity of Novel Salicylaldehyde Hydrazones against Leukemia and Breast Cancer

“…Abemaciclib, palbociclib, and ribociclib are targeted breast cancer drugs that block the activity of two proteins on cancer cells, CDK4 and CDK6. All three drugs are approved to treat advanced or metastatic breast cancer, based on data from large clinical trials showing that they can substantially improve how long patients live without their cancer getting worse [ 6 , 11 , 12 , 13 ]. Examples of such drugs for leukemia include tyrosine kinase inhibitors (TKIs), which target abnormal signaling pathways in cancer cells [ 14 , 15 ], and immunotherapeutic agents, which harness the body’s immune system to fight cancer [ 16 ].…”