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Clinical Trial
. 2021 Sep;28(5):1038-1050.
doi: 10.1007/s12282-021-01239-8. Epub 2021 Apr 1.

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy

Kenichi Inoue  1 , Norikazu Masuda  2 , Hiroji Iwata  3 , Masato Takahashi  4 , Yoshinori Ito  5 , Yasuo Miyoshi  6 , Takahiro Nakayama  7 , Hirofumi Mukai  8 , Jan-Stefan van der Walt  9 , Joji Mori  10 , Sachi Sakaguchi  10 , Tsutomu Kawaguchi  10 , Yoshinori Tanizawa  10 , Antonio Llombart-Cussac  11   12 , George W Sledge Jr  13 , Masakazu Toi  14
Affiliations
Clinical Trial

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy

Kenichi Inoue et al. Breast Cancer. 2021 Sep.

Abstract

Background: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC).

Methods: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety.

Results: In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380-1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390-1.463).

Conclusions: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population.

Clinical trial registration: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703 .

Keywords: Abemaciclib; Breast cancer; Cyclin-dependent kinase 4 and 6 inhibitor.

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Conflict of interest statement

Kenichi Inoue reports personal fees and grants to institution from Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., and Pfizer Japan; and grants to institution from AstraZeneca, Bayer, MSD, Novartis Pharma K.K., Parexel/Puma Biotechnology, and Taiho Pharmaceutical Co., Ltd. Norikazu Masuda reports personal fees, grants, and other support (research funding to institution) from Chugai Pharmaceutical Co., Ltd. and Eisai Co., Ltd.; personal fees and other support (research funding to institution) from AstraZeneca, Eli Lilly Japan K.K., Pfizer Japan, Inc., Daiichi Sankyo Co., Kyowa Kirin Co. Ltd., Novartis Pharma K.K., and Takeda Pharmaceutical Company, Ltd; and other support (research funding to institution) from MSD and Nippon-Kayaku. Hiroji Iwata reports personal fees and grants from AstraZeneca, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co. Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co. Ltd., Novartis Pharma K.K., and Pfizer Japan, Inc.; grants from Bayer, Boehringer Ingelheim, MSD, Nippon Kayaku, and Sanofi, and personal fees from Eisai Co., Ltd. Masato Takahashi reports personal fees from Astra Zeneca, Eisai Co., Ltd., Eli Lilly Japan K.K., and Pfizer Japan, Inc. Yoshinori Ito reports grants from A2 Healthcare, AstraZeneca, Covance, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., EPS International Holdings Co., Ltd., Kyowa Kirin Co., Ltd., MSD, Novartis Pharma K.K., Parexel, QVIA Services Japan K.K., and Taiho Pharmaceutical Co., Ltd. Yasuo Miyoshi reports personal fees and grants from AstraZeneca, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Kyowa Kirin Co., Ltd., MSD, Pfizer Japan, Inc., and Taiho Pharmaceutical Co., Ltd. Takahiro Nakayama reports personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., and Taiho Pharmaceutical Co., Ltd. Hirofumi Mukai reports personal fees and grants from Daiichi Sankyo Co., Ltd. and Pfizer Japan, Inc.; research grants from the Japanese government; personal fees from Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Company Ltd.; and membership on the Board of Directors of the Japan Breast Cancer Society. Antonio Llombart-Cussac reports grants, personal fees, and non-financial support from AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, and Roche; grants and non-financial support from Eisai Co., Ltd.; grants and personal fees from Genomic Health, Inc. and GSK Tesaro; personal fees and non-financial support from Bristol; personal fees from MSD; and stock, patents, and intellectual property with MedSIR. George W. Sledge, Jr. reports personal fees from Syndax and Verseau, Inc.; grants from Pfizer; and other (board of directors) from Tessa Therapeutics. Masakazu Toi reports personal fees, grants, and other role or support from Daiichi Sankyo Co. Ltd. and Kyowa Kirin Co. Ltd.; personal fees and grants from AstraZeneca, C&C Research Laboratories, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Nippon Kayaku, Pfizer Japan, Inc., Shimadzu, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company, Ltd., and Yakult; grants and other role or support from Luxonus, Inc.; personal fees and other role or support from Eli Lilly Japan K.K. and Konica Minolta, Inc.; grants from AFI Technologies, Astellas Pharma, Inc., GL Sciences, the Japanese Breast Cancer Research Group Association, and Shionogi; personal fees from Exact Science, Genomic Health, Inc., MSD, and Novartis Pharma K.K.; other role or support from Athenex Oncology, Bertis, Inc., BMS, Terumo Corporation, and Kansai Medical Net; and membership on the Board of Directors of the Japanese Breast Cancer Research Group Association, Organisation for Oncology and Translational Research, and Kyoto Breast Cancer Research Network. Joji Mori, Sachi Sakaguchi, Tsutomu Kawaguchi, and Yoshinori Tanizawa are employees and minor shareholders of Eli Lilly Japan K.K. Jan-Stefan van der Walt is an employee and minor shareholder of Eli Lilly and Company, UK.

Figures

Fig. 1
Fig. 1
Progression-free survival. PFS analysis at the February 14, 2017 data cutoff date for the MONARCH 2 Japanese subpopulation. PFS was defined as the time from the date of randomization until the date of radiographic documentation of progression, based on investigator assessment, or the date of death, whichever was earlier. The curves and medians (95% CI) were estimated using the Kaplan–Meier method. CI confidence interval, HR hazard ratio, No. number, PFS progression-free survival
Fig. 2
Fig. 2
Pharmacokinetic analysis of abemaciclib in patients receiving abemaciclib plus fulvestranta. Blood samples for assessment of abemaciclib concentration in plasma were obtained at the indicated prescheduled times on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2 and 3 and measured with a validated assay. Plasma concentrations of abemaciclib for individual patients over the course of the analysis are shown in the top graph, with geometric mean trough and peak concentrations (CV%) for the Japanese subpopulation and MONARCH 2 study population summarized in the table. aThe PK analyses are for patients receiving the 200-mg dose (pre-amendment dose) and patients receiving the 150-mg dose (post-amendment dose) combined. PK analyses of abemaciclib were conducted on patients who had received at least 1 dose of abemaciclib and had PK samples collected, and included ET-naïve patients who were excluded from the ITT population. AUCτ,ss area under the concentration versus time curve during one dosing interval at steady state, Cmax,ss maximum concentration at steady-state, Cmin,ss minimum/trough concentration at steady state, CV coefficient of variation, ET endocrine therapy, ITT intent-to-treat, PK pharmacokinetics
Fig. 3
Fig. 3
Forest plots of time to sustained deterioration of individual scales on the EORTC QLQ-C30 and QLQ-BR23. a EORTC QLQ-C30; and b EORTC QLQ-BR23 assessments in the Japanese subpopulation of MONARCH 2. In (a), deterioration of symptoms represents an increase in scores of ≥ 10; deterioration of global health status and functioning scores represents a decrease in scores of ≥ 10. In (b), deterioration of symptoms of Body Image, Sexual Functioning, and Future Perspectives represents a decrease in scores of ≥ 10; deterioration of symptoms of Systemic Therapy side effects, Arm, and Breast represents an increase in score of ≥ 10. Death was included as a deterioration event and follow-up improvement was taken into consideration. Data cutoff date: February 14, 2017. CI confidence interval, EORTC European Organization for Research and Treatment of Cancer, HR hazard ratio, QLQ-BR23 Quality of Life Questionnaire-Breast subscale, 23 items, QLQ-C30, Quality of Life Questionnaire-Core 30
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