MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2- advanced breast cancer: the multinational randomized phase III study

Abstract

Aim: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa.

Methods: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A.

Results: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346-0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240-0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B).

Conclusion: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Keywords: abemaciclib; aromatase inhibitors; breast neoplasms; cyclin-dependent kinase 4; cyclin-dependent kinase 6; fulvestrant.

Conflict of interest statement

Conflict of interest: RBH, YL and HDC are employees and minor shareholders of Eli Lilly and Company. XHW has received research funding from Eli Lilly and Company. QYZ, TS, YMY, HPL, MY, ZST, CPO, YPL, RC, ML, YC, QCO, XC, NL, XJW, JFF, RH, GBK, MAC-P, ZJ and XCH have no conflicts of interest to declare.

© The Author(s), 2020.

Figures

Figure 1.

Study design. aAbemaciclib 150 mg twice daily (continuous schedule). bAnastrozole 1 mg daily or letrozole 2.5 mg daily per physician’s choice. cFulvestrant 500 mg on days 1 and 15 of the first 28-day cycle and then every 28 days. ABC, advanced breast cancer; CBR, clinical benefit rate; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; ET, endocrine therapy; FULV, fulvestrant; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mBC, metastatic breast cancer; NSAI, non-steroidal aromatase inhibitor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; R, randomization.

Figure 2.

Progression-free survival in the ITT population in (A) cohort A and (B) cohort B. CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; NSAI, non-steroidal aromatase inhibitor; PFS, progression-free survival.

Figure 3.

Progression-free survival subgroup analyses in the ITT population in (A) cohort A and (B) cohort B.Progression-free survival hazard ratios are indicated by squares and 95% CIs are indicated by the crossing horizontal lines. Hazard ratios are unstratified and estimated with the adjustment of treatment arm by subgroup interaction, with the exception of the PFS hazard ratio for the overall study population, which is also presented as the stratified hazard ratio. Groups with n = 15) in the ‘study entry disease status’ category (panel A)]. In panel A, the error bar for the subgroup of patients aged ⩾65 years is clipped at the upper limit. In panel B, the error bars for the subgroups of patients with no measurable disease at baseline, two organs involved in metastasis, high tumor grade, and most recent endocrine therapy in the locally advanced/metastatic setting are clipped at the lower limit. A, abemaciclib; AI, aromatase inhibitor; CI, confidence interval; DFI, disease-free interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; ITT, intent-to-treat; NSAI, non-steroidal aromatase inhibitor; P, placebo; PgR, progesterone receptor; PS, performance status.