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.

Biomarkers for Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced/Metastatic Breast Cancer: Translation to Clinical Practice

“…A number of biomarkers tested in phase II and III clinical trials in HR+/HER2– advanced/mBC (including CDK4 and CDK6 mRNA expression, CCND1 amplification, and p16 loss) have thus far been unable to demonstrate a biomarker-treatment interaction to predict PFS with CDK4/6 inhibitors, despite a mechanistic rationale (Table 3). 6,8,16,18-20,24-35,38,39…”

“…A number of biomarkers tested in phase II and III clinical trials in HR+/HER2-advanced/mBC (including CDK4 and CDK6 mRNA expression, CCND1 amplification, and p16 loss) have thus far been unable to demonstrate a biomarkertreatment interaction to predict PFS with CDK4/6 inhibitors, despite a mechanistic rationale (Table 3). 6,8,16,[18][19][20][24][25][26][27][28][29][30][31][32][33][34][35]38,39 ESR1 gene expression, circulating tumor fraction, TP53 mutation, and FGFR1 gain were significantly associated with PFS in both the placebo and CDK4/6 inhibitor arms. 28,31 Although no significant biomarker-treatment interaction was observed, these markers could be potential general prognostic markers of clinical outcome for patients with advanced/metastatic HR+ breast cancer.…”

A Randomized Phase I Study of Abemaciclib in Chinese Patients with Advanced and/or Metastatic Cancers

“…Considering the limited sample size, caution should be exercised in interpreting any incidence from the study. When evaluated in larger population, the incidence of embolism for abemaciclib in breast cancer was less than 5%, including predominantly Chinese patients trial (MONARCH plus) [ 13 , 14 , 20 ]. Venous thromboembolic events have been reported with other CDK4 and 6 inhibitors [ 21 ].…”

A eficácia dos novos tratamentos de hormonioterapia na sobrevida livre de progressão de pacientes com câncer de mama metastático RH+/HER2-: uma revisão sistemática

“…• Abemaciclibe + letrozol: este regime de tratamento foi estudado nos ensaios clínicos randomizados MONARCH 3 e MONARCH plus, que evidenciaram aumento expressivo da sobrevida livre de progressão, com média de 28,2 meses, e maior taxa de resposta objetiva quando comparado com o uso de placebo mais letrozol, 61,9% e 41,8% respectivamente, como primeira linha de tratamento para o câncer de mama metastático RH+/HER2-. (Goetz et al, 2017;Johnston et al, 2019;Toi et al, 2021;Zhang et al, 2020).…”

“…Os ensaios clínicos MONARCH 2 e MONARCH plus apresentaram sobrevida livre de progressão média de 16,5 meses (95% IC 11,5-21,2), notando-se maior benefício dentre o subgrupo de mulheres na pré-menopausa, cuja SLP média foi de 28,6 meses. A análise da sobrevida global na população do MONARCH 2, demonstrou aumento de 9,4 meses, com SG média de 46,7 meses no braço abemaciclibe e 37,3 para o placebo (Neven et al, 2021;Sledge et al, 2020;Toi et al, 2021;Zhang et al, 2020).…”