Abstract PD13-11: PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer
Authors: Llombart-Cussac Antonio , Sledge George , Toi Masakazu , Neven Patrick , Sohn Joo Hyuk , Inoue Kenichi , Pivot Xavier , Okera Meena , Masuda Norikazu , Kaufman Peter A. , Koh Han , Grischke Eva-Maria , Conte PierFranco , Andre Valerie , Bian Yuanyuan , Shahir Ashwin , van Hal Gertjan 
Published: March 2023

Abstract
Background Abemaciclib is approved for patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) with progression on prior endocrine therapy (ET). The MONARCH 2 trial showed a statistically significantly benefit in progression-free survival (PFS) (hazard ratio [HR]: 0.553; 95% CI: 0.449-0.681; p &lt; 0.001), overall survival (OS) (HR: 0.757; 95% CI: 0.606-0.945; p = 0.01) and a manageable safety profile for abemaciclib plus fulvestrant compared with fulvestrant alone. Here we report the pre-specified final overall survival (OS) analysis from the MONARCH 2 trial (NCT02107703). Methods MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib or placebo, plus fulvestrant for treatment of pre-, peri- or postmenopausal women with CDK 4 & 6 inhibitor naïve HR+, HER2- ABC that progressed during ET. Pts were randomized 2:1 to receive abemaciclib or placebo, 150 mg twice daily, plus fulvestrant. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary versus secondary). OS and safety were key secondary endpoints, and chemotherapy-free survival was an exploratory endpoint defined as the time from randomization to initiation of chemotherapy or death, whichever occurs the earliest. Kaplan-Meier (KM) method was used to analyze time-to-event variables. A stratified Cox proportional hazards model was used to estimate treatment effect hazard ratio (HR). The prespecified final analysis was planned to occur based on approximately 441 OS events. Data cutoff was March 18, 2022. Results 669 women were randomized 2:1 to receive abemaciclib (n = 446) or placebo (n = 223), plus fulvestrant. Baseline characteristics have been previously reported (Sledge et. al., Jama Oncol 2020). The median follow-up time was approximately 80 months and at the time of the data cutoff, 11% of pts were still receiving study drug in the abemaciclib arm versus 2% in the placebo arm. 440 OS events were observed in the ITT population (abemaciclib arm: 283 events; placebo arm: 157 events). The median OS was 45.8 months in the abemaciclib arm and 37.2 months in the placebo arm (HR: 0.784; 95% CI: 0.644-0.955). The maintained separation of the KM curves beyond the medians is illustrated by the differences in the estimated 5- and 6-year OS rates between arms (5-year: 41.2% versus 29.2%; 6-year: 34.7% versus 23.7%; abemaciclib versus placebo respectively). While OS benefit was generally consistent across subgroups, a more pronounced benefit is noted in subgroups associated with a poorer prognosis such as visceral disease (HR: 0.643; 95% CI: 0.499-0.829), primary resistance to ET (HR: 0.634; 95% CI: 0.436-0.922) or negative progesterone receptor status (HR: 0.623; 95% CI: 0.405-0.959). Moreover, the addition of abemaciclib to fulvestrant deferred the initiation of chemotherapy (HR: 0.674; 95% CI: 0.562-0.809), with substantial difference in yearly chemotherapy-free survival rates (3 year: 42% vs 29.3%; 4 year: 37% vs 18.6%; 5 year: 32.4% vs 14.7%). Notably with longer exposure to abemaciclib, no new additional safety risks or cumulative toxicities were identified. Conclusions At the prespecified final OS analysis of the MONARCH 2 trial, with a median follow-up of 6.5 years, the statistically significant benefit previously demonstrated was confirmed and maintained. OS benefit was generally consistent across subgroups, with numerically greater effect size observed among patients with poorer prognosis. Importantly, the survival benefit came with a substantial extension of the chemotherapy-free survival time, which is an important consideration for pts with ABC. The results also provide assurance of the safety of abemaciclib with longer-term use.
Citation Format: Antonio Llombart-Cussac, George Sledge, Masakazu Toi, Patrick Neven, Joo Hyuk Sohn, Kenichi Inoue, Xavier Pivot, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Valerie Andre, Yuanyuan Bian, Ashwin Shahir, Gertjan van Hal. PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-11.