Jaliffe, Georgina Garnica

Abstract Background Adjuvant abemaciclib (a CDK4 and 6 inhibitor) combined with ET resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high risk EBC in the monarchE trial, and is an approved adjuvant therapy for these patients. Here we present efficacy results from a pre-specified overall survival interim analysis (OS IA2) which was planned to occur 2 years (yrs) after the primary outcome analysis. Methods Pts were randomized (1:1) to receive ET for up to 10 yrs +/- abemaciclib for 2 yrs (study treatment period). High-risk EBC was defined as either ≥4 positive axillary lymph nodes (ALN), or 1-3 ALN with either Grade 3 disease and/or tumor ≥5 cm (Cohort 1). While the proliferation biomarker Ki-67 was centrally assessed in all pts with available tissue sample, an additional smaller group of pts with 1-3+ ALN and central Ki-67 ≥20% as the only high-risk feature were included (Cohort 2). The intent-to-treat (ITT) population consisted of both Cohort 1 (5120 pts) and Cohort 2 (517 pts). Hazard ratios (HR) were estimated using Cox proportional hazard model. Results At a median follow-up of 42 months, all pts were off abemaciclib. IDFS and DRFS data illustrate a sustained benefit beyond the treatment period. In the ITT population, the HR for IDFS was 0.664 (95% CI: 0.578, 0.762) and DRFS was 0.659 (95% CI: 0.567, 0.767). At 4 yrs, this reflected an improvement in IDFS rates from 79.4% to 85.8% (absolute difference 6.4%), and in DRFS rates from 82.5% to 88.4% (absolute difference 5.9%). The continued separation of the curves was associated with an increase in absolute benefit in IDFS 4-year rates compared to 2-and 3-year IDFS rates (absolute difference 2.8% and 4.8% respectively). While OS remained immature, there was a lower number of deaths observed in the abemaciclib plus ET arm compared to the ET alone arm (157 [5.6%] vs 173 [6.1%], HR 0.929 [95% CI: 0.748, 1.153], p = 0.503), suggesting that the robust benefit in IDFS and DRFS began to translate into a numerically favorable OS HR. As previously described, within Cohort 1, a Ki-67 index of ≥20% was associated with a worse prognosis, but similar abemaciclib treatment effects were observed regardless of Ki-67 index. No new safety signals were observed. Conclusion The clinically meaningful benefit of adjuvant abemaciclib added to ET in HR+, HER2-, node-positive, high-risk EBC persists beyond completion of abemaciclib therapy, yielding an increase in absolute IDFS and DRFS benefit at 4 yrs. While OS remains immature at this time, the lower number of deaths in the abemaciclib arm compared to the ET arm suggest that a survival signal favoring abemaciclib is emerging. Citation Format: Stephen Johnston, Masakazu Toi, Joyce O’Shaughnessy, Priya Rastogi, Mario Campone, Patrick Neven, Chiun Sheng Huang, Jens Huober, Georgina Garnica Jaliffe, Irfan Cicin, Sara Tolaney, Matthew P. Goetz, Hope Rugo, Elżbieta Senkus, Laura Testa, Lucia Del Mastro, Chikako Shimizu, Ran Wei, Ashwin Shahir, Maria Munoz, Belen San Antonio, Valerie Andre, Nadia Harbeck, Miguel Martín. Abemaciclib plus endocrine therapy for HR+, HER2-, node-positive, high-risk early breast cancer: results from a pre-planned monarchE overall survival interim analysis, including 4-year efficacy outcomes [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 GS1-09.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.