Abstract PS2-02-20: Treatment patterns and clinical outcomes following progression on first-line ET + CDK4/6i among patients with HR+/HER2− metastatic breast cancer (mBC) in the US

Abstract Background Endocrine therapy (ET) in combination with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a preferred first-line (1L) treatment for patients (pts) with HR+/HER2− mBC. However, ET resistance frequently emerges after 1L treatment, with many pts receiving subsequent chemotherapy or other targeted regimens. This study aimed to assess treatment patterns and clinical outcomes in pts with HR+/HER2− mBC that progressed on 1L ET + CDK4/6i in real-world (rw) practice settings. Methods This was a noninterventional, retrospective, observational cohort study using the US-based Flatiron Health Enhanced Datamart. Adult pts with HR+/HER2− mBC (with no other actionable genomic alterations [ESR1, PIK3CA, AKT1, PTEN, or gBRCA]) that progressed on 1L ET + CDK4/6i were included if they initiated a second-line (2L) therapy between Jan 2017 and Sep 2024 with ≥90 d of potential follow-up. Pt demographics, clinical characteristics, and treatment utilization were assessed descriptively. Treatment data were recorded as documented by physicians and may reflect off-label use. The primary (rw progression-free survival [rwPFS]) and secondary (rw overall survival [rwOS], rw time to discontinuation or death [rwTTD/D], and rw time to next treatment or death [rwTTNT/D]) endpoints were assessed using Kaplan-Meier methods. Analyses were performed in all pts, by 2L regimen, and by time to progression on 1L treatment. Results 1415 pts with HR+/HER2− mBC were included (median age, 65 y; 66.2% were White). Of these, 57.3% (n=811) had disease progression on ET + CDK4/6i within 12 mo of 1L initiation (early progression; 33.3% in ≤6 mo); 25.5% had disease progression in 12 to 24 mo and 17.2% within >24 mo. In the 2L, 63.6% of pts received an ET-based regimen, 27.1% received chemotherapy (CT; monotherapy, 23.8%; multiagent, 3.3%), and 9.3% received other regimens (including AKTi, PARPi, and the ADC sacituzumab govitecan or trastuzumab deruxtecan). Pts with early vs later times to disease progression on 1L ET + CDK4/6i used 2L CT more frequently (40.6% [≤6 mo] vs 14.0% [>24 mo]); the opposite was true for 2L ET (52.2% [≤6 mo] vs 75.3% [>24 mo]). With a median follow-up of 14.6 mo, the 2L median rwPFS ranged from 4 to 8 mo and median rwOS ranged from 14 to 32 mo; the shortest estimates were among pts on 2L CT and with early disease progression on 1L ET + CDK4/6i (Table). Conclusions In this study of pts with HR+/HER2− mBC that progressed on 1L ET + CDK4/6i, over half had 1L disease progression within 12 mo and about one-third received CT in a subsequent line. The median rwPFS on 2L treatments was shorter among those who were using CT in 2L or had early progression (<12 months) on 1L ET + CDK4/6i, highlighting the emergence of ET resistance and a need for more effective therapeutic alternatives to improve pt outcomes. Citation Format: V. Kaklamani, S. Valliant, S. Hunter, O. Tymejczyk, A. Yu, P. Earla, S. Mehta, E. Pang. Treatment patterns and clinical outcomes following progression on first-line ET + CDK4/6i among patients with HR+/HER2− metastatic breast cancer (mBC) in the US [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-20.