Abstract PS1-10-01: Updated analyses from the retrospective rAMBER study exploring abemaciclib monotherapy after prior CDK4/6 inhibitor progression in metastatic hormone-receptor positive breast cancer

Abstract Introduction: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have become the standard of care for patients with advanced hormone-receptor positive (HR+)/HER2- breast cancer. The phase III postMONARCH trial demonstrated a modest improvement in progression free survival with fulvestrant and abemaciclib in the second-line advanced setting after prior CDK4/6i progression. However there remains uncertainty regarding the efficacy of CDK4/6i re-introduction. Here, we provide updated data from the rAMBER (retrospective multi-center, biomarker study to evaluate efficacy of Abemaciclib Monotherapy Beyond first line CDK4/6 inhibition in ER+ breast cancer) study exploring clinical outcomes with abemaciclib monotherapy after prior CDK4/6i progression. Methods: We collected retrospective data at 4 academic cancer centers (Massachusetts General Hospital, Washington University in St. Louis, University of Pittsburgh Medical Center, Moffitt Cancer Center) in accordance with site-specific IRB protocols. We identified patients with metastatic HR+/HER2- breast cancer with disease progression on CDK4/6i-based therapy who later received abemaciclib monotherapy. We abstracted clinical outcomes, analyzed radiographic data using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and explored genetic correlates of response and resistance from cell free DNA retrospective data. Results: A total of 30 patients were treated with abemaciclib monotherapy following progression on CDK4/6i-based regimens (all included palbociclib). The median duration of palbociclib treatment was 7.9 months (95% CI: 4.6-12.7 months), with a median number of 2 intervening lines of therapy prior to abemaciclib initiation. In this cohort, 23 patients remained on abemaciclib until disease progression or death, while 7 discontinued treatment due to adverse effects, including gastrointestinal issues and bone marrow suppression. The median duration of abemaciclib treatment was 4.0 months (95% CI: 2.8-13.9 months). Notably, 11 patients continued abemaciclib for more than 180 days before experiencing progression or death, whereas 6 patients had disease progression within 90 days of initiation. The majority (22) of patients had visceral and bony disease, while 6 patients had bone-only disease and 2 only had visceral disease. Preliminary review of radiographic images with RECIST criteria from 16 patients revealed 1 patient with partial response, 8 patients with stable disease, and 7 patients with progressive disease. Preliminary analysis of cell free DNA sequencing from 10 patients revealed RB1 alterations in 4 patients; 3 patients had rapidly progressive disease while 1 patient who initially responded to abemacliclib had an the RB1 alteration discovered at time of progression. Ongoing analyses will be presented at the meeting, including characterization of radiographic response across the entire cohort and exploration of genomic sequencing. Conclusions: Approximately one third of patients derived benefit from abemaciclib monotherapy, tolerating the regimen for 180 days, despite progression on palbociclib. In addition, preliminary genetic analyses revealed enrichment in RB1 alterations in patients with rapid disease progression. The rAMBER study is the first effort to evaluate the effectiveness of abemaciclib monotherapy following resistance to prior CDK4/6i, offering new perspectives on the role of sequential CDK4/6-targeted treatments. These results highlight potential benefit for continued CDK4/6 blockade and ongoing efforts may elaborate new insights related to genetic mechanisms of response and resistance and help identify patients who are likely to benefit from similar clinical strategies. Citation Format: S. Shahamatdar, K. Clifton, H. Maynard, U. Joshi, J. Wu, A. Dedeoglu, A. Putur, I. Kuter, A. Bardia, D. Juric, L. Spring, K. Harris, B. Moy, J. Shin, N. Vidula, A. Medford, T. Mulvey, A. Brufsky, H. Han, C. Ma, S. Wander. Updated analyses from the retrospective rAMBER study exploring abemaciclib monotherapy after prior CDK4/6 inhibitor progression in metastatic hormone-receptor positive breast cancer 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 PS1-10-01.