Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used for pts with HR+/HER2- MBC. The MONARCH-1 trial of abemaciclib monotherapy in pre-treated pts demonstrated a median progression free survival (PFS) of 6.0 months, leading to approval as monotherapy in a CDK4/6i-naïve population. There are no data on abemaciclib in HR+/HER2- MBC after progressive disease (PD) with CDK4/6i. Methods: We evaluated clinical outcomes in pts with HR+/HER2- MBC who received abemaciclib following PD on prior palbociclib or ribociclib at 4 US academic centers. We conducted genomic analysis utilizing next-generation sequencing of tissue samples and blood (cell-free/cfDNA) when available. Results: From 2/2015 through 1/2019, 58 pts with HR+/HER2- MBC received abemaciclib following PD on prior palbociclib. 20 pts (34%) received sequential courses of therapy, while 38 pts (66%) had at least one intervening non-CDK4/6i regimen. 14 pts (24%) received abemaciclib monotherapy and 44 pts (76%) received it in combination with an antiestrogen, including fulvestrant (52%), an aromatase inhibitor (22%), and tamoxifen (2%). 22 pts (38%) required dose reduction, while 7 (12%) discontinued due to toxicity. At data cutoff (1/23/2019), 20 pts (34%) had early PD (duration < 90 days), while 21 pts (36%) had treatment duration exceeding 6 months, including 10 who remain on treatment at interim analysis (range 181-413 days). The median PFS was 5.8 months (95%CI 3.4 – 8.0). Preliminary analysis of cfDNA revealed RB1 and FGFR1 alterations in pts with PD on abemaciclib. Additional analyses with mature clinical data and genomic sequencing will be provided at the meeting. Conclusions: This is the first multi-center experience to demonstrate that a substantial proportion of pts continue to derive clinical benefit with abemaciclib after prior CDK4/6i, highlighting the potential for its use following CDK4/6 blockade. A second subset had early progression, suggesting cross-resistance to CDK4/6i via common pathways. Future effort should be directed towards validating potential biomarkers to guide optimal utilization of continued CDK4/6 blockade in HR+/HER2- MBC.