631 Background: Third-generation nonsteroidal aromatase inhibitors (AIs) are used as adjuvant and 1st-line metastatic therapy for postm HR+ ABC. However, many patients (pts) subsequently experience disease progression. A phase 2 study of the Src/Abl kinase inhibitor bosutinib (BOS) as monotherapy (400 mg) in unselected, heavily pretreated ABC pts revealed an overall response rate (ORR) of 9.4% and 16-wk progression-free survival (PFS) rate of 29.8%, with a median PFS of 9.9 wks. As all responses were seen in HR+ pts, combination BOS and endocrine therapy was explored. Methods: This randomized, open-label, multicenter, phase 2 trial evaluated BOS and EXE vs EXE alone as 2nd-line therapy after AI failure in postm HR+ HER2– ABC. The primary end point was PFS. Prior to randomization, a 28-day safety lead-in phase was conducted; BOS 400 mg/EXE 25 mg was administered orally once daily, with reduction to BOS 300 mg if the higher dose had unacceptable toxicity. Results: 42 pts participated in the safety lead-in phase. 14 pts received BOS 400 mg/EXE 25 mg; common drug-related adverse events (AEs; any grade/grade ≥3) were diarrhea (93%/7%), nausea (79%/7%), vomiting (57%/0), increased alanine aminotransferase (ALT; 29%/29%), increased aspartate aminotransferase (AST; 21%/0), fatigue, (21%/0), and rash (21%/0). 5 of 13 (38.5%) evaluable pts experienced a dose-limiting toxicity (DLT) of increased ALT (n = 4), increased AST (n = 1), diarrhea (n = 1), and vomiting (n = 1). Therefore, another 28 pts were enrolled at a dose of BOS 300 mg/EXE 25 mg. At this dose level, grade ≥3 drug-related AEs included diarrhea (11%), nausea (7%), and ALT elevations (4%). Across dose levels, 5 pts discontinued due to diarrhea. All transaminase elevations were reversible upon BOS discontinuation. Median investigator-assessed PFS was 12.3 wks, and the ORR was 3.6%. Conclusions: The safety profile of BOS 300 mg/EXE 25 mg was generally manageable, albeit with limited efficacy. Because of the lower than expected efficacy and high rate of transaminase elevations, this study was stopped prematurely. Given prior evidence of efficacy of BOS monotherapy, new regimens with BOS should be explored for ABC.