Background: Current therapeutic efforts in the management of HER2+ MBC focus on targeting the HER receptor family, however co-inhibition of targets downstream of the HER2 pathway, such as cyclin D-CDK 4/6, could enhance therapeutic efficacy. We conducted a phase 1b study of the CDK4/6 inhibitor ribociclib and T-DM1 in patients (pts) with HER2+ MBC. The primary objective was to determine the recommended phase 2 dose (RP2D) of ribociclib plus T-DM1. Secondary objectives included safety, PK assessments, and efficacy. Methods: Pts with HER2+ MBC who previously received at least 1 taxane and trastuzumab-containing regimen in any setting were eligible. Pts with previous CDK4/6 inhibitor exposure, QTcF > 450msec, or unstable brain metastases were excluded. Ribociclib was given orally for 2 weeks of a 21-day cycle (days 8-21), with T-DM1 given at 3.6 mg/kg every 3 weeks on day 1. A standard 3+3 dose escalation design was used to evaluate various doses of ribociclib in combination with T-DM1 to determine the RP2D. Results: From 5/2016 – 10/2018, 10 pts (8/10 ER+) were enrolled with a median age of 53 (38-72) and median of 1 (0-2) prior therapies for MBC. During dose-escalation, pts received doses of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 1). No DLTs were observed. The most common treatment related grade 3 or higher AEs were neutropenia (50%), infection (20%), anemia (10%), and thrombocytopenia (10%). 4/10 pts had dose reductions due to toxicity. The average concentration of ribociclib at steady state was similar at each dose level, ranging from 273 to 413 ng/mL. Among 9 evaluable pts, the ORR was 33% (3/9) and the other 6 pts had stable disease. After a median follow-up time of 10.9 months, the median PFS was 12.5 months (95% CI [10.5. 20.9]). Biomarker results will be presented at the meeting. Conclusions: Co-targeting HER2 and CDK4/6 with the combination of ribociclib with T-DM1 was well tolerated with evidence of clinical activity. Based on PK analysis and dose reductions, 400 mg is the RP2D. Further evaluation is warranted for patients with HER2+ MBC. Clinical trial information: NCT02657343