Background: Everolimus (EVE; 10 mg) and exemestane (EXE; 25 mg) doublet therapy improved progression-free survival in women with hormone receptor-positive (HR+)/ HER2– advanced breast cancer (aBC; BOLERO-2), but was associated with significant mucositis as well as eventual disease progression. Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown clinical activity in combination with endocrine therapy and could potentially overcome phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor resistance by acting downstream of the PI3K pathway. Methods: In this ongoing Phase Ib/II study (NCT01857193), postmenopausal women with anastrozole- or letrozole-resistant HR+/HER2– aBC received escalating doses of the CDK4/6 inhibitor ribociclib (LEE011 [LEE]; once daily [QD], days 1–21 of 28-day cycles) with EVE (1–5 mg QD) and EXE (25 mg QD). Dose escalation was guided by a Bayesian logic regression model with overdose control principle and real-time pharmacokinetics. Pre-treatment tumor samples were sequenced by the Foundation Medicine platform. Here we report on the safety and efficacy of triplet therapy, and explore potential predictive biomarkers of response. Results: At the cut-off date March 2, 2015, 84 patients (pts) had been treated; here we present results from the 70 pts in the triplet arm treated with LEE (200–350 mg), EVE (most at 2.5 mg), and EXE. The median number of prior regimens was 5, and 18 (25.7%) pts had received prior PI3K/AKT/mTOR or CDK4/6 inhibitors for metastatic disease. Grade 3/4 treatment-related adverse events (AEs; ≥5% pts) were neutropenia (45.7%), leukopenia (8.6%), and thrombocytopenia (5.7%). Two (2.9%) pts discontinued due to AEs. Grade 3 dose-limiting toxicities were reported in 6 pts treated with LEE (300 mg) and EVE (2.5 mg): increased alanine aminotransferase/aspartate aminotransferase (2 pts), febrile neutropenia and hypophosphatemia (1 pt), oral mucositis (1 pt), rash and thrombocytopenia (1 pt), and thrombocytopenia with bleeding (1 pt). The recommended Phase II dose will be reported at the meeting. Among 55 pts evaluable for best overall response, there was 1 (1.8%) complete response (CR), 2 (3.6%) confirmed and 3 (5.5%) unconfirmed partial responses (PR), 7 (12.7%) non-CR, non-progressive disease (NCRNPD), and 26 (47.3%) stable disease (SD). Disease control rate (CR+PR+SD+NCRNPD) was 70.9%. One pt received treatment for ≥14 months, and 23 (32.9%) pts for ≥4 months. There was a trend towards longer duration of treatment in the CCND1 amplified group (n=10; median 166 days) than in the non-amplified group (n=22; median 60 days). A retrospective analysis of BOLERO-2 showed no differential effect of CCND1 amplification on PFS. Conclusions: Triplet combination of endocrine therapy with mTOR and CDK4/6 inhibition is feasible, permits lower dosing of EVE (resulting in better tolerability), and shows encouraging signs of clinical activity, including in some pts with prior exposure to PI3K/AKT/mTOR or CDK4/6 inhibitors. Duration of treatment was longer in pts with cyclin D amplification, possibly due to inclusion of a CDK4/6 inhibitor. These results suggest that that triplet therapy might be beneficial for pts who progress on doublets or who have cyclin D amplification. Citation Format: Bardia A, Modi S, Oliveira M, Campone M, Ma B, Dirix L, Weise A, Nardi L, Zhang V, Bhansali SG, Hewes B, Chavez-MacGregor M. Triplet therapy with ribociclib, everolimus, and exemestane in women with HR+/HER2– advanced breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-01.