Abstract Background:Although ER+/HER2– breast cancer has a better overall prognosis than other breast cancer subtypes, there is a high-risk subpopulation characterized by high-grade tumors and decreased sensitivity to endocrine therapy, higher responsiveness to chemotherapy and worse prognosis. A large meta-analysis of prospective studies focusing on neoadjuvant chemotherapy (NAC) for treatment of stage I-III breast cancer demonstrated that increased pathologic complete response (pCR) rates at surgery were associated with improved survival. This correlation was observed across triple-negative breast cancer (TNBC), HER2+ breast cancer, and high-grade HR+/HER2- breast cancer. Specifically, patients with a pCR after NAC had a 5-year event-free survival (EFS) rate of 90%, whereas patients who did not achieve a pCR had a 5-year EFS rate of 60%.Therefore, increasing pCR rates after NAC may have a substantial impact for patients with high-risk early-stage HR+/HER2– breast cancer. KEYNOTE-756 is a global, randomized, double-blind, phase III study of pembrolizumab (vs placebo) + chemotherapy as neoadjuvant treatment, followed by pembrolizumab (vs placebo) plus endocrine therapy as adjuvant treatment for patients with high-risk, early-stage ER+/HER2– breast cancer. Methods: Patients with T1c-2 cN1-2 or T3-4 cN0-2 grade 3 or grade 2 with Ki-67 ≥30%, invasive, ductal ER+/HER2– breast cancerwill be stratified by lymph node involvement (positive vs negative), tumor PD-L1 status (positive vs negative), ER positivity (≥10% vs <10%), and anthracycline dosing schedule (Q3W vs Q2W), and then randomized 1:1 to receive neoadjuvant treatment with pembrolizumab 200 mg Q3W or placebo in combination with paclitaxel (80 mg/m2 QW) for 4 cycles followed by (doxorubicin [60 mg/m2] or epirubicin [100 mg/m2]) plus cyclophosphamide (600 mg/m2) Q2/3W for another 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment with pembrolizumab (200 mg Q3W) or placebo for 9 additional administrations, in combination with endocrine therapy, which can be given for up to 10 years. Co-primary end points are pCR rate and EFS. Secondary end points are safety and overall survival. The global study will open in North America and Latin America, Europe, and Asia Pacific in the second half of 2018. Citation Format: Cardoso F, Bardia A, Andre F, Cescon DW, McArthur H, Telli M, Loi S, Cortés J, Schmid P, Harbeck N, Denkert C, Jackisch C, Jia L, Tryfonidis K, Karantza V. KEYNOTE-756: A randomized, double-blind, phase III study of pembrolizumab versus placebo in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk early-stage ER+/HER2– breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-04-03.