Background: Patients (pts) diagnosed with primary estrogen receptor-positive (ER+), human epidermal growth factor 2-negative (HER2−) breast cancer (BC) of high grade and/or low ER expression are at increased risk of relapse, despite current standard of care (SoC). Promising data assessing programmed death-1 (PD-1) inhibition coupled with neoadjuvant chemotherapy for pts with high-risk ER+, HER2− BC noted improved pathologic complete response (pCR), which is identified as a valid surrogate endpoint for long-term clinical outcomes. Methods: CheckMate 7FL (NCT04109066) is a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study evaluating nivolumab (NIVO) vs placebo (PBO) in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy (ET) in pts with high-risk, ER+, HER2− primary BC. Eligible pts are male or female, aged ≥18 years with newly diagnosed grade 2 with ER expression of 1–9%, or grade 3, T1c-2, cN1-2 (tumor size ≥2 cm) or T3-T4, cN0-cN2 ER+, HER2− BC. Pts eligible for neoadjuvant chemotherapy and surgery, with adequate organ function, ECOG PS of 0 or 1, and tissue available for biomarker assessments will be enrolled. Approximately 1200 pts will be randomized 1:1 to NIVO or PBO, stratified by programmed death ligand 1 (PD-L1) expression, tumor grade (2 or 3), axillary nodal status (+ or −), and anthracycline + cyclophosphamide schedule (Q3W or Q2W). In the neoadjuvant phase, pts will receive NIVO 360 mg Q3W or PBO + paclitaxel 80 mg/m² QW for four 3-week cycles, followed by NIVO 360 mg Q3W (or 240 mg Q2W) or matching PBO in combination with either doxorubicin 60 mg/m² or epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² Q3W or Q2W for 4 cycles. Pts will undergo surgery after completion of the neoadjuvant phase. Following surgery, pts will enter the adjuvant phase and receive NIVO 480 mg Q4W or PBO for 7 cycles + investigator’s choice of ET per local SoC. Primary endpoints are pCR (ypT0/is, ypN0) and event-free survival. Secondary endpoints include overall survival, disease-free survival, distant-metastasis-free survival, safety, pCR (ypT0 ypN0 and ypT0/is) rates, overall response rates, residual cancer burden, and quality of life. Interim analyses are planned. The study is currently enrolling. Clinical trial information: NCT04109066.