Background: Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer with poor prognosis and is often resistant to neoadjuvant chemotherapy with risk of early recurrence and systemic spread of disease. PD-L1 expression in IBC is frequent (Bertucci et al. Oncotarget 2015), and blockade of the PD-1/PD-L1 axis with checkpoint inhibitors has emerged as a promising treatment to enhance anti-tumor immunity and clinical response. We hypothesize that PD-1 blockade with nivolumab in combination with neoadjuvant (primary) chemotherapy will increase the rate of pathologic complete response (pCR) and reduce risk of recurrence in patients with IBC. Methods: This is a single-arm open-label multicenter phase II study of nivolumab with neoadjuvant chemotherapy in patients with non-metastatic IBC (n = 52) (ClinicalTrials.gov: NCT03742986). All breast cancer subtypes (based on ER/PR/HER2) will be allowed. Patients will receive nivolumab 360 mg IV on day 1 (21-day cycle) for four cycles in addition to standard chemotherapy. Cohort 1 (patients with triple negative breast cancer or hormone receptor-positive (HR)/HER2-negative IBC) will receive nivolumab in combination with paclitaxel followed by doxorubicin and cyclophosphamide (AC). Cohort 2 (patients with HER2-positive IBC) will receive nivolumab in combination with a taxane (docetaxel or paclitaxel), trastuzumab, and pertuzumab followed by AC. All patients will then undergo mastectomy followed by radiation. The primary study objective is pCR rate (ypT0/Tis ypN0). Secondary objectives will be safety, tolerability and invasive recurrence-free interval. Association of correlative biomarkers with pCR and sensitivity or resistance to therapy with the combination of nivolumab and chemotherapy will be evaluated. Analyses will include mutational and neoantigen load, tumor-infiltrating lymphocytes (TILs) by histopathological assessment, T-cell receptor (TCR) by immunosequencing, and immune gene profiles in the tumor. PD-L1 expression in tumor tissue is not required for enrollment but will be assessed as a predictive marker. Clinical trial information: NCT03742986