Background: Chest wall disease from breast cancer has limited treatments. Given the inflammatory nature of this disease and the increased expression of PD-1 seen with lymphocytic infiltration, we hypothesize that pembrolizumab may be effective. Combining immunotherapy with platinum chemotherapy may facilitate anti-tumor immunity, as demonstrated in lung cancer. This study is evaluating the combination of pembrolizumab and carboplatin in breast cancer patients with chest wall disease. Methods: This is a randomized phase II multicenter trial in the Translational Breast Cancer Research Consortium. Eighty-four patients with breast cancer (hormone resistant, triple negative, or refractory HER2+) with chest wall disease will be enrolled. Patients may have had prior surgery but prior radiation is not required, and patients may have distant metastases. Patients will be randomized 2:1 to treatment with pembrolizumab 200 mg IV and carboplatin AUC 5 every 3 weeks for at least 6 cycles followed by pembrolizumab 200 mg IV alone (n = 56, Arm A) or carboplatin AUC 5 every 3 weeks (n = 28, Arm B) until progression. Patients in Arm B may cross over to pembrolizumab 200 mg IV every 3 weeks (Arm Bx) on progression. After 18 patients are enrolled in Arm B, an interim analysis for futility will be performed, to allow for early closure if lack of efficacy. The primary objective is to determine the disease control rate in both arms at 18 weeks of treatment; the study is powered to detect a 20% difference between arms, with a hazard ratio of 0.52 (α = 0.10, β = 0.20). The secondary objectives are to determine toxicity, progression free survival, and response based on irRECIST and PD-L1 expression. Exploratory objectives, using tumor biopsy and peripheral blood testing before and after treatment, include correlations of response with biomarkers including tumor PD-L1 expression, tumor and peripheral blood immune composition, circulating tumor cells, circulating tumor DNA, soluble PD-L1 and tumor MYC expression. This study is open to accrual; the first patient was enrolled in 11/17. Clinical trial information: NCT03095352