Background: Two trials have demonstrated overall response rates of 19% with immune checkpoint inhibitors alone in chemotherapy-resistant triple negative breast cancer (TNBC). Radiation therapy (RT) is frequently used to enhance local control in TNBC and has been reported to induce distant (abscopal) tumor responses when combined with immunotherapy. We evaluate the safety and efficacy of the combination of RT and pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, in a single-arm, two-stage, phase II study in metastatic TNBC. Results from the first stage are reported. Methods: Eligibility criteria includes women with biopsy-proven TNBC, ECOG performance status 0-2, ≥ 2 measurable sites of metastatic disease with at least one site requiring RT. A total RT dose of 3000 cGy is delivered in one week in 5 fractions. Pembrolizumab is given intravenously at 200 mg/kg D1+/- 3 days and then every 3 weeks until disease progression as defined by RECIST v 1.1. The primary endpoint is overall response rate at week 13 in the non-targeted, non-irradiated lesions. Secondary endpoints include safety and overall survival. Tumor biopsies are obtained at baseline and at week 7. PD-L1 expression was not required for study entry. Results: Nine patients were enrolled in the first phase and assessed for antitumor activity and safety. Median age was 52 years (range 37-73). Three patients died secondary to disease-related complications (at weeks 2, 6 and 8) and 1 came off study due to disease progression prior to week 13. Of the 5 patients evaluable at week 13, 2 had a partial response, 1 had stable disease and 2 had disease progression. Common toxicities were mild and included fatigue, myalgia and nausea. One grade 3 event was reported - hyperbilirubinemia not attributable to study therapy after one dose of pembrolizumab. Conclusions: The combination of pembrolizumab and RT was well-tolerated in the first stage of a phase II study. Responses were observed outside of the RT fields in 2 of 5 patients who were evaluable at 13 weeks. The contribution of RT to pembrolizumab is unknown and will be investigated in the second stage of the study, which is ongoing. Correlative studies are planned. Clinical trial information: NCT02730130