Background: Immune checkpoint inhibitors are active in a broad range of advanced cancers. Antibody dependent cell mediated cytotoxicity is a mechanism of action of trastuzumab. The combination of the two may enhance activity and/or overcome acquired resistance. We performed a phase I study of durvalumab and trastuzumab in HER-2 positive MBC previously treated with chemotherapy and anti HER-2 antibodies to assess safety, efficacy and correlative end-points. Methods: Patients with HER-2 positive MBC, PS 0-2, and previously treated with taxanes and trastuzumab were enrolled on a standard 3+3 dose escalation schedule. Dose level 1 was standard doses of durvalumab (1125 mg i.v. day 1) and trastuzumab (8 mg/kg i.v. loading then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed baseline and post cycle 1 tumor biopsies. The primary endpoint of the study was to establish the RP2D. Results: 15 patients were accrued across 3 Canadian centres from April – December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86), the majority had visceral disease (87%); ≥3 prior lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%) and TDM1 (93%) for MBC. No dose limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed ≥ grade 3 irAE (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4/14 (29%) demonstrating stable disease as best response at week 6 (median duration 2.7 months). All patients had < 1% PD-L1 expression on archival tissue (7/15) or pre-study biopsy (8/15). In the dose expansion cohort, evaluable pre-treatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration. Work on the serial ctDNA collected is ongoing. Conclusions: The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in heavily pre-treated HER-2 positive MBC patients with evidence of cytotoxic T-cell exhaustion. Clinical trial information: NCT02649686