Background: Adrenocortical carcinomas (ACC) are rare and aggressive. Treatment options are limited and marked by poor efficacy and substantial toxicity. In this phase II single-center study, the efficacy and safety of pembrolizumab was assessed in patients (pts) with advanced ACC. Methods: Enrolled pts were aged ≥18 y with advanced ACC, ECOG ≤ 1, available tumor samples for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, intolerable toxicity, physician/patient decision to stop treatment. Imaging was performed every 9 wks. Tumor PD-L1 positivity (modified proportion score ≥ 1% or presence of stromal interface) was evaluated. Primary endpoint was ORR (by RECIST v1.1). Secondary endpoints included DOR, PFS, OS, safety. Somatic and germline next-generation sequencing was performed. Results: 39 pts were treated. Median age 62 (range, 19-87), 28% ECOG 0, 72% received ≥ 1 therapy. In available samples to date, 7/31 (23%) PD-L1+. At time of analysis, median follow-up among survivors was 17.8 mo (range, 5.4-34.7). ORR was 23.1% (95% CI, 11.1-39.3); 0 CR, 9PR. Seven pts (17.9%) had SD as best response. Among the 9 PRs, median time to PR was 4.1 mo (range, 1.7-10.5) and median DOR was not reached (95% CI, 4.1-not reached). Three pts achieving PR have completed 2 y of treatment with ongoing response noted. Tumor PD-L1 status is currently available in 6 pts with PR, 2/6 (33%) PD-L1+. Median PFS was 2.1 mo (95% CI, 2.0-10.7). Median OS was 24.9 mo (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% CI, 36-69%). In the 34 tested tumors, germline testing identified 2 PR pts with Lynch syndrome; the remaining 7 PRs were MSS. Median tumor mutation burden for all PRs was 4.1 mutations/megabase (range, 0-31.5). There was no significant relationship between somatic alterations and response to treatment. Grade 3/4 treatment-related AEs occurred in 7/39 (17.9%) pts. Two pts discontinued therapy due to AEs; both pts achieved PRs and continue to respond. All pts with PRs had LFT elevation ≥ grade 2. Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated in advanced ACC. Durable responses were noted. Complete evaluation of tumor PD-L1 and microsatellite status will be reported at the meeting. Clinical trial information: NCT02673333