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Simple Summary: Aromatase inhibitors (AIs) remain key elements of endocrine therapy for patients with hormone receptor positive HER2 negative metastatic breast cancer (HR+ HER2− MBC). Recent advances include the use of CDK 4/6 inhibitors or PIK3CA inhibitor in the clinic; however, few immunotherapy trials have been conducted in HR+ HER2− metastatic disease. The current phase II trial was designed to test the safety and efficacy of AIs in combination with immune checkpoint inhibitor pembrolizumab in patients with HR+ HER2− MBC (NCT 02648477). This combination was well tolerated, but minimal clinical activity was observed likely due to lack of PD-L1 pre-selection and heavily pretreated patient population. This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT 02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2− MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3–46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone. [ABSTRACT FROM AUTHOR]