Background: Systemic chemotherapy and targeted therapies (TT) are almost ineffective in R/M ACC patients (pts). Sorafenib and axitinib showed some activity, possibly through their antiangiogenic effect. LEN is a stronger second-generation antiangiogenic inhibitor. Here we report the activity of LEN in R/M ACC pts. Methods: Pts with R/M disease, 1 previous line of chemotherapy and/or TT, received oral LEN 24 mg/day. Progression within 6 months at study entry was required. Primary endpoint was objective response rate (ORR) according to RECIST 1.1; secondary endpoints were progression free survival (PFS), overall survival (OS), toxicities (CTC 4.0) and assessment of quality of life (QoL) with EORTC QLQ C-30, EORTC QLQ-H&N35, EQ-5D. A 2-stage Simon design was applied, to test the null hypothesis of response ≤ 5% versus the alternative response ≥ 20%; 3 responses were required to reject the null hypothesis. Results: Twenty-eight pts were enrolled, F 16/M 12, median age 55 years (range: 22-73), 14 ACC of major and 14 of minor SGs, 96% metastatic. PS was 0 in 14 cases, 1 in 12 and 2 in 2 pts. Treatment related adverse events (AEs) were frequent (all grades 96%): asthenia 79%, hypertension 75%, stomatitis and weight loss 71%, TSH elevation 68%, were the most common. Grade ≥ 3 occurred in 50% of pts (asthenia 25%, hypertension 18%). No G5 toxicities occurred neither bleeding. Nine SAEs were reported, 6 of them drug-related. Dose was reduced in 21 pts within 12 weeks from therapy start, only 4 pts maintained the full dose throughout treatment. Among 26 evaluable pts, partial responses were 3 (11.5%) (3/26). Target lesions reduction between 23% and 28% was observed in 4 out 20 pts with stable disease. At a median follow up of 21.9 months (95% CI, 13.8-27.8), 6 pts are still on LEN and 12 died due to progression. Median PFS and DoR were 9 (95%CI 5.5-14.2) and 3.1 (1.8-21.7+) months, respectively. Median OS was 26.1 months (95% CI, 11.1-NR). QoL analysis is ongoing. Conclusions: Tumor size reduction was seen in 27% of pts suggesting activity of LEN in ACC. Toxicity was common but manageable. QoL has been studied for the first time. A randomized study is needed to confirm efficacy. Clinical trial information: NCT02860936.