Background: Salivary gland cancers (SGC) are histologically uncommon but heterogeneous, accounting for less than 5% of all head and neck cancers. No specific therapy including targeted agents has been associated with improved clinical outcome in recurrent/metastatic SGC. Recent studies suggest VEGF and PDGFR might play an important role in SGC. Nintedanib is a potent small molecule triple receptor tyrosine kinase inhibitor (VEGFR1-3, FGFR 1-2, and PDGFR α/ß). We sought to determine nintedanib’s antitumor activity in patients with recurrent or metastatic SGC. Methods: This open-label, multicenter, phase II, single-arm study was conducted at 11 hospitals in Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC who had undergone cytotoxic chemotherapy were enrolled. Nintedanib was given orally at 200mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was response rate. Secondary endpoints were progression-free survival, overall survival, toxicity, and disease control rates. Simon two-stage optimal design was used. Results: Median age was 54 years, 62% of patients were female, and 95% had an ECOG performance status of 0 or 1. The majority of patients had adenoid cystic carcinoma (65%), and 40% of all of patients had received at least two prior chemotherapies. After 20 patients were enrolled, the study was stopped because no responder was observed at Stage I. There was no partial response, but the disease control rate was 75% (15/20). The median duration of stable disease was 8.3 months (range 3.5-12.4). At the time of data cutoff with median follow-up of 9.5 months, median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (CI.0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Five patients required dose reduction. Conclusions: Single agent nintedanib did not show partial response, but did achieve a 75% control rate with long stabilization in these SGC patients. Nintedanib was tolerable and toxicities were manageable. Given the high rate and long duration of disease control, further investigation is needed. Clinical trial information: NCT02558387