BACKGROUND Treatment options for advanced solid tumors are limited. In recent years, anti-programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immunotherapy as monotherapy has shown significant efficacy, albeit in a limited subset of patients. In the MOVIE trial, metronomic chemotherapy was combined with two immune checkpoint inhibitors (ICIs) to improve clinical outcomes in patients with advanced solid tumors. METHODS MOVIE was a phase I/II French, multicenter, open-label, nonrandomized study with a Bayesian design that evaluated the antitumor activity and safety of metronomic vinorelbine associated with durvalumab plus tremelimumab. Here, we report on the cohort of patients with head and neck squamous cell carcinoma (HNSCC) from the MOVIE phase II study. Patients were aged ≥18 years with histologically confirmed recurrent or metastatic HNSCC, resistant to conventional therapies, and presented a measurable disease according to RECIST version 1.1. They received oral vinorelbine 40 mg three times a week, and durvalumab 1500 mg plus tremelimumab 75 mg via intravenous infusion on day 1 of 28-day cycles, for a maximum of four cycles of tremelimumab. The primary endpoint was the clinical benefit rate (CBR), defined as the rate of complete response (CR), partial response (PR), or stable disease (SD) lasting at least 24 weeks. RESULTS Fifteen HNSCC patients were included between May 2019 and October 2020. The mean estimated CBR according to a noninformative prior distribution was 23.5% (95% credible interval 7.3-45.6). One patient achieved CR, 1 PR, and 1 SD > 24 weeks, leading to an objective response rate of 14.3%. The median progression-free survival was 1.8 months (95% confidence interval 1.0-1.9 months), and the median overall survival was 8 months (95% confidence interval 2.5-12.7 months). The most common vinorelbine-related grade ≥3 adverse events were anemia (n = 2, 13%) and neutropenia (n = 3, 20%). The most common ICI-related grade ≥3 adverse events were anemia (n = 1) and hypokalemia (n = 1). There were no treatment interruptions for toxicity and no treatment-related deaths. CONCLUSIONS Metronomic vinorelbine in combination with dual durvalumab plus tremelimumab immunotherapy had only moderate activity in pretreated advanced HNSCC.