Background: surgery w/wo adjuvant radiotherapy (RT) for (recurrent) advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% 5-year OS, indicating the need for novel treatment options. In recurrent metastatic HNSCC nivolumab nearly tripled the 2-year OS. Aiming at improving clinical outcome in advanced HNSCC in a curative setting, we tested the feasibility of nivolumab ± ipilimumab neoadjuvant to (salvage) surgery w/wo RT. Methods: investigator-initiated phase-IB/II trial to assess feasibility of neoadjuvant nivolumab monotherapy (240 mg in week 1&3: arm-A) or in combination with ipilimumab (1 mg/kg in week 1: arm-B) before surgery (≤ week 5) w/wo RT for advanced HNSCC. Results: 12 patients were included (3+3 design, both arms) in phase-IB of this study; 7/12 (58%) patients had pre-existent moderate-to-severe comorbidities (ACE-27). All patients were HPV negative. All patients received surgery as planned (25-33 days after start of immunotherapy) with no unexpected wound healing problems. In both groups, 4 patients (67%) experienced immune-related toxicity: grade 1-2 (n = 4) and grade 3-4 (n = 1; colitis) in arm-A; grade 1-2 (n = 5) and grade 3-4 (n = 2; colitis and elevated liver enzymes) in arm B. Immune-related toxicity was managed with prednisone (n = 2) and infliximab (n = 1). There was 1/6 (12.5%) pathological response in arm-A (1 near complete response, nCR) and 3/6 (50%) in arm-B (1x partial response and 2x nCR). No patients with nCR had a recurrence at follow-up (median 10 months). Preliminary data (mutational load will be added) show increased H7-B3 gene expression in non-responders before treatment, and increased endothelial cell and NK cell gene expression in responders post-treatment. Overall, in these 12 patients, neoadjuvant ipilimumab + nivolumab resulted in a significant increase in immune-related gene expression when compared to nivolumab only, irrespective of treatment response. Conclusions: neoadjuvant ipilimumab + nivolumab can safely be administered prior to major surgery for advanced HNSCC. Efficacy is promising and will be further evaluated in the phase-II trial continuation. Clinical trial information: NCT03003637