Background: Pembrolizumab (a humanized monoclonal antibody blocking programmed death receptor-1[PD-1]), and cetuximab (a chimeric monoclonal antibody inhibiting epidermal growth factor receptor) are both FDA-approved, second-line monotherapies for R/M HNSCC. This is the first trial to evaluate anti-tumor efficacy of dual therapy with pembrolizumab and cetuximab. Previously reported safety data demonstrated favorable toxicity. An interim futility analysis of cohort 1 (anti-PD-1/PD-L1 and cetuximab naïve) was completed per protocol. Methods: Patients (pts) with platinum-refractory/ineligible, R/M HNSCC were treated with pembrolizumab 200mg IV on day 1 and cetuximab 400mg/m2 loading dose followed by 250mg/m2 weekly (21-day cycle). Primary endpoint: overall response rate (complete and partial responses) by 6 months (mo). Secondary endpoints: 12-mo progression-free survival (PFS) probability, overall survival, response duration, safety, correlative analyses. Results: 14 evaluable pts were enrolled March 2017-October 2018. Median age 60y (range 47-86y), M:F 6:8, ECOG (0:1) 2:12, 14 mucosal primaries (9 oral cavity, 2 HPV-mediated oropharynx, 2 non-EBV-associated nasopharynx, 1 larynx). 11 pts (79%) had no prior lines of systemic therapy for R/M HNSCC (range 0-1). 6 pts (42.8%) had a partial response by 6 months, meeting pre-planned criteria for trial continuation. 4 pts (28.6%) had stable disease and 4 (28.6%) had progressive disease. Median PFS was 128 days (4.3 mo). Median duration of response was 160.5 days (5.4 mo) for partial responders and 133 days (4.4 mo) for pts with stable disease. Disease control rate (partial + stable) was 71.4%. There were 7 grade 3 treatment-related toxicities. 2 pts discontinued cetuximab due to toxicity, however, both continued pembrolizumab. Conclusions: Interim analysis indicates that pembrolizumab plus cetuximab is potentially active for platinum-refractory/ineligible pts with R/M HNSCC. These results meet protocol specifications for trial continuation. Final results will include PD-L1 expression data. Clinical trial information: NCT03082534