The management of R/M HNSCC is rapidly evolving with new available treatment molecules and combination modalities. Anti-EGFR cetuximab (CTX) and immune checkpoint inhibitors (ICI) can be used either alone or in combination with conventional platinum-based doublet chemotherapy (with taxanes or fluorouracil). No data have been reported to date on the association of doublet chemotherapy concomitantly with both CTX and ICI. We present a case series of patients treated with 4 cycles of quadritherapy, every 3 weeks, including paclitaxel 175 mg/m2, carboplatin AUC 5, pembrolizumab 200 mg, and weekly 250 mg/m2 CTX. All patients achieved an objective response (6 complete responses, 2 partial responses). Clinical response was fast, so 1 patient avoided an emergency tracheostomy for laryngeal dyspnea. Four patients furtherly benefited from cisplatin-based chemoradiotherapy on residual tumor sites after the response to quadritherapy. Adverse events were manageable, except for an ICI-related liver toxicity in a patient. Overall, this short series indicates that a quadruple therapy with carboplatin-paclitaxel-CTX and pembrolizumab seems to be safe and active in patients with R/M HNSCC. This observation could be confirmed through further clinical trials.