Background: PD-1 inhibitors and EGFR inhibitors are effective and may provide potential synergy in R/M HNSCC. We launched an open-label, single-arm, multicenter phase Ib/II study of toripalimab (a humanized IgG4K monoclonal antibody specific for PD-1) with cetuximab in platinum-refractory R/M-HNSCC (NCT04856631). We report the results of the phase Ib portion of this study. Methods: Eligible patients with R/M HNSCC progressed upon 1^st-line platinum-containing treatment or developed R/M disease within 6 months of platinum-containing neo-adjuvant/adjuvant or chemo-radiation therapy were enrolled in this study. Exclusion criteria included prior immunotherapy or EGFR inhibitors therapy. Toripalimab was administered at 240mg intravenously Q3W and cetuximab was given as a loading dose of 400mg/m² IV followed by 250mg/m² QW. Dose-limiting toxicities (DLTs) and de-escalating dose were evaluated by a Safety Monitoring Committee (SMC). If less than 2 DLTs were observed in the first 6 patients, 6 more patients were enrolled to confirm safety. If 2 or more DLTs were observed, the next 6 patients would be enrolled at a lower dose level. The primary endpoint was safety. Secondary endpoints included determination of recommended phase 2 dose (RP2D), ORR, DCR, DOR, and PFS by an independent review committee (IRC) per RECIST v1.1, OS, and PK. Results: A total of 13 patients were enrolled in the phase Ib portion, including 11 (84.6%) male and 2 (15.4%) female patients. The median age was 58 (range 36-74) years. 7 (53.8%) patients had distant metastases and 9 (69.2%) were PD-L1 CPS ≥1. By the data cutoff date of Dec 21, 2021, the median follow-up was 19.3 (1.6-36.3) weeks. No DLT was observed, and the initial dose was chosen as RP2D. 10 (76.9%) patients experienced TRAEs; the most common TRAEs were rash (46.2%) and paronychia (38.5%). 5 (38.5%) patients experienced irAEs, including immune-related skin adverse reactions, hypothyroidism, thyroid function abnormal and duodenitis. No Grade≥3 TRAEs or irAEs occurred. No TRAEs led to discontinuation of study drug. 2 patients reported fatal AEs, both of which were caused by tumor hemorrhage and were judged not related to the study treatment by the SMC. Among 12 patients with at least one post-treatment tumor assessment, 6 confirmed PR (ORR 50%) and 6 SD (DCR 100%) were observed as assessed by the IRC. By the cutoff date, 5 patients have ongoing responses, with 3 over 12 weeks. Conclusions: Toripalimab combined with cetuximab were well tolerated and showed preliminary clinical efficacy in patients with R/M HNSCC. Clinical trial information: NCT04856631.