Background Patients (pts) with HPV negative R/M HNSCC have a worse median overall survival (OS) than those with HPV positive disease and current treatment options are limited.[1] Ficlatuzumab is a humanized IgG1 mAb that binds HGF, the ligand for the c-MET tyrosine kinase receptor. HGF/c-MET pathway dysregulation is frequently observed in HPV negative HNSCC and has been linked to EGFR inhibitor resistance, limiting the potential efficacy of EGFR-targeting drugs like cetuximab. A phase 2 study, using ficlatuzumab+cetuximab in pts with HPV negative R/M HNSCC suggested further research was indicated.[2] FIERCE-HN compares the efficacy and safety of ficlatuzumab+cetuximab vs placebo+cetuximab in pts with R/M HPV negative HNSCC. Methods This is an international, multicenter, randomized, double-blind, placebo-controlled phase 3 study. Major enrollment criteria include confirmed diagnosis of R/M HNSCC primary tumors of the oropharynx (p16 negative only), oral cavity, hypopharynx, or larynx. Pts must have progressed on, or be intolerant to, previous anti-PD-1/PD-L1 ICI and platinum-based chemotherapy; have received ≤2 prior lines of anticancer therapy and received no prior treatment with cetuximab/alternative EGFR inhibitors in the R/M setting. Pts with feeding tubes are eligible. The primary endpoint is OS; key secondary endpoints are PFS and ORR. The study initially randomized pts 1:1:1 to ficlatuzumab 20mg/kg, 10mg/kg, or placebo, each in combination with cetuximab 500mg/m2. Following the 1st interim analysis (IA), only ficlatuzumab 20mg/kg+placebo continued in 1:1 randomization. The 2nd IA occurs after ~ 163 OS events to assess efficacy and re-estimate the required number of events. The final analysis will occur upon accrual of 232-279 OS events; 410-500 pts will be enrolled. The study is enrolling (NCT06064877; Eli Lilly provided cetuximab in N. America and Merck KGaA, Darmstadt, Germany in Europe, United Kingdom and Asia-Pacific). 1.JITC. 2019;7:184 2.JCO. 2023;41:3851