A multicenter, randomized, double-blind, phase 2/3 study of ficerafusp alfa (BCA101) or placebo in combination with pembrolizumab for first-line treatment of HPV-negative, PD-L1–positive, recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): FORTIFI-HN01.

TPS6129 Background: HPV-negative HNSCC is an aggressive disease characterized by high rates of recurrence, metastasis, and resistance to standard treatments. Most HPV-negative HNSCC tumors overexpress tumorigenic factors EGFR and TGF-β. In a phase 1/1b trial (NCT04429542), ficerafusp alfa demonstrated promising efficacy and a manageable safety profile in first-line R/M HNSCC. FORTIFI-HN01 (NCT06788990) is an ongoing randomized, double-blind, placebo-controlled, phase 2/3 trial designed to assess the efficacy and safety of ficerafusp alfa combined with pembrolizumab vs placebo plus pembrolizumab in patients with PD-L1-positive first-line R/M HPV-negative HNSCC. Methods: Eligible patients must have histologically confirmed R/M HNSCC with primary lesions in the oral cavity, larynx, or hypopharynx, or HPV-negative OPSCC confirmed by central laboratory testing. Additional eligibility criteria include no prior systemic therapy for R/M disease, PD-L1-positive tumor (CPS ≥1), measurable disease per RECIST v1.1, and ECOG performance status 0 or 1. The phase 2 objective was to determine the optimal biological dose (OBD) of ficerafusp alfa through an integrated analysis of safety, tolerability, PK, PD, and efficacy. Following OBD determination (1500 mg QW), the trial transitioned seamlessly into the phase 3 portion with 2:1 randomization (ficerafusp alfa:control). Randomization is stratified by PD-L1 CPS (1-19 vs ≥20) and disease extent (local/regional recurrence only, distant metastasis only, or both). Patients receive pembrolizumab (200 mg IV every 3 weeks for up to 35 cycles) and either ficerafusp alfa or placebo IV QW until disease progression or unacceptable toxicity. Tumor imaging occurs every 6 weeks during the first year and every 9 weeks thereafter. The primary endpoints are objective response rate (ORR) per RECIST v1.1 (blind independent committee review) and overall survival. An interim analysis evaluating ORR is planned. Secondary endpoints include safety, duration of response, progression free survival, clinical benefit rate, and patient-reported outcomes. The trial is actively recruiting, with planned enrollment of ~650 subjects. Clinical trial information: NCT06788990 .