Depth and durability of response with TGF-β trapping in recurrent or metastatic (R/M) HPV-negative head and neck squamous cell carcinoma (HNSCC): Long-term results from two expansion cohorts of a phase 1/1b study of ficerafusp alfa plus pembrolizumab.

6040 Background: In HPV-negative HNSCC, TGF-β overexpression creates fibrotic barriers within the tumor microenvironment that limit tumor penetration and drive resistance to anti-EGFR and anti-PD1 therapy. Ficerafusp alfa is the first and only bifunctional EGFR-directed antibody designed to trap TGF-β, enabling tumor penetration of immune cells and driving deep and durable responses for potential overall survival (OS) benefit. Methods: Two dose-expansion cohorts of an ongoing phase 1/1b study (NCT04429542) enrolled adults with 1L R/M HNSCC with PD-L1 CPS ≥1. Patients received ficerafusp alfa 750 or 1500 mg IV on D1, 8, and 15 plus pembrolizumab (pembro) 200 mg IV Q3W. Assessments included objective response rate (ORR), duration of response (DOR), and progression free survival (PFS) per RECIST v1.1; OS; safety; and pharmacodynamic (PD) and pharmacokinetic analyses. This is the first report of long-term efficacy follow-up across two cohorts of ficerafusp alfa. Results: As of December 16, 2025, 61 HPV-neg pts were treated in two cohorts (750 mg, n=31; 1500 mg, n=30); 58 pts were efficacy evaluable. Exposure increased in an approximately dose-proportional manner with manageable safety observed in both cohorts. A higher proportion of pts had exposure levels associated with meaningful efficacy with 1500 mg vs 750 mg dosing. Improved outcomes were observed in the 1500 mg vs 750 mg cohort, including deep responses (≥80% tumor shrinkage in 80% vs 47% of responders) and mPFS (9.9 mo vs 6.9 mo), along with increased markers of TGF-β inhibition and tumor penetration in paired biopsies, and increased pro-inflammatory cytokines in blood (Table). Conclusions: Deeper and more durable tumor responses were observed with ficerafusp alfa 1500 mg vs 750 mg. Exposure and PD markers of TGF-β inhibition demonstrated dose-related trends consistent with mechanism of action. Together, these data suggest that TGF-β inhibition with ficerafusp alfa facilitates T-cell infiltration, enhancing immunologic activity, contributing to deep and durable responses for patients with HPV-neg HNSCC. These findings support the rationale for FORTIFI-HN01, an ongoing phase 2/3 trial evaluating this combination in 1L PD-L1 pos, HPV-neg, R/M HNSCC (NCT06788990). Clinical trial information: NCT04429542 . Endpoint (efficacy set) Ficerafusp alfa750 mg + pembroN=30 Ficerafusp alfa1500 mg + pembroN=28 Confirmed ORR/complete response rate, n (%) 17 (57)/4 (13) 15 (54)/6 (21) Responders with ≥80% shrinkage, n (%) 8/17 (47) 12/15 (80) Median DOR, mo NR 21.7 Proportion of responses >12 mo, n (%) 9/17 (53) 9/15 (60) Median PFS, mo 6.9 9.9 Median OS, mo NR 21.3 Tumor TGF-β inhibition: mean change from baseline in pSMAD2, % −16.4 (n=5) −33.2 (n=7) Immune activation: mean change from baseline in blood TNF-α/IFN-γ, % 25.6/163, (n=24) 64.9/346 (n=20)