6058 Background: 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. Depth of response has been shown to correlate with prolonged progression free survival (PFS) and overall survival (OS) in several solid tumors. However, such data are limited in R/M HPV-negative HNSCC. Here we performed exploratory analyses to evaluate whether depth of response achieved with ficerafusp alfa and pembrolizumab is associated with prolonged duration of response (DOR), PFS and OS. Methods: Three cohorts of a phase 1/1b study (NCT04429542) in 1L, R/M HNSCC, with PD-L1 CPS ≥1 evaluated ficerafusp alfa (750mg QW,1500 mg QW, or 2000 mg Q2W) IV combined with pembrolizumab IV. Objective response rate (ORR) per RECIST v1.1, DOR, PFS, and OS were assessed. In the pooled efficacy evaluable set from the three cohorts, we explored if the magnitude of tumor regression, comparing tumor regression ≥80% regression (defined as a deep response) vs. tumor regression 0 to <80%, is predictive of longer-term clinical outcomes (DOR, PFS, OS). Results: As of December 16, 2025, 85 patients with HPV-negative disease were efficacy evaluable across three cohorts (n=30, n=28, and n=27 at 750mg, 1500mg, and 2000mg doses of ficerafusp alfa, respectively). Among these, the confirmed ORRs were 57%, 54%, and 48%, respectively, including 47%, 80%, and 77% of responders achieving a deep response. In the pooled efficacy evaluable set the percentage of patients with a deep response was 36%, with tumor regression 0 to <80% was 46%, and no tumor regression was 18%. mDOR was longer for patients with a deep response compared to patients with tumor regression 0 to <80% (21.9 mo vs 8.2 mo, HR 0.27). mPFS was also longer in patients with a deep response compared to patients with tumor regression 0 to <80% (26.4 mo vs 6.5 mo, HR 0.19). mOS was not reached (NR) in patients with deep response and 14.9 mo in patients with tumor regression 0 to <80% (NR vs 14.9 mo, HR 0.17). Conclusions: Ficerafusp alfa plus pembrolizumab demonstrated deep responses across multiple dose levels. Deep responses were associated with improved long-term efficacy outcomes, including DOR, PFS, and OS. This suggests that depth of response may represent a clinically meaningful surrogate for understanding long-term efficacy outcomes in HPV-negative HNSCC. Clinical trial information: NCT04429542 . Tumor Regression0 to <80%N=39 Tumor Regression ≥ 80% (Deep Response)N=31 mDoR (mo) 8.2 21.9 HR vs < 80% tumor regression (95% CI) N/A 0.27 0.10, 0.71 mPFS (mo) 6.5 26.4 HR vs No DR (95% CI) N/A 0.19 0.09, 0.40 mOS (mo) 14.9 NR HR vs No DR (95% CI) N/A 0.17 0.07, 0.41
Kaczmar et al. (Wed,) studied this question.