Ficerafusp alfa with pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: Updated results from an expansion cohort of an open-label, multicenter, phase 1/1b trial.

6017 Background: HPV-negative head and neck squamous cell carcinoma (HNSCC) is an aggressive disease characterized by high recurrence, metastasis (R/M), and resistance to standard treatments. While anti–PD-1 therapies have improved outcomes, the prognosis for R/M HNSCC remains poor, necessitating novel approaches to achieve deeper, more durable responses and improved overall survival (OS). Ficerafusp alfa is a first-in-class bifunctional antibody targeting EGFR and TGF-β. Methods: This single-arm, multicenter, dose expansion of an ongoing phase 1/1b study (NCT04429542) enrolled patients (pts) aged ≥18 years with treatment-naive, unresectable R/M HNSCC, with a CPS ≥1. Pts received ficerafusp alfa (1500 mg IV on days 1, 8, and 15) combined with pembrolizumab (200 mg IV on day 1) every 21 days. Study objectives included objective response rate (ORR) per RECIST v1.1, duration of response (DOR), progression-free survival (PFS), OS, safety (CTCAE v5), and pharmacodynamic analyses. This report presents updated findings after two years of follow-up. Results: As of December 16, 2024, 42 pts were treated (71% male, median age: 63 years [range: 31–84]); 39 were efficacy evaluable (EE). Among the EE pts, the ORR was 54% (21/39; 95% CI: 37–70) in the overall cohort and 64% (18/28; 95% CI: 44–81) in HPV-negative pts. Notably, 21.4% of HPV-negative pts achieved a complete response (CR). A confirmed durable response of ≥6 and ≥12 months was observed in 72% (13/18) and 56% (10/18) of overall and 73% (11/15) and 60% (9/15) of HPV-negative responders, respectively. Median PFS was 7.4 months (95% CI: 2.9–14.5 overall, and 9.8 months (95% CI: 4.4–23.2) in the HPV-negative subgroup. The 12-month OS rate was 61.5% (95% CI: 44.5–75.7) across the cohort and 60.7% (95% CI: 40.4–76.0) for HPV-negative pts. At data cutoff, all evaluable pts had been followed for at least 20 months. Median OS and DOR had not been reached yet in HPV-negative pts, with mOS surpassing 20 months. Safety findings were consistent with the known safety profile of ficerafusp alfa plus pembrolizumab, while pharmacodynamic analyses demonstrated encouraging post-treatment downregulation of pSMAD2 supporting targeted TGF-β inhibition. Conclusions: Ficerafusp alfa combined with pembrolizumab continues to show promising efficacy relative to historical data on the current standard of care, particularly in HPV-negative HNSCC. Median PFS and 12-month OS, ORR, and CR rates are encouraging relative to historical benchmarks in pts with HPV-negative HNSCC. 24-month OS and mature OS/DOR outcomes are anticipated. These findings provide compelling rationale for FORTIFI-HN01, the ongoing multicenter, randomized, double-blind phase 2/3 clinical trial evaluating this combination in first-line PD-L1–positive, HPV-negative R/M HNSCC. Clinical trial information: NCT04429542 .