Phase 1/2 ficerafusp alfa EGFR×TGF-β bifunctional antibody with pembrolizumab + neoadjuvant SBRT

Washington University School of Medicine is running this open-label, sequential-assignment Phase 1/2 trial testing whether short-course neoadjuvant SBRT plus pembrolizumab (Merck’s anti–PD-1 antibody) can be safely intensified with ficerafusp alfa (Bicara Therapeutics’ EGFR-targeting antibody fused to a TGF-β “trap,” designed to block EGFR signaling while neutralizing immunosuppressive TGF-β in the tumor microenvironment). Patients with newly diagnosed, resectable, high-risk locoregionally advanced HPV-negative HNSCC (oral cavity, larynx, hypopharynx, and HPV-negative oropharynx) and PD-L1 CPS ≥1 receive SBRT (dose de-escalation across cohorts), 1–2 doses of neoadjuvant pembrolizumab, and 4 weekly doses of ficerafusp alfa, then proceed to standard surgery about 6 weeks after SBRT. Post-op adjuvant chemoradiation is delivered per NCCN-based institutional practice (not dictated by protocol), which reflects today’s real-world path for many high-risk HPV-negative patients (surgery followed by cisplatin-based chemoradiation when adverse features like extranodal extension/positive margins are present). The key angle is multi-modal immune priming (ablative-ish SBRT + PD-1 blockade) paired with dual EGFR/TGF-β targeting to potentially deepen pathologic response before surgery in a biologically aggressive, HPV-negative population.