Shaping next decade of systemic therapy for head and neck squamous cell carcinoma: where do we go next?

Outcomes of patients with relapsed or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remain poor, despite the widespread incorporation of immune checkpoint inhibitors into contemporary treatment algorithms. Although programmed death-1 (PD-1) blockade with pembrolizumab, administered either alone or in combination with chemotherapy, has become the cornerstone of first line therapy for patients with PD-L1 positive disease, durable clinical benefit is achieved in only a minority of cases. This narrative review explores the most promising systemic treatment strategies expected to shape the management of R/M HNSCC over the coming decade, including bispecific antibodies, HPV directed therapeutic vaccines, antibody–drug conjugates, and other emerging modalities. We discuss their underlying mechanisms of action, review clinical data from early phase studies, and highlight ongoing phase III trials with the potential to redefine future treatment paradigms in R/M HNSCC.