Immunotherapy for locally advanced head and neck squamous cell carcinoma: A review

The standard of care (SoC) for locally-advanced (LA) head and neck squamous cell carcinoma (HNSCC) has remained relatively unchanged for decades, usually consisting of multimodal treatment that can include surgery, radiotherapy, and systemic therapy. Survival rates are low, so there is a key unmet need to improve clinical outcomes. Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein-1 (PD-1) agents, redefined the SoC for recurrent/metastatic HNSCC, and based on recent positive outcomes in Phase III studies, the SoC for resectable LA-HNSCC has evolved to include ICI-based therapy; however, key challenges remain. Integrating ICIs within multimodal treatment strategies has, thus far, yielded very limited success in unresected LA-HNSCC, and intrinsic and acquired resistance to ICIs remains a challenge. In this review, we outline the current and evolving treatment landscape for both resectable and unresected LA-HNSCC, with a focus on emerging immunotherapy-based approaches. We summarize key completed studies, highlighting important insights and key learnings based on trial designs and observed clinical outcomes, and explore novel strategies that may enhance therapeutic efficacy and address limitations of ICIs. Finally, we review ongoing clinical trials of ICI-based regimens that are expected to further shape the treatment landscape for unresected LA-HNSCC.