This activity reviews data from the KEYNOTE-689 and NIVOPOSTOP trials evaluating perioperative immune checkpoint inhibition in resectable, locally advanced head and neck squamous cell carcinoma (HNSCC). Experts examine trial design, efficacy outcomes, and the role of PD-L1 combined positive score (CPS) in patient selection. Drs. Uppaluri and Lee discuss how surgical, medical, and radiation oncology teams can coordinate treatment sequencing and integrate perioperative pembrolizumab into practice for patients with locally advanced HNSCC.