Perioperative Immunotherapy in Locally Advanced HNSCC: Current Evidence and Future Perspectives

For over two decades, the standard of care for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC) has remained radical surgery followed by risk-adapted adjuvant therapy. Despite this, high-risk patients experience significant relapse; in particular, current adjuvant concurrent chemoradiotherapy regimens fail to adequately control distant metastasis. Preclinical studies suggest that neoadjuvant immune checkpoint inhibitor (ICI) induces superior antitumor immunity compared to adjuvant therapy by leveraging the primary tumor as an antigen source for systemic T-cell priming. Phase II data further indicate that neoadjuvant ICI, either as monotherapy or in combination, can enhance pathological response rates without compromising surgical safety. Building on these findings, recent two pivotal Phase III KEYNOTE-689 and NIVOPOSTOP confirmed the definitive roles of perioperative immunotherapy. KEYNOTE-689 demonstrated that neoadjuvant-adjuvant pembrolizumab significantly improves event-free survival, primarily by reducing distant recurrence. Conversely, the NIVOPOSTOP trial, which utilized only adjuvant/concomitant nivolumab, showed significant improvement in disease-free survival driven by locoregional control but failed to significantly impact distant relapse. Perioperative ICI represents a transformative shift in LA-HNSCC management. The contrasting results of KEYNOTE-689 and NIVOPOSTOP highlight that the neoadjuvant window is critical for systemic disease control via immune priming. Future strategies will shift away from “one-size-fits-all” models toward risk-stratified, response-adapted approaches. Landmark trials in melanoma, which proved that extensive lymph node dissection can be safely omitted in patients with favorable pathologic responses, provide a blueprint for using pathological response as a surrogate marker to guide treatment de-escalation, aiming to maximize survival while preserving organ function and quality of life in LA-HNSCC.