Neoadjuvant immunotherapy in locally advanced head and neck squamous cell carcinoma: From oncologic outcomes to...

Head and neck squamous cell carcinoma (HNSCC) are associated with poor 5-year survival and substantial treatment-related morbidity. Neoadjuvant immunotherapy (NIT) is emerging as a strategy to improve oncologic outcomes while enabling response-adaptive treatment de-escalation.

The landmark KEYNOTE-689 phase 3 trial demonstrated that perioperative pembrolizumab significantly improved 36-month event-free survival (57.6% vs 46.4%, HR=0.73, P = 0.008) and achieved 9.4% major pathological response, prompting FDA approval (June 2025) and European Commission approval (October 2025) for resectable locally advanced HNSCC with PD-L1 CPS ≥ 1. Response-adaptive de-escalation trials have shown compelling benefits: DEPEND demonstrated that HPV-negative deep responders (≥50% tumor regression) safely received 66 Gy without elective nodal irradiation, maintaining 69% 2-year progression-free survival while significantly reducing mucositis (74% vs 94%) and xerostomia (37% vs 63%). OPTIMA II achieved de-escalation in 86% of HPV-positive oropharyngeal cancer patients, reducing feeding tube requirements from 75% to 7.1%. Surgical de-escalation enabled 75% of patients to avoid mandibulectomy, 72% to avoid free flap reconstruction, and achieved 80-90% laryngeal preservation rates in responders.

Significant discordance between radiographic (4.9%) and pathological (41.5%) complete responses limits reliable preoperative patient stratification. HNSCC heterogeneity across anatomical subsites and the absence of validated multimodal response-assessment strategies remain critical barriers to widespread de-escalation implementation.

Biomarker-driven personalized therapy integrating CPS, tumor mutational burden, circulating tumor DNA, multi-omics profiling, and artificial intelligence models will optimize patient selection. NIT fundamentally transforms therapeutic objectives from maximum-tolerated intensity toward response-adaptive treatment de-intensification, achieving an optimal balance between oncologic control, functional preservation, and quality of life.