Trial Overview
Design: International, open-label, randomized Phase III study (NCT03765918) enrolling 714 adults with stage III or IVA resectable LA‑HNSCC (tumors of the oropharynx, larynx, hypopharynx, or oral cavity), performance status 0–1. Patients were stratified by PD‑L1 combined positive score (CPS) and HPV status. Arms: Experimental Arm: Neoadjuvant pembrolizumab (2 cycles) → surgery → postoperative radiotherapy ± cisplatin with concurrent pembrolizumab (3 cycles) → adjuvant pembrolizumab (12 cycles) Control Arm: Standard of care (SOC): surgery → adjuvant radiotherapy ± cisplatin
Event‑Free Survival (EFS) Results
After a median follow-up of 38.3 months:
Overall (Intent-to-Treat): Median EFS: 51.8 months (pembrolizumab arm) vs 30.4 months (SOC) Hazard Ratio (HR): 0.73, with a 27% risk reduction (P = .0041) PD‑L1 CPS ≥ 10: Median EFS: 59.7 months vs 26.9 months HR: 0.66 (34% risk reduction, P = .0022) PD‑L1 CPS ≥ 1: Median EFS: 59.7 months vs 29.6 months HR: 0.70 (30% risk reduction, P = .0014)
Pathological Response
Major pathological response (MPR, defined as <10% viable tumor): Significant increase across all groups: CPS ≥ 10: +13.7 percentage points (pp) CPS ≥ 1: +9.8 pp Total population: +9.3 pp (all P < .001) Pathologic complete response: Modest improvement (~3 pp increase across groups)
Overall Survival (OS)
Interim trends (not yet formally tested): CPS ≥ 10: 3‑year OS 68.2% vs 59.2% (HR 0.72; P = .04) CPS ≥ 1: 69.0% vs 60.2% (HR 0.72) Overall: 68.4% vs 61.1% (HR 0.76) Follow-up ongoing: OS data are immature; future readings are event-driven.
Safety Profile
Any-grade treatment-related adverse events (TRAEs): ~81% in both arms Grade 3+ TRAEs: 44.6% (pembrolizumab) vs 42.9% (SOC) Serious TRAEs: 19.1% vs 10.5% TRAEs-related deaths: 1.1% vs 0.3% Immune-related ≥Grade 3: 10.0% vs 0.6% Common ≥Grade 3 events: Stomatitis (~12%), pneumonitis (1.9%), hypothyroidism (24.7%)
No new safety signals emerged, and surgical feasibility and timing of adjuvant treatment were preserved.
Additional Efficacy Insights
Distant Metastases–Free Survival: Improved with pembrolizumab addition—consistent with EFS gains Reduction of High-Risk Pathology: Neoadjuvant pembrolizumab reduced high-risk pathologic features (32.5% vs 44.4% in SOC), also lowering need for adjuvant high-dose cisplatin (38.9% vs 50.5%)
Regulatory Update
On June 12, 2025, the FDA granted approval for perioperative pembrolizumab (neoadjuvant + adjuvant) in resectable LA‑HNSCC with PD‑L1 CPS ≥ 1, representing the first perioperative approval in this setting
Why It Matters
First major advance in two decades for this patient population.
EFS gains are robust and clinically meaningful, nearly doubling median EFS in CPS ≥ 10 patients.
Surgical safety and productivity unaffected, making integration practical in multidisciplinary care.
Toxicity profile manageable, with no new concerns identified.
FDA approval now enables implementation in PD‑L1 expressing (CPS ≥ 1) resectable LA‑HNSCC.