Pembrolizumab Significantly Improves Event-Free Survival in Head and Neck Cancer: NEJM

HNSCC is a highly recurrant cancer, and outcomes with surgery and adjuvant treatment continue to be suboptimal for most patients. Immunotherapy, such as checkpoint inhibition with agents like pembrolizumab, has been of value in recurrent and metastatic disease, but its place in locally advanced disease treated with curative intent has remained unclear. This large phase 3 trial gives vital proof that the addition of pembrolizumab in both the neoadjuvant and adjuvant environments can enhance long-term outcomes. This open-label, phase 3 randomized trial included patients with locally advanced HNSCC. The participants were randomly assigned in a 1:1 ratio to receive: • Pembrolizumab group: 2 cycles of neoadjuvant pembrolizumab and then 15 cycles of adjuvant pembrolizumab (200 mg every 3 weeks) plus standard treatment. • Control group: Standard treatment alone (surgery and radiotherapy ± cisplatin). The main endpoint was event-free survival (EFS), which was measured sequentially in patients with CPS ≥10, CPS ≥1, and the overall population. Key Results • 714 participants were randomized: 363 to pembrolizumab and 351 to control. Of these, 234 pembrolizumab vs. 231 control patients had CPS ≥10, and 347 pembrolizumab vs. 335 control patients had CPS ≥1. • Surgical completion rate: ~88% in both groups. • Median follow-up: 38.3 months. • Event-free survival at 36 months: • CPS ≥10 population: 59.8% (pembro) vs. 45.9% (control); HR 0.66; 95% CI 0.49–0.88; P=0.004. •CPS ≥1 population: 58.2% vs. 44.9%; HR 0.70; 95% CI 0.55–0.89; P=0.003. • Total population: 57.6% vs. 46.4%; HR 0.73; 95% CI 0.58–0.92; P=0.008. • Grade ≥3 treatment-related adverse events: 44.6% (pembro) vs. 42.9% (control). • Deaths due to treatment: 1.1% (pembro) vs. 0.3% (control). • Immune-mediated grade ≥3 adverse events: 10.0% in the pembro group. This extensive phase 3 trial reaffirms that perioperative pembrolizumab added to surgery and adjuvant therapy greatly enhances event-free survival in locally advanced HNSCC without sacrificing surgical procedure or adding new safety issues. The trial is a significant advancement in the management of head and neck cancer, with immunotherapy entering earlier stages of disease. Reference: Uppaluri, R., Haddad, R. I., Tao, Y., Le Tourneau, C., Lee, N. Y., Westra, W., Chernock, R., Tahara, M., Harrington, K. J., Klochikhin, A. L., Braña, I., Vasconcelos Alves, G., Hughes, B. G. M., Oliva, M., Pinto Figueiredo Lima, I., Ueda, T., Rutkowski, T., Schroeder, U., Mauz, P.-S., … KEYNOTE-689 Investigators. (2025). Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer. The New England Journal of Medicine, 393(1), 37–50. https://doi.org/10.1056/NEJMoa2415434