Perioperative pembrolizumab and the changing paradigm of adjuvant therapy in head and neck squamous cell carcinoma: the case of T1-2, pN1

The KEYNOTE-689 trial showed that adding pembrolizumab before and after surgery to standard therapy significantly improved event-free survival in patients with resectable, locally advanced head and neck squamous cell carcinoma. All patients, including those with low-risk disease (pN1 without adverse features), received postoperative radiotherapy. Before this study, NCCN Guidelines recommended considering adjuvant radiotherapy on a case-by-case basis for T1–2 pN1 disease without adverse pathological factors, reflecting the variability of nodal disease. After the publication of KEYNOTE-689, the 2025 NCCN Guidelines introduced PD-L1 Combined Positive Score (CPS) as a key factor in postoperative management. Patients with CPS ≥ 1 should now receive perioperative pembrolizumab plus postoperative radiotherapy, while those with CPS < 1 undergo surgery and selective consideration of radiotherapy. This CPS-based approach allows for more individualized treatment, but further subgroup analyses are needed to determine whether pembrolizumab and radiotherapy provide similar benefits in patients with limited nodal disease, since all participants in the trial received postoperative radiotherapy.