Patients with newly diagnosed, locally advanced head and neck squamous cell carcinoma (HNSCC) may soon benefit from a major shift in treatment strategy, as Phase III trial data show that perioperative pembrolizumab significantly improves outcomes when added to standard care.
The findings, presented at the 2025 American Association for Cancer Research Annual Meeting, are from the randomized, open-label KEYNOTE-689 trial involving 714 patients with stage 3–4 HNSCC of the larynx, hypopharynx, or oral cavity. Investigators tested whether introducing immunotherapy both before and after surgery could reduce recurrence and death compared with standard treatment alone.
Traditionally, patients undergo surgery followed by radiation therapy, with or without chemotherapy. Despite decades of use, outcomes have remained poor for many. According to Dr. Ravindra Uppaluri, lead investigator and director of head and neck surgical oncology at Dana-Farber Brigham Cancer Center, the introduction of pembrolizumab in both the neoadjuvant and adjuvant settings enhances immune activation and targets residual disease.
Among the 714 participants, 363 were randomized to receive pembrolizumab before and after surgery in addition to standard adjuvant therapy. At a median follow-up of at least 38.3 months, those who received pembrolizumab were 27% less likely to experience recurrence or death. Major pathologic response (mPR)—defined as ≥90% tumor reduction—was also higher in this group, especially among patients with tumors expressing high PD-L1 levels. In those with a combined positive PD-L1 score of 10 or higher, the mPR rate rose by 13.7%, and the recurrence risk was reduced by 34%.
Importantly, the safety profile remained consistent. Grade 3 or higher immune-mediated adverse events were observed in 10% of pembrolizumab-treated patients, including one grade 5 pneumonitis case.
Dr. Uppaluri emphasized the global impact of the study, noting that “for the first time in over 20 years, patients with this challenging disease have a new therapeutic approach.” Future work will focus on refining treatment intensity and exploring the individual contributions of neoadjuvant and adjuvant phases.
Reference:
Uppaluri R. Adding Perioperative Pembrolizumab to Standard of Care Improves Outcomes in Patients With Newly Diagnosed Head and Neck Cancer. AACR Annual Meeting. 2025;Abstract CT005.
