KEYNOTE-689: pembrolizumab in resectable locally advanced HNSCC

In this video, Prof Jean-Pascal Machiels and Dr Michel Bila discuss an exploratory analysis from the phase III KEYNOTE-689 trial, evaluating perioperative pembrolizumab added to standard of care in resectable locally advanced head and neck squamous cell carcinoma (HNSCC).¹

KEYNOTE-689 investigated two cycles of neoadjuvant pembrolizumab before surgery, followed by adjuvant pembrolizumab given with postoperative radiotherapy or chemoradiotherapy, compared with surgery and postoperative treatment alone. The trial previously showed an event-free survival benefit with the pembrolizumab-containing approach.

This analysis focused on surgical outcomes and high-risk pathological features, including extranodal extension and positive surgical margins. Event-free survival benefit with perioperative pembrolizumab was observed across surgical subgroups, including patients with or without these high-risk features. Fewer patients in the pembrolizumab arm had extranodal extension or positive margins after surgery, suggesting potential downstaging with neoadjuvant treatment.

The discussion highlights practical considerations for implementation, particularly the need to carefully select patients who are expected to remain operable after neoadjuvant therapy. Apparent early tumour enlargement may reflect immune-related inflammation rather than true progression, but close multidisciplinary monitoring remains essential. Overall, these data support perioperative pembrolizumab as a new treatment strategy for selected patients with resectable locally advanced HNSCC.