Earlier Use of Pembrolizumab Is Advocated in HNSCC

KEYNOTE-689 (NCT03765918) is a landmark study demonstrating that perioperative pembrolizumab (Keytruda) improves event-free survival and pathologic responses without compromising surgical outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC). Although overall survival (OS) data are still maturing, these results strongly support a shift toward incorporating immunotherapy earlier in the treatment paradigm for resectable disease. This strategy not only improves prognosis but may also allow for future treatment deintensification in selected patients. Findings were presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting (PAGE 37).

As a discussant during the AACR plenary session, I noted that KEYNOTE-689 addresses the persistent challenge in treating locoregionally advanced HPV-negative HNSCC, which continues to have a 5-year survival rate of approximately 50% despite aggressive multimodality therapy. Limited progress has been made in HNSCC since the approval of PD-1 inhibitors in the recurrent and metastatic setting in 2016. Immunotherapy improved OS in that context, response rates remained modest, and no major advances have been made for patients with HPV-negative tumors and locally advanced disease.

The trial data demonstrated statistically significant improvements in event-free survival, particularly in patients with higher PD-L1 expression. Moreover, there was also a notable increase in major pathological responses. Several important questions arise from the results. A key consideration is whether patients who do not achieve a major pathological response might benefit from pembrolizumab or whether treatment should be intensified or extended for this subgroup. It is unclear if pathological responses in the range of 50% to 90% could represent a meaningful clinical benefit short of complete response. Finally, is pembrolizumab alone sufficient in the neoadjuvant setting, or does combining it with chemotherapy or a second immune checkpoint inhibitor produce more durable responses?

The findings signal that perioperative immunotherapy can improve outcomes in locally advanced HNSCC. Further research is needed to refine the use of immune checkpoint inhibitors, including identifying predictive biomarkers, optimizing treatment regimens, and determining which patients are most likely to benefit.