Dr Adkins on the FDA Approval of Pembrolizumab for Neoadjuvant/Adjuvant Treatment in Resectable, Locally Advanced HNSCC

“These results establish that…there’s a new standard of care for patients with locally advanced, resectable head and neck cancer [and] that is neoadjuvant pembrolizumab [Keytruda], followed by surgery and adjuvant pembrolizumab, given concurrently [with] and after radiotherapy or chemoradiotherapy. This is the first advancement…in treatment outcomes of patients with locally advanced head neck cancer that is resectable in over 20 years.”

Douglas R. Adkins, MD, professor of medicine in the Division of Oncology at Washington University School of Medicine, Siteman Cancer Center, discussed the design and clinical implications of the phase 3 KEYNOTE-689 trial (NCT03765918), which supported the FDA approval of pembrolizumab for neoadjuvant and adjuvant treatment in patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC).

On June 12, 2025, the FDA approved pembrolizumab as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with or without cisplatin after surgery, and then as a single agent, for adult patients with resectable, locally advanced HNSCC whose tumors express PD-L1 with a combined positive score (CPS) of at least 1, as determined by an FDA-approved test.

Findings supporting the approval showed that among patients with PD-L1 CPS of at least 1 (n = 682), the addition of pembrolizumab to standard therapy resulted in a median event-free survival (EFS) of 59.7 months (95% CI, 37.9-not reached) compared with 29.6 months (95% CI, 19.5-41.9) in the control arm (HR, 0.70; 95% CI, 0.55-0.89; P = .0014), representing a 30% reduction in the risk of recurrence, progression, or death.

At the time of analysis, overall survival (OS) data were immature, with 76% of prespecified events reported; however, no trend toward detriment was observed. Regarding safety, 1.4% of patients in each arm were unable to proceed to surgery due to adverse effects. The overall safety profile of pembrolizumab was consistent with prior clinical trial experience, and no new safety signals were identified.

According to Adkins, this approval marks the first advancement in curative-intent therapy for resectable, locally advanced HNSCC in over 2 decades. He noted that the observed improvement in EFS—along with a reduction in distant metastases—supports the integration of pembrolizumab into perioperative treatment strategies.

Although locoregional recurrence rates were similar between arms, the systemic benefit of immunotherapy was reflected in reduced rates of distant spread, he noted.

Adkins concluded that this approval of pembrolizumab in the neoadjuvant and adjuvant settings establishes a new standard of care for patients with high-risk, resectable disease. He noted that further follow-up is required to determine the impact on OS, but the current data reflect a clinically meaningful improvement in long-term disease control.