Neoadjuvant and adjuvant pembrolizumab is approved by the USFDA for resectable locally advanced head and neck squamous cell carcinoma

On June 12, 2025, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) for adults with advanced head and neck squamous cell carcinoma (HNSCC) that can be surgically removed and shows PD-L1 expression [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test. It is indicated as monotherapy for neoadjuvant treatment, followed by adjuvant therapy in conjunction with radiotherapy (RT) with or without cisplatin post-surgery and subsequently as monotherapy.

This sanction marks the first approval for HNSCC in six years and the first comprehensive perioperative approval for locally advanced HNSCC.

Effectiveness and Safety

The effectiveness was evaluated in KEYNOTE-689 (NCT03765918), a study where 714 patients with operable locally advanced (Stage III-IVA) head and neck squamous cell carcinoma [AJCC, 8th edition] were randomly assigned to one of two groups. We randomly assigned patients in a 1:1 ratio to one of the following groups:

Patients received either neoadjuvant pembrolizumab every three weeks for two cycles, followed by adjuvant pembrolizumab every three weeks for three cycles along with radiotherapy, with or without cisplatin, and then twelve more cycles of pembrolizumab alone every three weeks; or they had no neoadjuvant treatment before surgery, followed by adjuvant radiotherapy with or without cisplatin.

In all treatment groups, patients received cisplatin with adjuvant radiotherapy if they had high-risk features, like positive margins less than 1 mm or extranodal extension, found during surgery.

The main goal of the study was to measure event-free survival (EFS), which is the time from when patients were assigned to a treatment until they experienced any of the following: their disease got worse and they couldn’t have surgery, their disease spread or came back, or they died from any reason. Supplementary efficacy outcome measures encompassed overall survival (OS). In patients with tumors exhibiting PD-L1 CPS ≥1 (n=682), the median event-free survival (EFS) was 59.7 months (95% CI: 37.9, not achieved [NR]) in the pembrolizumab group and 29.6 months (95% CI: 19.5, 41.9) in the control group (hazard ratio 0.70 [95% CI: 0.55, 0.89]; p-value 0.00140).

Although overall survival data were preliminary in the current investigation, with 76% of pre-specified fatalities in the CPS ≥1 population, no indication of harm was detected.

Among patients administered neoadjuvant pembrolizumab, 1.4% were precluded from surgery due to adverse events, as opposed to 1.4% in the control group. The instructions for using pembrolizumab include warnings about possible immune system reactions, problems from the infusion, and risks to unborn babies. Adverse effects were in accordance with previous experiences with pembrolizumab.

Suggested Dosage

The advised dosage of pembrolizumab is 200 mg every three weeks or 400 mg every six weeks. When delivering both on the same day, pembrolizumab must come before chemotherapy.