Pembrolizumab Approved for Perioperative Treatment of Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma
Expert Perspectives · Lyn Brook · 2025-06-18
The FDA has granted approval to pembrolizumab (Keytruda®, Merck) for use as a perioperative treatment in adults with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express programmed death-ligand 1 (PD-L1) with a combined positive score (CPS) ≥1, as determined by an FDA-approved test. Pembrolizumab may be used as a single agent in the neoadjuvant setting, continued as adjuvant therapy in combination with radiotherapy (RT) with or without cisplatin after surgery, and then as a single agent. This marks the first FDA approval for HNSCC in six years and the first perioperative approval for locally advanced HNSCC.
Why This Approval Matters
The approval of pembrolizumab for perioperative use in HNSCC introduces a new standard of care for patients with resectable, locally advanced disease whose tumors express PD-L1. By integrating immunotherapy into both the neoadjuvant and adjuvant settings, this regimen offers the potential for improved event-free survival (EFS) and long-term outcomes. This approval provides clinicians with a validated immunotherapy-based approach for a population with historically limited perioperative options.
Breaking Down the KEYNOTE-689 Trial
The efficacy of pembrolizumab was evaluated in the KEYNOTE-689 trial (NCT03765918), a randomized, multicenter, open-label study enrolling 714 patients with resectable, locally advanced (stage III-IVA) HNSCC. Patients were randomized 1:1 to receive either neoadjuvant pembrolizumab every three weeks for two cycles, followed by adjuvant pembrolizumab every three weeks for three cycles with RT, with or without cisplatin, and then pembrolizumab every three weeks for up to 12 cycles as a single agent; or no neoadjuvant therapy prior to surgery followed by adjuvant RT, with or without cisplatin. In both arms, patients received cisplatin with adjuvant RT if high-risk pathological features, such as positive margins <1 mm or extranodal extension, were present at surgery.
Key efficacy end points included EFS, defined as the time from randomization to disease progression precluding definitive surgery, local or distant progression or recurrence, or death from any cause. In patients with PD-L1 CPS ≥1, median EFS was 59.7 months in the pembrolizumab arm versus 29.6 months in the control arm. Overall survival (OS) results were immature at the time of analysis, with 76% of pre-specified deaths in the CPS ≥1 population, but no trend toward detriment was observed.
Managing Adverse Events
The adverse event profile observed in patients receiving pembrolizumab was consistent with prior experience. Among those who received neoadjuvant pembrolizumab, 1.4% were unable to proceed to surgery due to adverse reactions, compared with 1.4% in the control arm. The prescribing information for pembrolizumab includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, and embryo-fetal toxicity.
Clinical Implications and Future Outlook
“Adding neoadjuvant and adjuvant pembrolizumab to standard of care significantly improved EFS and major pathological response rate difference in patients with resectable locally advanced HNSCC independent of CPS. The safety profile of pembrolizumab was consistent with expectations,” concluded Dr. Ravindra Uppaluri, MD, PhD, Director of Head and Neck Surgical Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, and colleagues, in their published results of the KEYNOTE-689 study.
Dosing and Administration
The recommended dose is 200 mg of pembrolizumab every three weeks or 400 mg every six weeks. When administered with chemotherapy, pembrolizumab should be given prior to chemotherapy on the same day. Treatment should continue as indicated in the perioperative regimen or until disease progression or unacceptable toxicity.