A First in Head and Neck Cancer: Pembrolizumab Receives FDA Approval Before and After Surgery

On June 12, 2025, the US Food and Drug Administration (FDA) approved treatment for patients whose tumors show PD-L1 expression [Combined Positive Score (CPS) ≥1] and who are adults with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC), using pembrolizumab (Keytruda, Merck) . This approval covers its use as a single agent before surgery in the neoadjuvant setting, then after surgery in combination with radiotherapy (RT), with or without cisplatin, in the adjuvant setting, followed by continued single-agent maintenance treatment.

A Long-Awaited Advance in Head and Neck Cancer

Head and neck squamous cell carcinoma (HNSCC) carries a high risk of recurrence and progression for patients diagnosed with locally advanced disease, despite combinations of surgery, radiotherapy, and chemotherapy. Integrating immunotherapies that target the immune system into treatment for this challenging patient population has long been under investigation.

Following the striking results presented at the AACR Congress in April 2025 from KEYNOTE-689 , the anticipated FDA approval has finally arrived. With this development, pembrolizumabhas received approval for both neoadjuvant (before surgery) and adjuvant (after surgery) use in locally advanced, resectable head and neck cancer.

Details of the FDA Approval

📌 Approval Date: June 12, 2025
📌 Approving Authority: US Food and Drug Administration (FDA)
📌 Indication:
In adults with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) expressing PD-L1 (CPS ≥1):

• In the neoadjuvant setting, single-agent pembrolizumab
• In the adjuvant setting, combination with postoperative radiotherapy ± cisplatin
• Subsequently, single-agent maintenance pembrolizumab

This is the first FDA approval in head and neck cancer in 6 years . It is also the first treatment regimen approved in the perioperative setting.

Study Design and Findings: KEYNOTE-689

📋 Participants: 714 patients
📋 Stage: Locally advanced, resectable (Stage III–IVA, AJCC 8th edition)
📋 Number of patients with PD-L1 CPS ≥1: 682

Treatment Arms:

1. Experimental Arm:
   • Neoadjuvant: Pembrolizumab 200 mg every 3 weeks for 2 cycles
   • After surgery:
     • Adjuvant: Pembrolizumab + RT ± cisplatin (3 cycles)
     • Then: Single-agent pembrolizumab (12 cycles)
2. Control Arm:
   • No neoadjuvant treatment
   • After surgery: RT ± cisplatin

Primary Endpoint:

📈 Event-Free Survival (EFS):

• Pembrolizumab Arm: Median EFS = 59.7 months (CI: 37.9 – Not Reached)
• Control Arm: Median EFS = 29.6 months (CI: 19.5 – 41.9)

➡️ Risk reduction: 30%
➡️ HR: 0.70 (95% CI: 0.55–0.89)
➡️ p-value: 0.0014

These results show that pembrolizumab offers a clear advantage in delaying disease recurrence or progression.

Safety and Tolerability

💉 Adverse events preventing surgery: Occurred in 1.4% of patients in both arms.

⚠️ Warnings:

• Immune-mediated adverse reactions (hypothyroidism, pneumonitis, etc.)
• Infusion-related reactions
• Fetal toxicity during pregnancy

🧪 Dosing:

• 200 mg every 3 weeks or 400 mg every 6 weeks
• Note: If given with chemotherapy on the same day, pembrolizumab should be administered first.

Clinical and Scientific Commentary

KEYNOTE-689 demonstrated the potential for perioperative immunotherapy to become a new standard in the management of head and neck cancer. The nearly twofold improvementin EFS highlights the strength of this approach, particularly in patients with PD-L1 CPS ≥1.

⏳ Although overall survival (OS) data are not yet mature, no unfavorable trend has been identified.

Conclusion: A New Era in Oncology Begins

With this approval of pembrolizumab, a promising new treatment paradigm for patients with head and neck cancer has entered clinical practice. The goal now is to integrate this strategy into care for the most suitable patients, with appropriate timing and multidisciplinary teams.

📍 In multidisciplinary tumor boards, consideration of this new approval before surgical planning is recommended.

Before and After Surgery, or Only After Surgery?

The FDA approval of pembrolizumab through KEYNOTE-689 concerns patients in circumstances similar to those in the nivolumab (NIVOPOSTOP) study recently presented at ASCO 2025. However, there are clear differences in goals, timing, patient selection, and treatment strategies between them.

The following comparison table and explanations summarize the key differences between the two studies and their approval statuses:

📊 Comparative Summary Table

✅ Conclusion: Two Treatments, Two Different Turning Points

Both studies signal a new era in head and neck cancer treatment. Future guidelines appear likely to be reshaped by these data.