What is the indication for pembrolizumab (Keytruda) as neoadjuvant and adjuvant therapy in head‑and‑neck cancer, which head‑and‑neck squamous cell carcinoma sites were included in the pivotal trial, and what was the trial design?

Pembrolizumab Neoadjuvant/Adjuvant Indication for Head and Neck Cancer

Pembrolizumab is FDA-approved for perioperative (neoadjuvant plus adjuvant) treatment of resectable locally advanced head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1, based on the KEYNOTE-689 trial which demonstrated significant improvement in event-free survival. 1, 2

FDA-Approved Indication

The FDA label specifies pembrolizumab for head and neck squamous cell carcinoma (HNSCC) in three distinct settings 1:

1. First-line combination therapy: Pembrolizumab + platinum + fluorouracil for metastatic or unresectable recurrent HNSCC
2. First-line monotherapy: For metastatic or unresectable recurrent HNSCC with PD-L1 CPS ≥1
3. Perioperative therapy (June 2025 FDA approval): Neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab for resectable locally advanced HNSCC

KEYNOTE-689 Trial Design

The pivotal phase 3 trial that established the neoadjuvant/adjuvant indication enrolled 714 participants with locally advanced HNSCC 2:

Patient Population Included:

• Resectable locally advanced HNSCC (stage III-IVA disease)
• All mucosal head and neck squamous cell carcinoma subsites were eligible
• Stratified by PD-L1 expression: CPS ≥10 (n=465), CPS ≥1 (n=682), and total population (n=714)

Trial Design:

Randomized 1:1 open-label phase 3 trial 2:

Pembrolizumab arm (n=363):

• Neoadjuvant: 2 cycles of pembrolizumab 200 mg IV every 3 weeks
• Surgery: Standard surgical resection
• Adjuvant: 15 cycles of pembrolizumab 200 mg IV every 3 weeks + standard adjuvant radiotherapy ± cisplatin

Control arm (n=351):

• Surgery: Standard surgical resection
• Adjuvant: Standard radiotherapy ± cisplatin (no pembrolizumab)

Primary Endpoint:

Event-free survival, sequentially assessed in:

1. CPS ≥10 population (first)
2. CPS ≥1 population (second)
3. Total population (third)

Clinical Trial Results

At 36 months median follow-up 2:

Event-free survival improvements:

• CPS ≥10: 59.8% vs 45.9% (HR 0.66,95% CI 0.49-0.88, P=0.004)
• CPS ≥1: 58.2% vs 44.9% (HR 0.70,95% CI 0.55-0.89, P=0.003)
• Total population: 57.6% vs 46.4% (HR 0.73,95% CI 0.58-0.92, P=0.008)

Critical surgical feasibility finding: Surgery was completed in approximately 88% of participants in both arms, demonstrating that neoadjuvant pembrolizumab does not compromise surgical resectability 2.

Major pathological response rate: 9.4% achieved major pathological response 3

Head and Neck Cancer Subsites Included

While the FDA label and KEYNOTE-689 trial specify "head and neck squamous cell carcinoma" broadly, this encompasses 1, 2:

• Oral cavity squamous cell carcinoma
• Oropharyngeal cancer (HPV-positive and HPV-negative)
• Laryngeal cancer
• Hypopharyngeal cancer

Important exclusion: The indication is specifically for mucosal squamous cell carcinoma. Nasopharyngeal carcinoma, salivary gland tumors, and cutaneous head and neck cancers are not included in this indication 4, 5.

Safety Profile

Grade ≥3 treatment-related adverse events occurred in 44.6% with pembrolizumab vs 42.9% with standard care 2. Immune-mediated adverse events of grade ≥3 occurred in 10.0% of pembrolizumab-treated patients 2. Treatment discontinuation due to adverse events occurred in 12.4-17.7% of patients 6.

Critical safety consideration: One death (1.1%) was attributed to treatment-related adverse events in the pembrolizumab arm versus 0.3% in the control arm 2. Bilateral ophthalmoplegia has been reported as a rare immune-mediated complication 7.

Clinical Context from Guidelines

The 2019 SITC consensus statement describes multiple early-phase neoadjuvant trials with pembrolizumab in HNSCC, including the KEO trial (pembrolizumab + epacadostat) 4, but these were phase 2 studies. KEYNOTE-689 represents the first and only phase 3 randomized trial establishing perioperative pembrolizumab as standard of care 2.

The NCCN 2017 guidelines previously recommended pembrolizumab only for recurrent/metastatic HNSCC after platinum failure (category 2A) 8. The perioperative indication represents a paradigm shift toward earlier integration of immunotherapy in the curative-intent setting 9, 3.