FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma

Regulatory approval: On June 12, 2025, the FDA approved pembrolizumab (Keytruda) for adults with resectable locally advanced head and neck squamous cell carcinoma whose tumors express PD-L1 (CPS ≥1) by an FDA-approved test. The perioperative regimen includes neoadjuvant pembrolizumab, continuation postoperatively with adjuvant radiotherapy (with or without cisplatin), then pembrolizumab monotherapy. Approval was supported by KEYNOTE-689, which showed longer event-free survival versus standard postoperative RT ± cisplatin in the CPS ≥1 population.

FDA approval (June 12, 2025)

The FDA approved pembrolizumab (Keytruda; Merck) for adults with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1 (FDA-approved test). The approved use is pembrolizumab monotherapy as neoadjuvant therapy, continued after surgery as adjuvant pembrolizumab with radiotherapy (RT) with or without cisplatin, followed by pembrolizumab monotherapy. The FDA noted this as the first HNSCC approval in 6 years and the first perioperative approval for locally advanced HNSCC.

Supporting evidence: KEYNOTE-689 (NCT03765918)

Randomized, multicenter, open-label trial (n=714) in resectable Stage III–IVA HNSCC (AJCC 8th edition).

  • Experimental arm: neoadjuvant pembrolizumab q3w ×2 cycles → surgery → adjuvant pembrolizumab q3w ×3 with RT ± cisplatin → pembrolizumab q3w ×12.
  • Control arm: surgery → adjuvant RT ± cisplatin. Cisplatin with adjuvant RT was given in both arms if high-risk pathology (positive margins <1 mm or extranodal extension) was present.

Primary endpoint: event-free survival (EFS) by blinded independent central review. In the PD-L1 CPS ≥1 population (n=682), median EFS was 59.7 months (95% CI 37.9–NR) with pembrolizumab vs 29.6 months (95% CI 19.5–41.9) control (HR 0.70, 95% CI 0.55–0.89; p=0.00140). OS was immature; no detriment trend was observed.

Safety and dosing

Adverse reactions were consistent with prior pembrolizumab experience; labeling includes warnings for immune-mediated adverse reactions, infusion-related reactions, and embryo-fetal toxicity. Recommended dosing: 200 mg q3w or 400 mg q6w; administer prior to chemotherapy when given the same day.

Regulatory notes

Review occurred under Project Orbis; reviews are ongoing at partner agencies (TGA, ANVISA, Health Canada, Swissmedic).

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