Pembrolizumab Receives FDA Approval for Treatment of Head and Neck Squamous Cell Carcinoma

Pembrolizumab (Keytruda; Merck Sharp & Dohme LLC) has been approved by the FDA for the treatment of adult patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1. The therapy is indicated for use as a neoadjuvant treatment, followed by adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin after surgery, and then continued as a single agent. This marks the first FDA approval for a perioperative treatment approach in locally advanced HNSCC.

Molecular model of pembrolizumab | Image Credit: © Dr_Microbe - stock.adobe.com

“The introduction of [pembrolizumab] as a perioperative treatment option for certain patients with resectable locally advanced [HNSCC] represents a potentially significant shift in how we manage this disease,” Ravindra Uppaluri, MD, principal study investigator and director of Head and Neck Surgical Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, said in a press release. “With this approval, we can now offer appropriate patients with resectable locally advanced head and neck squamous cell carcinoma a new treatment regimen that has been shown to reduce the risk of recurrence, progression, or death by 30%, compared with standard of care adjuvant chemoradiotherapy or radiotherapy alone.”¹

The FDA’s decision was based on data from the randomized, multicenter, open-label KEYNOTE-689 trial (NCT03765918). The study investigators evaluated 714 patients with HNSCC (stage 3-4A) who were randomized (1:1) to either neoadjuvant pembrolizumab every 3 weeks for 2 cycles followed by adjuvant pembrolizumab every 3 weeks for 3 cycles with RT, with or without cisplatin, and then every 3 weeks for 12 cycles of pembrolizumab as a single agent; or no neoadjuvant treatment prior to surgery followed by adjuvant RT with or without cisplatin.^2,3

The primary end point was event-free survival (EFS), which was defined as the time from randomization to the first occurrence of disease progression precluding definitive surgery, local or distant disease progression or recurrence, or death due to any cause. The key secondary end point was overall survival (OS).³

Among patients with tumors expressing PD-L1 CPS of 1 or greater (n = 682), median EFS was 59.7 months (95% CI: 37.9, not reached) with pembrolizumab, compared with 29.6 months (95% CI: 19.5, 41.9) in the control group (HR 0.70; 95% CI: 0.55–0.89; P = 0.00140). Although OS data were still immature—representing 76% of the pre-specified events—no indication of harm was observed in the CPS 1 or greater subgroup.³

The approval of pembrolizumab marks a significant advance in the treatment landscape for patients with resectable locally advanced HNSCC, offering the first perioperative immunotherapy option for this population. The KEYNOTE-689 trial supports the integration of immunotherapy into earlier stages of treatment. As OS data continue to mature, these findings suggest a promising new standard of care.³

“As the first perioperative anti-PD-1 treatment option for appropriate patients with resectable locally advanced head and neck squamous cell carcinoma, this new treatment regimen has the potential to shift the treatment paradigm for patients and their families affected by this disease,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, said in a press release. “Based on these trial results, [pembrolizumab] as part of this regimen shows potential to change long-standing standards of care for treating certain patients with locally advanced HNSCC.”¹

REFERENCES

1. FDA approves KEYTRUDA® (pembrolizumab) for PD-L1+ resectable locally advanced head & neck squamous cell carcinoma as neoadjuvant treatment, continued as adjuvant treatment combined with radiotherapy with or without cisplatin then as a single agent. Merck. June 13, 2025. Accessed June 13, 2025. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-pd-l1-resectable-locally-advanced-head-neck-squamous-cell-carcinoma-as-neoadjuvant-treatment-continued-as-adjuvant-treatment-combined-with-radiother/

2. Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689). Updated February 7, 2025. Accessed June 12, 2025. https://clinicaltrials.gov/study/NCT02358031

3. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. June 12, 2025. Accessed June 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-and-adjuvant-pembrolizumab-resectable-locally-advanced-head-and-neck