The FDA has approved Merck’s Keytruda (pembrolizumab) as the first perioperative anti-PD-1 therapy for adults with PD-L1–positive (CPS ≥1) resectable, locally advanced head and neck squamous cell carcinoma (HNSCC). The regimen is comprised of neoadjuvant Keytruda monotherapy, followed by adjuvant radiotherapy (with or without cisplatin) and continued treatment with Keytruda monotherapy. Approval was based on results from the Phase III KEYNOTE-689 trial.¹

How Could New Keytruda Indication Change the Standard of Care for Head and Neck Cancer?

“The introduction of Keytruda as a perioperative treatment option for certain patients with resectable locally advanced head and neck squamous cell carcinoma represents a potentially significant shift in how we manage this disease,” said Ravindra Uppaluri, KEYNOTE-689 principal investigator, director, head and neck surgical oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, 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.”

KEYNOTE-689 Trial Design and Treatment Arms

• The randomized, multicenter, open-label, active-controlled KEYNOTE-689 trial evaluated Keytruda as neoadjuvant treatment, continued as adjuvant treatment in combination with standard of care (SOC), radiotherapy (RT) with or without cisplatin, then as a single agent in 714 patients with resectable locally advanced HNSCC.
• Patients were randomly assigned in a 1:1 ratio.
• The first group received two doses of neoadjuvant Keytruda.
• Within six weeks of surgery, patients received three more cycles of Keytruda, followed by maintenance dosing every three weeks for up to 12 cycles.
• The control group received no preoperative treatment.
• Postoperatively, within six weeks, they received radiotherapy with or without up to three cycles of concurrent cisplatin.
• The primary endpoint of the trial was event-free survival (EFS) as assessed by blinded independent central review defined as the time from randomization to the first occurrence of progression of disease that precluded definitive surgery, local or distant disease progression or recurrence, or death due to any cause.

KEYNOTE-689Trial Efficacy Results

• Results showed up to a 30% reduction in EFS events—including recurrence, progression, or death—versus SOC.
• Median EFS doubled to nearly 59.7 months in the Keytruda arm among PD-L1 positive patients compared to 29.6 months in the SOC arm.
• Around 37% of patients in the Keytruda arm experienced an EFS event, compared to 47% in the control group.
• At the time of interim analysis, overall survival data were not mature.

Keytruda Safety Profile and Adverse Events

• The most frequent serious adverse events (AEs) in patients treated with Keytruda included pneumonia; pyrexia; stomatitis; acute kidney injury; pneumonitis; COVID-19; death not otherwise specified; diarrhea; dysphagia; gastrostomy tube site complication; and immune-mediated hepatitis.
• Fatal AEs were reported in 5% of patients, including acute kidney injury; high calcium levels; bleeding in the lungs; swallowing difficulties and malnutrition; blood clots in the intestines; sepsis; pneumonia; COVID-19; respiratory failure; cardiovascular issues; and gastrointestinal bleeding.¹

Global Burden of Disease

According to a study published in the National Center for Biotechnology Information, HNSCC accounts for approximately 4.5% of cancer diagnoses and deaths globally each year. This is equal to 890,000 new cases and 450,000 deaths.²

Merck sees Potential Paradigm Shift

“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,” said Marjorie Green, SVP, head of oncology, global clinical development, Merck Research Laboratories, in the press release. “Based on these trial results, Keytruda as part of this regimen shows potential to change long-standing standards of care for treating certain patients with locally advanced HNSCC.”

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. Epidemiology, Risk Factors, and Prevention of Head and Neck Squamous Cell Carcinoma. PubMed. Accessed June 13, 2025. https://pubmed.ncbi.nlm.nih.gov/37367741/#:~:text=Head%20and%20neck%20squamous%20cell%20carcinoma%20(HNSCC),roughly%204.5%25%20of%20cancer%20diagnoses%20and%20deaths.