FDA Approves KEYTRUDA® (Pembrolizumab) for Perioperative Treatment of Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma
Merck known as MSD outside the United States and Canada, recently announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA® (pembrolizumab), its flagship anti-PD-1 therapy, for the treatment of adult patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 (Combined Positive Score [CPS] of 1 or greater) as determined by an FDA-approved test. This approval marks a significant milestone in the perioperative treatment landscape for this aggressive form of head and neck cancer.
Under this new regimen, KEYTRUDA is administered as a single agent in the neoadjuvant setting — that is, prior to surgery — and then continued after surgery as adjuvant treatment in combination with standard radiotherapy (with or without cisplatin). Subsequently, KEYTRUDA is used as monotherapy following the completion of adjuvant therapy. This approach reflects growing understanding that adding an immunotherapy agent to standard treatments at multiple phases — before and after surgery — can enable a more robust and durable attack against the disease, reducing the likelihood of recurrence and progression.
The approval is supported by data from KEYNOTE-689, a pivotal Phase 3 trial that evaluated KEYTRUDA in this patient population. The results of this study were presented at the American Association for Cancer Research (AACR) annual meeting on April 27, 2025, and show a dramatic improvement in event-free survival (EFS) for patients treated with KEYTRUDA alongside standard care. Specifically, adding KEYTRUDA to the standard regimen resulted in a 30% reduction in the risk of event-free survival events — which include disease recurrence, progression, or death — with a hazard ratio (HR) of 0.70 (95% confidence interval [CI], 0.55–0.89; p = 0.00140).
Furthermore, for patients whose tumors fell into the PD-L1 CPS 1 or greater subgroup, the improvement in event-free survival was even more pronounced. Among these patients, the median event-free survival was 59.7 months (95% CI, 37.9–not reached) in the KEYTRUDA arm, as opposed to 29.6 months (95% CI, 19.5–41.9) in the standard care arm. This data highlights the strong and clinically meaningful benefit that KEYTRUDA can bring when incorporated into a perioperative treatment strategy for a population at high-risk for recurrence after standard therapy.
“The introduction of KEYTRUDA as a perioperative treatment option for patients with resectable, locally advanced head and neck squamous cell carcinoma marks a potentially significant shift in how we manage this disease,” said Dr. Ravindra Uppaluri, principal investigator for KEYNOTE-689 and Director of Head and Neck Surgical Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute. “With this approval, we can now provide an option that has demonstrated a 30% reduction in the risk of recurrence, progression, or death, offering a new standard of care for patients following their initial diagnosis and subsequent treatment with standard methods.”
While KEYTRUDA’s benefits are clear, it’s essential to appreciate its potential side effects. Immune-mediated adverse reactions — which can be severe or even fatal — may manifest in any organ or tissue and can affect multiple body systems at once. These include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, complications related to solid organ transplant rejection, corneal graft rejection, or allogeneic hematopoietic stem cell transplant rejection, among others. Importantly, these side effects may manifest during or after treatment with KEYTRUDA.
Safe administration involves close vigilance for symptoms and a careful approach to their management. Based on severity, KEYTRUDA may need to be temporarily held or permanently discontinued, with administration of appropriate treatment, typically high-dose corticosteroids. Furthermore, KEYTRUDA can cause severe or life-threatening infusion-related reactions. Importantly, due to its mechanisms of action, KEYTRUDA can harm a developing fetus if administered to a pregnant woman. Patients should be made aware of these potential risks, and appropriate measures should be taken to avoid pregnancy during treatment.
“As the first perioperative anti-PD-1 treatment option for appropriate patients with resectable, locally advanced head and neck squamous cell carcinoma, this new regimen has the potential to profoundly shift the standard of care for both patients and their families,” said Dr. Marjorie Green, Senior Vice President and Head of Oncology Global Clinical Development at Merck Research Laboratories. “Based on these trial results, KEYTRUDA as a key component of this regimen shows tremendous potential to enable patients to live longer without disease recurrence and hopefully improve their overall prognosis.”
This application was reviewed under Project Orbis, a collaborative framework by the FDA’s Oncology Center of Excellence. This framework brings together regulators from multiple jurisdictions to enable faster, more unified reviews of oncology medicines. Currently, marketing authorization applications for KEYTRUDA, based on the results from KEYNOTE-689, are under review by health authorities in Israel, Canada, Australia, Singapore, Brazil, and Switzerland. Furthermore, regulators in Europe and Japan are evaluating applications for this new regimen.
In the United States, KEYTRUDA is currently approved for a range of indications in head and neck squamous cell carcinoma:
- KEYTRUDA, in combination with platinum and fluorouracil (FU), is a first-round treatment for patients with metastatic or unresectable, recurrent disease.
- KEYTRUDA, as a monotherapy, is a first-round treatment for patients with metastatic or unresectable, recurrent disease whose tumors express PD-L1 with a Combined Positive Score (CPS) of 1 or greater.
- KEYTRUDA, as a monotherapy, is a subsequent treatment for patients with recurrent or metastatic disease after progression on or following platinum-containing chemotherapy.
Together, these approvals reflect a growing understanding of KEYTRUDA’s role in improving outcomes for patients with head and neck squamous cell carcinoma across multiple lines of therapy.
