A groundbreaking international Phase 3 clinical trial has demonstrated that adding the immunotherapy drug pembrolizumab (Keytruda) to standard treatment significantly improves survival outcomes for patients with locally advanced head and neck cancer. The study, co-led by Washington University School of Medicine and Dana-Farber Brigham Cancer Center, found that patients receiving pembrolizumab survived cancer-free for a median of 51.8 months compared to just 30.4 months for those receiving standard care alone.
The findings, presented at the American Association for Cancer Research (AACR) annual meeting in Chicago, could transform treatment protocols that have remained unchanged for more than two decades.
Significant Survival Benefits
The KEYNOTE-689 trial enrolled 714 patients with newly diagnosed stage III or stage IVA head and neck squamous cell carcinoma across 192 sites in 24 countries. Patients were randomly assigned to receive either standard-of-care therapy alone (surgery followed by radiation with or without chemotherapy) or standard therapy plus pembrolizumab administered both before and after surgery.
Data analysis through July 2024 revealed striking differences between the treatment groups:
- Median disease-free survival: 51.8 months with pembrolizumab vs. 30.4 months with standard care alone
- Three-year disease-free survival rate: 58% with pembrolizumab vs. 46% with standard care
- Greater tumor shrinkage prior to surgery in the pembrolizumab group
"The survival benefit we've seen in adding pembrolizumab to standard-of-care therapy for patients with locally advanced head and neck cancer is clinically meaningful and groundbreaking," said Dr. Douglas R. Adkins, professor of medicine and director of the Section of Head and Neck and Thyroid Medical Oncology at WashU Medicine.
Mechanism of Action
Pembrolizumab belongs to a class of drugs known as immune checkpoint inhibitors. It works by circumventing PD-L1, a protein on tumor surfaces that acts as a roadblock preventing the body's immune cells from attacking cancer cells. By bypassing this defense mechanism, pembrolizumab enables the patient's own immune system to recognize and destroy tumor cells.
The drug has previously been approved for various advanced cancers, including melanoma, lung cancer, colorectal cancer, and metastatic head and neck cancer. However, this would mark its first approval for locally advanced head and neck cancer, which has a poor prognosis with current treatments—only 40-50% of patients survive five years after standard therapy.
From Concept to Clinical Impact
The journey toward this breakthrough began at Washington University School of Medicine in 2013, when Dr. Adkins and Dr. Ravindra Uppaluri (now at Dana-Farber and Brigham and Women's Hospital) proposed investigating pembrolizumab's potential in locally advanced head and neck cancers.
Their initial Phase 2 trial found that adding pembrolizumab before and after surgery increased tumor cell death without compromising standard treatment delivery. These promising results led directly to the current international Phase 3 trial.
Professor Kevin Harrington from The Institute of Cancer Research, London, who led one of the international teams participating in the trial, emphasized the significance of the findings: "This research shows that immunotherapy could change the world for these patients—it significantly increases the chance of remaining free of disease."
Timing Is Key
Researchers believe the treatment's success stems from its specific timing—administering pembrolizumab both before surgery and as part of post-operative care. This approach primes the immune system to attack cancer cells before surgical removal and maintains this immune response during post-surgery treatments.
"The results of this trial show that pembrolizumab dramatically increases the duration of disease remission—for years longer than the current standard treatments," Professor Harrington noted. "It works particularly well for those with high levels of immune markers, but it's really exciting to see that the treatment improves outcomes for all head and neck cancer patients, regardless of these levels."
Patient Experience
Laura Marston, a 45-year-old trial participant from Derbyshire who was diagnosed with stage 4 tongue cancer in 2019, shared her experience: "I was so excited to be on a clinical trial and knowing I was in the best hands was really reassuring. I underwent two rounds of immunotherapy before undergoing surgery on August 13, 2019."
Following surgery, Marston received ten additional immunotherapy infusions along with chemotherapy and radiotherapy. "I am amazed I am still here," she said. "This treatment has given me the gift of life."
Regulatory Implications
The FDA is scheduled to announce a decision on approving pembrolizumab for locally advanced head and neck cancers in June. If approved, it would represent the first change in standard-of-care therapy for this cancer type in more than 20 years.
Head and neck cancers, which include tumors of the mouth, sinuses, nose, and throat, are associated with risk factors such as tobacco use and human papillomavirus (HPV) infection. The potential approval of pembrolizumab offers new hope for hundreds of thousands of patients diagnosed with these cancers worldwide each year.
The trial was funded by Merck, the manufacturer of pembrolizumab.
