A global phase 3 clinical trial orchestrated by Washington University School of Medicine in St. Louis and Dana-Farber Brigham Cancer Center indicates that individuals with specific locally advanced head and neck cancers experienced advantages from incorporating the immunotherapy agent pembrolizumab (trade name Keytruda) alongside standard care. Patients receiving pembrolizumab exhibited more significant tumor reduction before surgery and, on average, lived cancer-free nearly two years longer compared to those who underwent only standard treatment.
These findings were announced on April 27 during the annual conference of the American Association for Cancer Research (AACR) in Chicago. Researchers from WashU Medicine co-led the investigation at the Siteman Cancer Center, which operates within Barnes-Jewish Hospital and WashU Medicine.
In cases of locally advanced head and neck cancers, the tumor has dispersed to adjacent tissues or lymph nodes but has not yet spread to distant sites. The conventional treatment for these patients comprises surgery to excise the tumor, followed by radiation, either with or without chemotherapy. Merely 40% to 50% of such patients survive five years post-standard care.
Pembrolizumab, a form of immunotherapy that assists a patient’s immune system in targeting cancer cells, was initially authorized by the Food and Drug Administration (FDA) in 2014 for advanced melanoma. It has subsequently received approval for various other malignancies, including advanced lung cancer, colorectal cancer, cervical cancer, and lymphoma. In 2016, it was sanctioned for recurrent and metastatic head and neck cancer.
Should it gain approval for locally advanced head and neck cancers— the emphasis of the clinical trial— pembrolizumab, administered pre- and post-surgery, would represent the first modification in standard care for this cancer category in over twenty years.
“The survival advantage we’ve observed from adding pembrolizumab to standard treatment for patients with locally advanced head and neck cancer is clinically significant and revolutionary,” stated co-senior author Douglas R. Adkins, MD, a medicine professor and director of the Section of Head and Neck and Thyroid Medical Oncology at WashU Medicine. Adkins provides care at the Robert Ebert and Greg Stubblefield Head & Neck Tumor Center at Siteman Cancer Center.
The proposal to scrutinize pembrolizumab for this cancer type originated at WashU Medicine and laid the groundwork for an earlier phase 2 clinical trial that commenced at Siteman in 2013. The outcomes from that study directly informed the present international phase 3 investigation.
“It’s thrilling to witness our concepts transition into clinical usage with such remarkable and potentially transformative outcomes,” Adkins added.
The new phase 3 research involved 714 patients recently diagnosed with stage III or stage IVA head and neck squamous cell carcinoma. Starting in December 2018, participants were randomly assigned to receive either standard care alone, which encompasses surgery and radiation with or without chemotherapy, or standard care plus pembrolizumab given pre- and post-surgery.
Analyzing data gathered through July 2024, patients receiving standard care along with pembrolizumab lived cancer-free for a median of 51.8 months (approximately 4.3 years) compared to a median of 30.4 months (around 2.5 years) for those who received standard treatment alone. Those administered pembrolizumab also demonstrated more substantial reductions in tumor size before surgery, an impactful result, given that therapies diminishing a tumor’s size before excision may lower the chance of cancer recurrence later.
The phase 3 trial, supported by Merck, builds upon the work initiated in 2013 by Adkins and Ravindra Uppaluri, MD, PhD, who was formerly with WashU Medicine and currently is the director of Head and Neck Surgical Oncology at Dana-Farber and Brigham and Women’s Hospital. Adkins and Uppaluri proposed exploring whether administering pembrolizumab pre- and post-surgery would enhance outcomes for patients undergoing the surgical removal of locally advanced head and neck cancers that had not metastasized.
Merck had also financed the previous phase 2 trial, which indicated that the inclusion of pembrolizumab before and after surgery heightened tumor cell mortality. The therapy was deemed safe and did not obstruct the administration of standard care. Following this treatment, the researchers observed that the return rates of patients’ cancers were lower than anticipated based on historical data, establishing a foundation for the current phase 3 randomized trial, which encompassed a larger cohort and a control group, conducted at multiple locations globally.
Pembrolizumab is categorized as an immune checkpoint inhibitor, meaning it functions by bypassing barriers that hinder the body’s immune cells from destroying tumor cells. One such barrier is a protein on the surface of tumors known as PD-L1. By circumventing PD-L1, pembrolizumab enables the patient’s immune cells to target and eliminate tumor cells.
Head and neck cancers comprise tumors found in the mouth, sinuses, nose, and throat. Tobacco use, including smoking, as well as human papillomavirus (HPV) infection, augment the risk of developing these cancers.
The FDA is set to announce its decision on the approval of pembrolizumab for locally advanced head and neck cancers in June.
Uppaluri R, Haddad RI, Tao Y, Le Tourneau C, Lee NY, Westra W, Chernock R, Tahara M, Harrington K, Klochikhin AL, Brana I, Vasconcelos Alves G, Hughes BGM, Olivia M, Pinto Figueiredo Lima I, Ueda T, Rutkowski T, Schroeder U, Mauz P, Fuereder T, Laban S, Oridate N, Popovtzer A, Mach N, Korobko Y, Alpuim Costa D, Hooda-Nehra A, Rodriguez CP, Bell RB, Manschot C, Benjamin K, Gumuscu B, Adkins D. Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: phase 3 KEYNOTE-689 study. Advances in Immunotherapy, Clinical Trials Plenary Session. American Association for Cancer Research (AACR) Annual Meeting. April 27, 2025.
This research received funding from Merck Sharp & Dohme LLC.
About Washington University School of Medicine
WashU Medicine is a foremost institution in academic medicine, encompassing biomedical research, patient care, and educational initiatives with 2,900 faculty members. Its National Institutes of Health (NIH) research funding portfolio ranks second among U.S. medical schools and has increased by 56% in the past seven years. In conjunction with institutional investment, WashU Medicine allocates over $1 billion annually to advancing basic and clinical research and training. Its faculty practice consistently ranks among the top five nationwide, with over 1,900 faculty physicians practicing across 130 locations and serving as the medical staff for Barnes-Jewish and St. Louis Children’s hospitals within BJC HealthCare. WashU Medicine has a rich tradition in MD/PhD training, recently committing $100 million to scholarships and curriculum enhancement for its medical students, and hosts outstanding training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communication sciences.
Originally published on the WashU Medicine website
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