The addition of neoadjuvant and adjuvant pembrolizumab to standard-of-care therapy significantly improved event-free survival over the standard of care alone for patients with locally advanced head and neck cancer in the phase III KEYNOTE-689 trial, according to results presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 (Abstract CT001). Standard of care consisted of surgery and postoperative radiotherapy with or without concurrent chemotherapy.
The median event-free survival was 51.8 months for all patients in the pembrolizumab arm compared with 30.4 months in the standard-of-care-alone arm (hazard ratio [HR] = 0.73; 95% confidence interval [CI] = 0.58–0.92; P = .00411).
“Hundreds of patients all over the world participated in this important trial and implementing their contribution to changing the current standard of care is a major goal,” stated Ravindra Uppaluri, MD, PhD, the Brigham and Women’s Hospital Endowed Chair in Otolaryngology and Director of Head and Neck Surgical Oncology at the Dana-Farber Brigham Cancer Center, who presented the findings at the AACR meeting. “This new information supports changing the current standard of care to now include neoadjuvant and adjuvant pembrolizumab. For the first time in more than 20 years, patients with this challenging disease have a new therapeutic approach.”
Study Methods and Results
A total of 714 patients with resectable stage III or IVA head and neck squamous cell carcinoma were enrolled into the KEYNOTE-689 trial and randomly assigned to receive neoadjuvant and adjuvant pembrolizumab plus surgery and radiotherapy or surgery and radiotherapy alone. Chemotherapy was added for patients with high-risk disease.
Patients were also assessed by PD-L1 combined positive score (CPS), with 234 patients in the pembrolizumab arm showing a CPS of 10 or higher, and 231 patients in the standard-of-care arm.
The median event-free survival in the CPS of 10 or higher population was 59.7 months in the pembrolizumab arm and 26.9 months in the control arm (HR = 0.66; 95% CI = 0.49–0.88; P = .00217). Overall survival data are still awaiting further follow-up.
The difference between arms in terms of major pathologic response rate was 9.3% for all patients (95% CI = 6.7%–12.8%; P < .00001). In the CPS of 10 or higher population, the difference in major pathologic response rate between the two treatment arms was 13.7% (95% CI = 9.7%–18.7%; P < .00001).
The rates of grade 3 or higher treatment-related adverse events were similar between the two arms at 44.6% in the pembrolizumab arm and 42.9% in the standard-of-care arm. Four deaths due to treatment-related adverse events were reported in the pembrolizumab arm and one in the control arm. Immune-mediated adverse events were observed in 43.2% of patients in the pembrolizumab arm, with hypothyroidism being the most common event in 24.7% of patients.
Disclosure: For full disclosures of the study authors, visit aacr.org.
