By Leah D’Souza, MD, MSc, UK Markey Cancer Center, and Kelly C. Ho, MD, Chicago Medical School at Rosalind Franklin University
For resectable, locoregionally advanced head and neck squamous cell carcinoma (HNSCC), standard of care since the early 2000s has been adjuvant chemoradiation therapy (CRT) for high-risk pathology features, or adjuvant radiation therapy (RT) for intermediate pathology features. KEYNOTE-689 is a phase III open-label randomized controlled trial that has moved the needle for resectable locally advanced HNSCC.
At the 2026 Multidisciplinary Head and Neck Cancers Symposium, presenting author R. Bryan Bell, MD, Executive Medical Director of Providence Cancer Institute of Oregon and Director of the Earle A. Chiles Research Institute, demonstrated how the addition of pembrolizumab offers promising outcomes to head and neck cancers, just as in other tumor types and disease sites.
In this study, participants were randomized to the experimental arm of 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab to standard of care (surgery and adjuvant radiotherapy with or without concomitant cisplatin), versus standard of care alone. Trial eligibility included treatment-naive non-metastatic resectable locally advanced HNSCC with stage III oropharyngeal p16-positive disease with tumor size T4 and node stage N0 to N2, or stage III or IVA oropharyngeal p16-negative disease, or stage III or IVA laryngeal, hypopharyngeal, or oral cavity disease independent of p16 status. The study’s primary endpoint was event-free survival (EFS); EFS in patients with Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥10; EFS in patients with PD-L1 CPS ≥1 up to 66 months. The key secondary endpoint of this study was major pathological response (mPR), defined as ≤10% invasive SCC. The KEYNOTE-689 study met both its primary and key secondary endpoints during the first interim analysis.
From 2018 to 2025, 714 patients were recruited from 192 institutions; 630 patients were deemed treatment-naïve and resectable, stage III/IVA locoregionally advanced HNSCC. The pembrolizumab group was associated with major pathologic response (9.4%), pathologic complete response (3.0%), higher complete resection rates with negative margins (R0) (89.1%), and fewer high-risk pathologic features receiving cisplatin post-operatively (38.9%). The observed increase in margin-negative resections (R0) (89.1% pembro vs. 84.7%, control) and reduction in high-risk features requiring adjuvant cisplatin (38.9% pembro vs. 50.5% control) suggest a potential shift in adjuvant treatment, which may improve long-term outcomes.
The KEYNOTE-689 study represents a pivotal step in redefining the adjuvant treatment of resectable locoregionally advanced HNSCC. The primary endpoint of event-free survival and the secondary endpoint of major pathological response were met at the first interim analysis for this study, demonstrating that neoadjuvant and adjuvant pembrolizumab meaningfully impact surgical outcomes.
“These results demonstrate the survival impact of achieving major — and even partial — pathologic response to immune checkpoint blockade in patients with head and neck squamous cell carcinoma. They represent an important first step toward realizing the promise of neoadjuvant immunotherapy for this capricious disease: that with the right biomarker and the right combination of immunotherapies, tumors can be eradicated before surgery — translating into improved outcomes, the potential for less invasive surgical approaches, and the possibility of de-escalated adjuvant radiation or chemotherapy.”
We look forward to overall survival outcomes in the published manuscript, as these favorable early surgical endpoints suggest a function of immune checkpoint inhibitors in the micrometastatic setting after curative surgical therapy, setting it apart from prior trials evaluating the addition of immune checkpoint inhibitors to standard of care therapy in non-operated locally advanced HNSCC (e.g. KEYNOTE-412 and JAVELIN Head and Neck 100). If long-term survival outcomes confirm these early findings, the next question may be whether the addition of immunotherapy allows for treatment de-escalation strategies.
Published February 20, 2026
