FDA OKs Perioperative Pembrolizumab in HNSCC: Findings From KEYNOTE-689
Ravindra Uppaluri, MD, PhD, discusses findings from the KEYNOTE-689 trial in adult patients with resectable, locally advanced head and neck squamous cell carcinoma.
A significant shift in head and neck cancer treatment arrived on June 12, 2025, as the FDA granted approval to pembrolizumab (Keytruda) for adult patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) exhibiting a PD-L1 combined positive score (CPS) of ≥1. This new regimen involves pembrolizumab as a single agent before surgery, followed by adjuvant treatment with pembrolizumab plus radiotherapy (with or without cisplatin) after surgery, and then continued as a single agent.
This pivotal approval stems from the KEYNOTE-689 trial (NCT03765918), which showcased a statistically significant improvement in event-free survival (EFS). Patients receiving pembrolizumab had a median EFS of 51.8 months, a marked improvement over the 30.4 months seen in the standard of care (SOC) arm. Historically, SOC for locally advanced HNSCC has yielded suboptimal outcomes and considerable toxicities, making this advancement particularly impactful.
As Ravindra Uppaluri, MD, PhD, chief of head and neck surgery at the Dana-Farber Brigham Cancer Center, and chief of the otolaryngology group at the Brigham and Women's Hospital, noted, the trial also demonstrated significant major pathological responses in primary tumors and lymph nodes following neoadjuvant pembrolizumab. While overall survival data are still maturing, the EFS benefit strongly indicates improved patient prognosis.
Additionally, the safety profile was generally manageable, with immune-mediated events in the pembrolizumab arm being consistent with known effects and no new safety concerns emerging.
“The previous standard of care was established over 20 years ago, and despite this multimodality treatment, the outcomes were not optimal. KEYNOTE-689 findings dramatically improve over the standard of care. I think it is an exciting time for patients, providers, and all who take care of patients with head and neck cancer,” he shares.
This perioperative integration of pembrolizumab not only redefines the SOC but also opens doors for future investigations into similar therapeutic approaches in surgical oncology for HNSCC. The success of KEYNOTE-689 highlights the crucial need for multidisciplinary team collaboration to implement these innovative treatment strategies effectively.
