KEYNOTE-689 Leads to FDA Approval of Perioperative Pembrolizumab in HNSCC
Ravindra Uppaluri, MD, PhD, discusses the background regarding locally advanced head and neck cancer and what the trial design of KEYNOTE-689 entailed.
On June 12, 2025, the FDA granted approval to pembrolizumab (Keytruda) for the treatment of adult patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) displaying a PD-L1 combined positive score (CPS) of ≥1, as determined by an FDA-approved test. The approval covers use of pembrolizumab as a single agent in the neoadjuvant setting, followed by adjuvant treatment with pembrolizumab in combination with radiotherapy with or without cisplatin after surgery, and then continued as a single agent.1
This approval is based on findings from the KEYNOTE-689 trial (NCT03765918), which demonstrated a statistically significant improvement in event-free survival (EFS). In this randomized trial, the median EFS for the pembrolizumab arm was 51.8 months compared with 30.4 months in the standard of care (SOC) arm. Historically, outcomes for locally advanced HNSCC with SOC (upfront surgery followed by adjuvant therapy, or definitive chemoradiotherapy) have been suboptimal and associated with considerable toxicities.2,3
“It has been an exciting time in oncology, in general, because of immune checkpoint blockade therapies, and this has resulted in a new standard in recurrent/metastatic head and neck cancer. However, combining immune checkpoint blockade with chemoradiation in locally advanced head and neck cancer in the upfront setting has been negative in several phase 3 clinical trials,” explains Ravindra Uppaluri, MD, PhD, in an interview with Targeted OncologyTM.
The KEYNOTE-689 trial showed significant pathological responses in both the primary tumor and lymph nodes following neoadjuvant pembrolizumab. While overall survival data are still maturing, the EFS benefit is a strong indicator of improved patient outcomes. Importantly, the adverse event profile of pembrolizumab combined with SOC was generally comparable to SOC alone and manageable.
This perioperative integration of pembrolizumab represents a novel approach in HNSCC treatment, moving beyond the two-decade-old paradigm and offering a promising avenue for improving the lives of patients with this challenging disease.
In this video, Uppaluri, 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, discusses the background regarding locally advanced head and neck cancer and what the trial design of KEYNOTE-689 entailed.
“I want to highlight that it really requires multidisciplinary teams to make this happen. It is not just single-specialty folks saying we are going to treat cancer patients in a given way. It requires a multidisciplinary group of people to come together to implement this kind of workflow,” he says.
