Introduction
The KEYNOTE-689 clinical trial has provided a significant update on pembrolizumab’s role in treating resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Presented at the AACR 2025 Annual Meeting, this Phase 3 study (NCT03765918) evaluates neoadjuvant and adjuvant pembrolizumab alongside standard care. With promising event-free survival (EFS) results, this trial could reshape treatment for head and neck cancer. There is also an upcoming FDA priority review. Let’s dive into the findings.
What is KEYNOTE-689?
KEYNOTE-689 is a Phase 3, randomized, open-label trial assessing pembrolizumab in 734 patients with resectable stage III/IVA LA-HNSCC. Patients were split into two arms:
- Pembrolizumab Arm (N=383): Neoadjuvant pembrolizumab, surgery, adjuvant pembrolizumab with radiotherapy (RT) ± cisplatin, and maintenance pembrolizumab.
- Control Arm (N=351): Surgery followed by standard RT.
The primary endpoint was EFS, with secondary endpoints including overall survival (OS) and safety.
KEYNOTE-689 Study Design
Alt Text: KEYNOTE-689 study design flowchart showing neoadjuvant and adjuvant pembrolizumab phases for LA-HNSCC treatment (NCT03765918), presented at AACR 2025.
Key Findings: EFS Results
The KEYNOTE-689 pembrolizumab trial reported an EFS hazard ratio (HR) of 0.73 (95% CI 0.58–0.92). This indicates a 27% reduction in recurrence or death risk. Median EFS reached 51.8 months with pembrolizumab compared to 30.4 months in the control arm. The Kaplan-Meier curves showed early and sustained separation, highlighting a consistent benefit.
EFS Results for All Participants
Alt Text: Kaplan-Meier curve of EFS for all participants in KEYNOTE-689 pembrolizumab trial, showing HR 0.73 (95% CI 0.58–0.92), AACR 2025.
Subgroup Analysis: CPS ≥10 and Hypopharynx
Subgroup data revealed a stronger benefit in the CPS ≥10 subgroup, with an HR of 0.66 (95% CI 0.49–0.88). The 2-year EFS rates were 75% in the pembrolizumab arm versus 62% in the control arm. Benefits were consistent across PD-L1 strata and tumor stages. However, the hypopharynx subgroup showed no clear benefit due to a small sample size.
EFS by Subgroups
Alt Text: Forest plot of EFS by subgroups in KEYNOTE-689 pembrolizumab trial for LA-HNSCC, highlighting CPS ≥10 and hypopharynx data, AACR 2025.
Safety Profile and FDA Review
The safety profile of pembrolizumab in KEYNOTE-689 showed no new concerns, aligning with prior studies. The FDA has scheduled a priority review for pembrolizumab in this setting, with a target action date of June 2025. This raises questions about a potential new perioperative standard for LA-HNSCC treatment.
Discussion: What’s Next for KEYNOTE-689 Pembrolizumab in LA-HNSCC?
This trial marks the first positive Phase 3 study for resectable LA-HNSCC in over two decades. While the EFS results are encouraging, OS data is still pending. Some experts question whether EFS benefits will translate to OS gains in head and neck cancer. The hypopharynx subgroup’s lack of benefit also warrants further investigation.
Learn More About KEYNOTE-689 Pembrolizumab for LA-HNSCC
- ClinicalTrials.gov: NCT03765918
- Related Reading: AACR 2025 Annual Meeting Overview
- Watch Our Video: KEYNOTE-689 Clinical Trial Update | AACR 2025 News Report (#)
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