Abstract
There are many treatments that patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) undergo, such as surgery, radiotherapy, and chemotherapy, often with platinum agents. Recently, immunotherapies like pembrolizumab have transformed care in recurrent or metastatic disease. However, until now, integrating immunotherapy directly around surgery (in the neoadjuvant/adjuvant setting) hasn’t been proven in phase 3 trials. So, in 2025, scientists tackled this gap in the KEYNOTE-689 study by adding both neoadjuvant and adjuvant pembrolizumab to standard multimodal therapy—a first-of-its-kind approach in locally advanced HNSCC clinical practice.
What is HNSCC?
Head and neck squamous-cell carcinoma affects tissues in the mouth, throat, and larynx. Standard care involves removing the tumor surgically, followed by radiotherapy (often with concurrent cisplatin-based chemotherapy), depending on surgical margins and lymph node involvement. Pembrolizumab is a monoclonal antibody targeting PD-1, a checkpoint on T cells. By binding PD-1, it blocks inhibition from tumor-expressed PD-L1, boosting the immune response against cancer.
The Testing
In KEYNOTE-689 (NCT03765918), the trial enrolled 714 adults with locally advanced HNSCC, either resectable stage III/IV disease. They were randomized 1:1 to either standard care alone (surgery + radiotherapy ± cisplatin) or standard care plus pembrolizumab at 200 mg every 3 weeks: 2 neoadjuvant doses before surgery and 15 adjuvant doses afterward. The primary endpoint was event-free survival (EFS), time from randomization to disease progression, recurrence, or death, analyzed sequentially in subgroups by tumor PD-L1 expression: CPS ≥10, CPS ≥1, and the full trial population. At the first interim analysis, with a median follow-up of 38.3 months, EFS at 36 months was significantly improved in the pembrolizumab group:
CPS ≥10: 59.8% vs. 45.9% (HR 0.66; P=0.004)
CPS ≥1: 58.2% vs. 44.9% (HR 0.70; P=0.003)
Overall: 57.6% vs. 46.4% (HR 0.73; P=0.008)
Surgical completion rates were nearly identical (~88%), indicating that giving pembrolizumab before surgery did not delay or compromise operations.
However, adding pembrolizumab did increase toxicity slightly: Grade 3 or higher adverse events occurred in 44.6% versus 42.9% of patients, including a small increase in treatment-related death (1.1% vs. 0.3%). Grade ≥3 immune-mediated events occurred in 10% of the pembrolizumab group. Still, no unexpected new safety signals emerged. In context, this neoadjuvant/adjuvant strategy offers several theoretical advantages over standard care and immunotherapy administered only in advanced disease:
Neoadjuvant dosing exposes the intact tumor to immune activation, potentially amplifying T-cell priming by presenting neoantigens.
Adjuvant dosing continues to protect against micrometastatic relapse post-surgery. Unlike checkpoint inhibitors used only after relapse, this perioperative design aims to prevent recurrence upfront.
The KEYNOTE-689 results represent a paradigm shift: immunotherapy moving from the metastatic/recurrent setting into early intervention combined with surgery and radiation. The improvement in 3-year EFS, from ~46% to ~58% overall, and ~60% in high PD-L1 expressers, demonstrates both efficacy and a favorable benefit-risk profile.
Still, challenges remain. The trial was open-label, without an immune-only comparator arm, so precise attribution of benefit and toxicity to pembrolizumab is more complex. Long-term overall survival (OS) data are pending; EFS is encouraging, but definitive OS benefit is needed. Managing immune-related adverse events perioperatively requires careful coordination among multidisciplinary teams. Biomarker use (PD-L1 CPS) helped identify patients with the most benefit, but optimal cutoffs and use in practice need refinement.
Despite these caveats, KEYNOTE-689’s success is significant. It supports a new standard: perioperative pembrolizumab for resectable, locally advanced HNSCC, especially for patients with PD-L1–positive tumors. Regulatory approvals and guideline updates may follow soon, integrating this approach into routine care.
References
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