Detailed findings from the Phase III KEYNOTE-689 trial (NCT03765918) show that perioperative immunotherapy with Keytruda (pembrolizumab; Merck) produced a significant improvement in event-free survival (EFS) among patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC).

Perioperative Keytruda Improves Event-Free Survival in Resectable Locally Advanced Head and Neck Cancer

Results from the trial, published by The New England Journal of Medicine (NEJM), support perioperative immune checkpoint inhibition in this setting and could alter a standard of care that has seen little change in two decades, according to the study investigators.^1,2

KEYNOTE-689 Trial Demonstrates Durable Efficacy Across PD-L1 Subgroups

“Resectable locally advanced (HNSCC) is a burdensome disease with few treatment advances in recent decades,” the study authors wrote. “Adjuvant radiotherapy remains the standard of care for patients with locally advanced HNSCC without adverse pathological features (e.g., positive margins or extranodal extension). Two phase 3 trials, European Organization for Research and Treatment of Cancer (EORTC) 22931 and Radiation Therapy Oncology Group (RTOG) 9501, established radiotherapy with concomitant cisplatin after surgery as the standard of care for high-risk locally advanced HNSCC. Nevertheless, approximately a third of patients have disease relapse within 1 year, and less than half are likely to survive to 5 years.”¹

Ongoing Research of Keytruda Across Cancer Types

Keytruda is an anti-PD-1 therapy that improves the immune system's ability to detect and fight tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which leads to the activation of T lymphocytes that could affect the tumor and healthy cells.

To date, more than 1600 trials are evaluating Keytruda across a range of cancer types and treatment settings. Keytruda has approved indications in melanoma; non-small cell lung cancer; head and neck squamous cell cancer; classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma; urothelial carcinoma; gastric cancer; microsatellite instability-high or mismatch repair deficient cancer; microsatellite instability-high or mismatch repair deficient colorectal cancer; esophageal cancer; cervical cancer; hepatocellular carcinoma; Merkel cell carcinoma; renal cell carcinoma; endometrial carcinoma; tumor mutational burden-high cancer; cutaneous squamous cell carcinoma; and triple-negative breast cancer.

KEYNOTE-689 Trial Overview and Patient Population

• The randomized, active-controlled, open-label KEYNOTE-689 trial analyzed both neoadjuvant treatment with Keytruda, as well as in combination with standard of care (SOC) radiotherapy, with or without cisplatin, as an adjuvant therapy in previously untreated patients with newly diagnosed, stage III or IVA resectable locally advanced HNSCC.
• Treatment efficacy was determined as per PD-L1 combined positive score (CPS) status.
• The trial’s primary endpoint is EFS defined as time from randomization to first occurrence of radiographic disease progression; local or distant progression or recurrence; or death from any cause.
• Key secondary endpoints include overall survival, major pathological response, pathological complete response, and safety.

Event-Free Survival Significantly Extended With Perioperative Pembrolizumab

A total of 363 patients were randomly assigned to the Keytruda cohort, of whom 234 had a CPS of ≥10 and 347 had a CPS of ≥1, whereas 351 patients were assigned to the control cohort, of whom 231 had a CPS of ≥10 and 335 had a CPS of ≥1.

Patients were randomly assigned to receive either of the following dose levels:

• Neoadjuvant Keytruda at a dose of 200 mg administered intravenously (IV) every three weeks (Q3W) for two cycles, followed by either adjuvant Keytruda at a dose of 200 mg IV Q3W for 15 cycles plus SOC radiotherapy with cisplatin at a dose of 100 mg/m² IV Q3W for three cycles for high-risk patients or adjuvant Keytruda 200 mg IV Q3W for 15 cycles plus SOC radiotherapy without cisplatin for low-risk patients.
• No neoadjuvant treatment followed by adjuvant SOC radiotherapy with cisplatin at a dose of 100 mg/m² IV Q3W for three cycles as adjuvant treatment for high-risk patients or SOC radiotherapy without cisplatin as adjuvant therapy for low-risk patients.

Previously released interim data from KEYNOTE-689 show that perioperative treatment with Keytruda significantly lowered the risk of disease progression or recurrence in patients with stage III or IVA, resected, locally advanced HNSCC compared to SOC radiotherapy.³

• At a median follow-up of 38.3 months (range, 9.0-66.5), compared to adjuvant radiotherapy alone in the intent-to-treat (ITT) population, neoadjuvant Keytruda continued in combination with SOC radiotherapy post surgery followed by adjuvant Keytruda monotherapy lowered the risk of EFS events by 34% (HR=0.66 [95% CI, 0.49-0.88]; p=.0022) in the CPS ≥10 population; by 30% (HR=0.70 [95% CI, 0.55-0.89; p=.0014) in the CPS ≥1 population; and by 27% (HR=0.73 [95% CI 0.58-0.92]; p=.0041) in the ITT population.
• In patients with CPS ≥10, median EFS was 59.7 months in the Keytruda plus SOC cohort (95% CI, 41.1-not reached) compared to 26.9 months (95% CI, 18.3-51.5) in the SOC cohort.
• In the CPS ≥1 population, median EFS was 59.7 months (95% CI, 37.9-not reached) among patients administered Keytruda plus SOC compared to 29.6 months (95% CI, 19.5-41.9) among patients administered SOC.
• Among the ITT population, median EFS was 51.8 months (95% CI, 37.5-not reached) among patients administered Keytruda plus SOC compared to 30.4 months (95% CI, 21.8-50.1) among patients administered SOC.

Updated results show that surgery was completed in approximately 88% of the patients across both cohorts.

• EFS at 36 months among the CPS-10 population was 59.8% in the Keytruda plus SOC cohort compared to 45.9% in the placebo cohort (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P=0.004).
• In the CPS-1 population, EFS was 58.2% in the Keytruda plus SOC cohort compared to 44.9% in the placebo cohort (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P=0.003).
• For the total patient population, EFS was 57.6% in the Keytruda plus SOC cohort compared to 46.4% in the placebo cohort (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P=0.008).

Safety Profile and Adverse Events Reflect Known Immunotherapy Risks

• In terms of safety, grade 3 or higher treatment-related adverse events (AEs) were reported among 44.6% of patients in the Keytruda plus SOC cohort compared to 42.9% of patients in the placebo cohort, which includes death in 1.1% and 0.3%, respectively.
• Possible immune-mediated AEs of grade 3 or greater were reported among 10% of the patients in the Keytruda plus SOC cohort.

Implications for Standard of Care in Locally Advanced HNSCC

“The results of the KEYNOTE-689 trial, and the recently announced significant improvement in disease-free survival in the GORTEC 2018-01 NIVOPOSTOP trial (postoperative nivolumab–chemoradiotherapy vs. chemoradiotherapy), are encouraging and suggest a specific function of immune checkpoint inhibitors in targeting micrometastatic or minimally residual head and neck cancer after curative surgical therapy,” the study authors concluded. “Of note, the KEYNOTE-689 trial included participants with high- and low-risk disease on the basis of risk assessment guided by pathological findings, whereas the NIVOPOSTOP trial included only those with high-risk disease. The role of the neoadjuvant component of the KEYNOTE-689 regimen in pathological tumor response and potential immunogenic priming of the tumor microenvironment are of high interest and warrant further investigation beyond the scope of this trial.”¹

References

1. Uppaluri, R. et al. Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2415434 (2025)

2. Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689). ClinicalTrials.gov. Updated February 7, 2025. Accessed July 9, 2025. https://clinicaltrials.gov/study/NCT03765918

3. Merck’s KEYTRUDA® (pembrolizumab) Met Primary Endpoint of Event-Free Survival (EFS) as Perioperative Treatment Regimen in Patients With Resected, Locally Advanced Head and Neck Squamous Cell Carcinoma. News release. Merck. October 8, 2024. Accessed July 9, 2025. https://www.merck.com/news/mercks-keytruda-pembrolizumab-met-primary-endpoint-of-event-free-survival-efs-as-perioperative-treatment-regimen-in-patients-with-resected-locally-advanced-head-and-neck-squamous-c