Landmark Phase III Trial Shows Keytruda Significantly Improves Event-Free Survival in LA-HNSCC

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Interim data from the Phase III KEYNOTE-689 trial (NCT03765918) show that perioperative treatment with Keytruda (pembrolizumab; Merck) significantly lowered the risk of disease progression or recurrence in patients with stage III or IVA, resected, locally advanced head and neck squamous cell carcinoma (LA-HNSCC) compared to standard of care (SOC) radiotherapy.^1,2 These findings, presented at the American Association for Cancer Research Annual Meeting, are the first positive clinical trial data for this patient population in more than 20 years, according to Merck.

“As the first positive trial in over two decades for patients with resectable (LA-HNSCC), the presentation of these landmark results marks an important moment for these patients and those who care for them,” trial co-principal investigator Ravindra Uppaluri, MD, PhD, director of Head and Neck Surgical Oncology, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, said in a press release. “KEYNOTE-689 represents a meaningful development with a potential to provide an option that helps certain patients with LA-HNSCC reduce the risk of recurrence and disease progression earlier in their treatment journey.”¹

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.

Trial Design

The randomized, active-controlled, open-label KEYNOTE-689 trial analyzed both neoadjuvant treatment with Keytruda, as well as in combination with SOC radiotherapy, with or without cisplatin, as an adjuvant therapy in previously untreated patients with newly diagnosed, stage III or IVA resectable LA-HNSCC. Treatment efficacy was determined as per PD-L1 combined positive score (CPS) status.

The trial’s primary endpoint is event-free survival (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 (OS), major pathological response, pathological complete response, and safety.

Investigators randomly assigned 714 patients in a 1:1 ratio to receive either:

• 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/m²IV 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/m²IV Q3W for three cycles as adjuvant treatment for high-risk patients or SOC radiotherapy without cisplatin as adjuvant therapy for low-risk patients.

Results show that 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.

In terms of safety, treatment-related adverse events (TRAEs) reported with Keytruda were consistent with prior findings for the drug and no new safety signals were identified. Grade ≥3 TRAEs were reported in 44.6% of patients administered Keytruda plus SOC compared to 42.9% of patients administered SOC radiotherapy alone. A total 1.1% of patients administered Keytruda plus SOC (n=4) experienced TRAEs that led to death compared to 0.3% of patients administered SOC radiotherapy (n=1). Immune-mediated AEs of any grade were reported in 43.2% of patients administered Keytruda plus SOC, of which hypothyroidism was the most frequently reported (24.7%).

“The addition of immunotherapy using Keytruda to standard of care surgery and adjuvant (chemo)radiotherapy resulted in a significant reduction in the risk of (EFS) events by 27%, compared with standard of care therapy alone,” study co-principal investigator Douglas Adkins, MD, professor, Division of Oncology, Washington University School of Medicine in St. Louis, said in a press release. “These results are notable as they mark the first time an anti-PD-1 therapy has demonstrated a statistically significant and clinically meaningful improvement in (EFS) in the neoadjuvant and adjuvant setting in earlier stages of head and neck squamous cell carcinoma.”¹

References

1. KEYTRUDA® (pembrolizumab) as Perioperative Treatment With Standard of Care (SOC) Adjuvant Therapy Significantly Improved Event-Free Survival Compared to SOC Alone in Patients With Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma. News release. Merck. April 27, 2025. Accessed April 28, 2025. https://www.merck.com/news/keytruda-pembrolizumab-as-perioperative-treatment-with-standard-of-care-soc-adjuvant-therapy-significantly-improved-event-free-survival-compared-to-soc-alone-in-patients-with-resectable-loca/

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 April 28, 2025. https://clinicaltrials.gov/study/NCT03765918