Merck's Keytruda Breakthrough: First Positive Trial in Resected Locally Advanced HNSCC in Over 20 Years

Merck & Co.'s blockbuster immunotherapy drug Keytruda (pembrolizumab) has achieved a significant milestone in the treatment of head and neck cancer, marking the first positive trial in more than two decades for resected locally advanced head and neck squamous cell carcinoma (HNSCC). The results of the phase 3 Keynote-689 trial, presented at the American Association for Cancer Research Annual Meeting 2025, demonstrate that Keytruda's use in a perioperative setting can reduce the risk of cancer recurrence or death by 27% in patients with stage 3 or 4a HNSCC.

Keynote-689 Trial Results and Implications

The Keynote-689 trial evaluated the efficacy of Keytruda when added to the current standard of care, which consists of postoperative radiotherapy with or without chemotherapy. The study's findings suggest that the Keytruda regimen could represent a new standard of care in this disease setting, according to Dr. Ravindra Uppaluri, co-principal investigator of Keynote-689 and researcher at Brigham and Women's Hospital and Dana-Farber Cancer Institute.

Key results from the trial include:

• A 27% reduction in the risk of recurrence or death in patients treated with Keytruda
• At three years, 57.6% of patients in the Keytruda arm remained recurrence-free, compared to 46.4% in the control arm
• Median event-free survival (EFS) time of 51.8 months for Keytruda-treated patients versus 30.4 months for the control group

Dr. Marjorie Green, Merck's head of oncology global clinical development, emphasized the clinical significance of these results, noting that "There have been uptakes and adoptions of therapies for 2% to 3% absolute difference in outcomes, because we know most of the recurrences that have happened on the study were distant, which increases the risk of death."

PD-L1 Expression and Treatment Efficacy

The study results revealed a correlation between PD-L1 expression levels and the magnitude of Keytruda's benefit. Patients with higher PD-L1 expression, as measured by the combined positive score (CPS), showed greater improvements in event-free survival:

• 34% risk reduction in patients with CPS ≥ 10
• 30% risk reduction in patients with CPS ≥ 1
• 27% risk reduction across all patients, including PD-L1-negative cases

While these findings raise questions about the appropriateness of Keytruda for patients with low or no PD-L1 expression, Dr. Uppaluri suggested that the treatment should be considered for all participants, given that only about 5% of patients have a CPS below 1.

Ongoing Questions and Future Directions

Despite the overall success of the Keynote-689 trial, several questions remain unanswered:

1. The necessity of both neoadjuvant and adjuvant Keytruda treatment, especially in light of Roche's Tecentriq failing as an adjuvant therapy in a similar setting.
2. The potential for Keytruda to extend patients' lives, as overall survival data remain immature.
3. The optimal PD-L1 expression threshold for treatment efficacy.

Merck's application based on Keynote-689 is currently under FDA priority review, with a target decision date of June 23, 2025. As the pharmaceutical industry awaits this decision, the results of this trial represent a significant step forward in the treatment of head and neck cancer, potentially offering new hope to patients with this challenging disease.