Landmark Results Presented at AACR 2025
Merck (NYSE: MRK), known as MSD outside the U.S. and Canada, has announced encouraging results from its Phase 3 KEYNOTE-689 trial. The study evaluates KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, as a perioperative treatment for patients with stage III or IVA resectable, locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
For the first time, researchers presented the data during a Plenary Session at the American Association for Cancer Research (AACR) Annual Meeting 2025, where it was also selected for the AACR press program.
KEYTRUDA Significantly Improves Event-Free Survival
Following a median follow-up of 38.3 months, KEYTRUDA, when used in a perioperative setting (before and after surgery), significantly reduced the risk of event-free survival (EFS) events:
- 34% reduction in the CPS ≥10 population (HR=0.66; p=0.0022)
- 30% reduction in the CPS ≥1 population (HR=0.70; p=0.0014)
- 27% reduction in the intent-to-treat (ITT) population (HR=0.73; p=0.0041)
Patients in the KEYTRUDA plus standard of care (SOC) group showed markedly longer median EFS compared to those receiving SOC alone:
- CPS ≥10: 59.7 months vs. 26.9 months
- CPS ≥1: 59.7 months vs. 29.6 months
- ITT: 51.8 months vs. 30.4 months
Breakthrough in Head and Neck Cancer Treatment
Dr. Ravindra Uppaluri, co-principal investigator and Director of Head and Neck Surgical Oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, emphasized the importance of these results, calling KEYNOTE-689 the first positive trial in over two decades for this patient population.
Dr. Douglas Adkins, also a co-principal investigator from Washington University School of Medicine, highlighted the clinical significance of these findings, stating that this is the first time an anti-PD-1 therapy has improved EFS in both neoadjuvant and adjuvant settings for earlier-stage head and neck cancer.
Major Pathological Response (mPR) Rates Also Improved
As per the Merck Press release, the study also met a key secondary endpoint, showing statistically significant improvements in major pathological response (mPR):
- CPS ≥10: 13.7% improvement (p<0.00001)
- CPS ≥1: 9.8% improvement (p<0.00001)
- ITT: 9.3% improvement (p<0.00001)
Promising Overall Survival Trends
Although the overall survival (OS) benefit did not reach statistical significance at this interim analysis, there was a positive trend in the CPS ≥10 group (HR=0.72). Formal OS testing in the CPS ≥1 and ITT groups will occur during the next analysis phase due to the hierarchical design of the study.
Regulatory Progress and Future Outlook
A supplemental Biologics License Application (sBLA) for KEYTRUDA, based on the KEYNOTE-689 results, is currently under priority review by the U.S. FDA, with a PDUFA date of June 23, 2025. Dr. Marjorie Green, SVP and Head of Oncology at Merck Research Laboratories, noted that this marks the 12th positive pivotal trial for a KEYTRUDA-based regimen in earlier-stage cancers.
About the KEYNOTE-689 Study Design
KEYNOTE-689 is a randomized, open-label, active-controlled Phase 3 trial (NCT03765918) involving 714 treatment-naïve patients with newly diagnosed, resectable stage III or IVA LA-HNSCC. Patients were randomly assigned (1:1) to one of two arms:
- Experimental arm: Neoadjuvant KEYTRUDA (200 mg IV Q3W, 2 cycles) before surgery, followed by:
- KEYTRUDA (200 mg IV Q3W, 15 cycles) + SOC radiotherapy with cisplatin (for high-risk patients)
- or KEYTRUDA + SOC radiotherapy without cisplatin (for low-risk patients)
- Control arm: No neoadjuvant treatment, followed by:
- SOC radiotherapy with cisplatin (for high-risk patients)
- or SOC radiotherapy without cisplatin (for low-risk patients)
The primary endpoint was EFS, while secondary endpoints included OS, mPR, pathological complete response, and safety. PD-L1 combined positive score (CPS) was used for subgroup analysis.
Safety Profile Remains Consistent
The safety profile of KEYTRUDA aligned with previous studies. Grade ≥3 treatment-related adverse events (TRAEs) occurred in:
- 44.6% of patients in the KEYTRUDA + SOC group
- 42.9% in the SOC-alone group
TRAEs led to death in 1.1% of patients on the KEYTRUDA regimen (n=4) and 0.3% in the SOC group (n=1). Importantly, no new safety signals emerged. Immune-mediated AEs of any grade appeared in 43.2% of KEYTRUDA patients, with hypothyroidism (24.7%) being the most frequent.