Keytruda Significantly Improves Event-Free Survival in Phase III Trial for Resected Head and Neck Cancer

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Keytruda (pembrolizumab) produced a significant improvement in event-free survival (EFS) and major pathological response as a perioperative treatment for resected, locally advanced head and neck squamous cell carcinoma, according to data from the Phase III KEYNOTE-689 trial (NCT03765918).^1,2 With these results, KEYNOTE-689 becomes the first Phase III trial to show statistically significant and clinically meaningful EFS improvements among an intent-to-treat population in the neoadjuvant and adjuvant setting with an anti-PD-1 medication administered during the earlier stages of head and neck squamous cell carcinoma. Investigators stated that these findings could lead to a shift in the treatment paradigm for the disease.

“These results are substantial, as KEYNOTE-689 marks the first positive trial in two decades for patients with resected, locally advanced head and neck squamous cell carcinoma,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in a press release. “These statistically significant and clinically meaningful findings have the potential to be practice-changing and continue to highlight the promising role of Keytruda for certain patients with earlier stages of disease.”¹

Keytruda, an anti-PD-1 therapy, enhances 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.

The randomized, active-controlled, open-label KEYNOTE-689 trial is analyzing neoadjuvant Keytruda followed by Keytruda plus standard-of-care radiotherapy with or without cisplatin as an adjuvant treatment, followed by Keytruda as a maintenance therapy compared with adjuvant radiotherapy (with or without cisplatin) alone in treatment-naïve patients with newly diagnosed, stage III or IVA resected locally advanced, head and neck squamous cell carcinoma. Investigators are classifying the efficacy outcomes by PD-L1 Combined Positive Score (CPS) status.

The trial’s primary endpoint is EFS, with secondary endpoints that include overall survival (OS), major pathological response (mPR), pathological complete response, and safety. Investigators randomly assigned approximately 704 patients in a 1:1 ratio to receive either

Keytruda administered at a dose of 200 mg intravenously (IV) every three weeks (Q3W) for two cycles as neoadjuvant therapy, followed by either Keytruda administered at a dose of 200 mg IV Q3W for 15 cycles plus standard-of-care radiotherapy with cisplatin at a dose of 100 mg/m2 IV Q3W for three cycles as adjuvant treatment after surgery in high-risk patients; or Keytruda at a dose of 200 mg IV Q3W for 15 cycles plus standard-of-care radiotherapy without cisplatin as adjuvant therapy after surgery in low-risk patients; or no neoadjuvant therapy before surgery, followed by either standard-of-care radiotherapy with cisplatin at a dose of 100 mg/m2 IV Q3W for three cycles as adjuvant therapy after surgery in high-risk patients or standard-of-care radiotherapy without cisplatin as an adjuvant therapy after surgery for low-risk patients.

Results from the first pre-specified interim evaluation conducted by an independent Data Monitoring Committee showed statistically significant and clinically meaningful improvements in EFS among the Keytruda perioperative treatment cohort. Further, investigators observed a statistically significant improvement in the key secondary endpoint of mPR among patients in the Keytruda cohort compared to patients administered adjuvant radiotherapy alone.

In terms of safety, the profile of Keytruda was consistent with prior findings and no new safety signals were reported. Deeper data from the trial will be presented at an upcoming medical meeting and submitted to regulatory authorities, according to Merck.

References

1. 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 October 9, 2024. 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/

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 April 16, 2024. Accessed October 9, 2024. https://clinicaltrials.gov/study/NCT03765918