The regulatory decision was based on data from the phase 3 KEYNOTE-689 trial (NCT03765918). Findings supporting the approval showed that the pembrolizumab-based regimen reduced the risk of recurrence, progression, or death by 30% compared with adjuvant radiotherapy with or without cisplatin alone (HR, 0.70; 95% CI, 0.55-0.89; P = .00140). Patients in the pembrolizumab arm achieved a median event-free survival (EFS) of 59.7 months (95% CI, 37.9-not reached [NR]) compared with 29.6 months (95% CI, 19.5-41.9) for those in the control arm.
“This approval brings a promising advancement to patients in Europe with resectable locally advanced HNSCC,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, at Merck Research Laboratories, stated in a news release. “We’re proud of the continued progress we’re making to broaden the impact of [pembrolizumab] in head and neck cancers and remain focused on working to deliver innovative approaches that have the potential to make a meaningful difference for patients.”
In June 2025, the FDA approved pembrolizumab as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with or without cisplatin after surgery, and then as a single agent, for adult patients with resectable locally advanced HNSCC whose tumors express PD-L1 with a CPS of at least 1, as determined by an FDA-approved test.2 The approval was supported by the same data from KEYNOTE-689.
What other data were reported from KEYNOTE-689?
Findings from the study’s first prespecified interim analysis published in the New England Journal of Medicine showed that at a median follow-up of 38.3 months (range, 9.0-66.5), patients with a PD-L1 CPS of at least 1 treated with the pembrolizumab regimen (n = 347) experienced a median EFS of 59.7 months (95% CI, 37.9-NR) vs 29.6 months (95% CI, 19.5-41.9) for those given the control regimen (n = 335; HR, 0.70; 95% CI, 0.55-0.89; 2-sided P = .003).3
Among patients with a CPS of at least 10, the median EFS was 59.7 months (95% CI, 41.1-NR) in the pembrolizumab arm (n = 234) compared with 26.9 months (95% CI, 18.3-51.5) for the control arm (n = 231; HR, 0.66; 95% CI, 0.49-0.88; 2-sided P = .004).
What was the design of KEYNOTE-689?
Investigators of the multicenter, open-label, randomized, active-controlled trial enrolled patients at least 18 years of age with newly diagnosed, nonmetastatic, resectable locally advanced HNSCC who had stage III oropharyngeal p16-positive disease that was T4 and N0 to N2; stage III/IVA oropharyngeal p16-negative disease; or stage III/IVA laryngeal, hypopharyngeal, or oral cavity disease independent of p16 status. Other key inclusion criteria comprised an ECOG performance status of 0 or 1 and eligibility for primary surgery.
Patients were randomly assigned 1:1 between the 2 arms. In the experimental group, pembrolizumab was administered at 200 mg every 3 weeks for 2 cycles in the neoadjuvant setting, followed by adjuvant pembrolizumab at 200 mg once every 3 weeks for 15 cycles plus standard-of-care radiotherapy.1 Those classified as high risk also received adjuvant cisplatin at 100 mg/m2 once every 3 weeks for 3 cycles. In the control arm, patients received adjuvant radiotherapy with or without cisplatin on the same schedule.
EFS served as the trial’s primary end point. Secondary end points included overall survival, major pathological response rate, pathological complete response rate, and safety.
What safety data were reported for the pembrolizumab combination?
Data also published in the New England Journal of Medicine showed that treatment-related adverse effects (TRAEs) of any grade occurred in 81.4% of patients in the pembrolizumab arm (n = 361) vs 81.9% of patients in the control arm (n = 315).3 The rates of grade 3 or higher TRAEs were 44.6% and 42.9%, respectively. The respective rates of serious TRAEs were 19.1% and 10.5%.
TRAEs led to treatment discontinuation in 17.7% of patients in the pembrolizumab group compared with 12.4% of patients in the control group. TRAEs led to death in 1.1% of patients in the pembrolizumab arm vs 0.3% in the control arm.
References
- European Commission approves Keytruda (pembrolizumab) as part of a treatment regimen for adults with resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC) expressing PD-L1 (CPS >1). News release. Merck. October 29, 2025. Accessed October 29, 2025. https://www.merck.com/news/european-commission-approves-keytruda-pembrolizumab-as-part-of-a-treatment-regimen-for-adults-with-resectable-locally-advanced-head-and-neck-squamous-cell-carcinoma-la-hnscc-expressing-pd-l1/
- FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. June 12, 2025. Accessed October 29, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-and-adjuvant-pembrolizumab-resectable-locally-advanced-head-and-neck
- Uppaluri R, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer. N Engl J Med. 2025;393(1):37-50. doi:10.1056/NEJMoa2415434
