Neoadjuvant Pembrolizumab/Radiotherapy Earns EU Approval in HNSCC Group

The European Commission has approved pembrolizumab (Keytruda) monotherapy as neoadjuvant treatment, continued as adjuvant treatment in combination with radiation therapy with or without concomitant cisplatin, then as monotherapy in patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) with a PD-L1 combined positive score (CPS) of 1 or higher.¹

The developer, Merck, highlighted that this is the first and only anti–PD-1 treatment option for patients with resectable locally advanced HNSCC in the European Union (EU).

Previously, in September 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended the regimen for approval.² Additionally, in June 2025, the treatment regimen was approved by the FDA.³

The approval was supported by results from the phase 3 KEYNOTE-689 trial (NCT03765918), which evaluated the pembrolizumab regimen compared with radiotherapy with or without cisplatin given after surgery alone. Results from the trial were published in the New England Journal of Medicine in June 2025.⁴

At the first pre-specified interim analysis, with a median follow-up of 38.3 months (range, 9.0-66.5) in the population of patients with a CPS of 1 or higher, the median event-free survival (EFS) was 59.7 months (95% CI, 37.9-not reached [NR]) with the approved pembrolizumab regimen vs 29.6 months (95% CI, 19.5-41.9) in the control arm (HR, 0.70; 95% CI, 0.55-0.89; P = .003). The estimated 3-year EFS rates were 58.2% (95% CI, 51.9%-64.0%) and 44.9% (95% CI, 38.4%-51.2%), respectively.

A major pathological response per blinded independent pathological review was observed in 34 patients with a CPS of 1 or higher, with an estimated rate difference vs the control arm of 9.8% (95% CI, 7.0%-13.3%; P <.001); 11 patients experienced a pathological complete response (pCR), with an estimated rate difference of 3.1% (95% CI, 1.6%-5.6%).

The estimated 3-year overall survival (OS) rate was 69.0% (95% CI, 63.3%-74.0%) in the pembrolizumab group vs 60.2% (95% CI, 54.1%-65.8%) in the control group (HR, 0.72; 95% CI, 0.56-0.94).

“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, said in the press release.¹ “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.”

For the population of patients with a CPS of 1 or higher, KEYNOTE-689 enrolled 347 patients in the pembrolizumab arm and 335 patients in the control arm. To be enrolled, patients had to be 18 years or older with newly diagnosed, nonmetastatic, resectable locally advanced HNSCC with stage III oropharyngeal p16-positive disease and node stage N0 to N2; stage III or IVA oropharyngeal p16-negative disease; or stage III or IVA hypopharyngeal, laryngeal, or oral cavity disease independent of p16 status. Patients also had an ECOG performance status of 0 or 1.

Treatment in the experimental arm consisted of neoadjuvant therapy with intravenous (IV) pembrolizumab at 200 mg every 3 weeks for 2 cycles, followed by adjuvant therapy after surgery with IV pembrolizumab at 200 mg every 3 weeks for 15 cycles plus standard-of-care radiotherapy with IV cisplatin at 100 mg/m² every 3 weeks for 3 cycles for high-risk patients, or without cisplatin for low-risk patients. In the control arm, patients received no neoadjuvant therapy prior to surgery, then standard-of-care radiotherapy with IV cisplatin at 100 mg/m² every 3 weeks for 3 cycles as adjuvant therapy for high-risk patients, or without cisplatin for low-risk patients.

The primary end point of the trial was EFS. Secondary end points were major pathological response, pCR, and safety.

Regarding safety, any-grade treatment-related adverse events (TRAEs) occurred in 81.4% of the pembrolizumab group vs 81.9% of the control group; grade 3 or higher TRAEs occurred in 44.6% vs 42.9%. In the pembrolizumab and control arms, the most common any-grade TRAEs were radiation skin injury (39.3% vs 47.0%), stomatitis (38.8% vs 52.1%), hypothyroidism (19.4% vs 1.9%), and fatigue (18.0% vs 13.0%).

Serious AEs occurred in 19.1% of the pembrolizumab arm vs 10.5% of the control arm, treatment was discontinued due to an AE by 17.7% vs 12.4%, and death due to an AE occurred in 1.1% and 0.3%.

References

1. 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://tinyurl.com/4uee5kdr
2. Merck receives two positive EU CHMP opinions for KEYTRUDA® (pembrolizumab), for subcutaneous (SC) administration and for new indication for earlier-stage head and neck cancer. News release. Merck. September 19, 2025. Accessed October 29, 2025. https://tinyurl.com/mraxhjyc
3. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. News release. FDA. June 12, 2025. Accessed October 29, 2025. https://tinyurl.com/yt9p66xz
4. 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