Health Canada Authorizes Perioperative Pembrolizumab in Resectable, Locally Advanced HNSCC

Health Canada has approved pembrolizumab (Keytruda) as neoadjuvant therapy, followed by its use as adjuvant therapy in combination with radiotherapy with or without cisplatin, and then continued as monotherapy, for the treatment of adult patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) whose tumors express a PD-L1 combined positive score (CPS) of 1 or greater, as determined by a validated test.1

The new Canadian indication was based on data from the phase 3 KEYNOTE-689 trial (NCT03765918) in which treatment with the perioperative pembrolizumab regimen led to a median event-free survival (EFS) of 59.7 months (95% CI, 37.9-not reached) vs 29.6 months (95% CI, 19.5-41.9) with adjuvant radiotherapy with or without cisplatin in patients with resectable locally advanced HNSCC whose tumors express PD-L1 (CPS ≥1; HR, 0.70; 95% CI, 0.55-0.89; P = .0014).

“We know that head and neck squamous cell carcinomas present significant treatment challenges because of their complexity,” André Galarneau, PhD, executive director and vice president of the Oncology Business Unit at Merck Canada, stated in a news release. “The introduction of a perioperative anti–PD-1 treatment option for eligible patients in Canada represents an important development with the potential to make a meaningful difference for patients and their families impacted by this disease.”

In June 2025, the FDA approved the regimen in the same indication based on data from KEYNOTE-689.2 Findings from the first interim analysis of the trial were presented at the 2025 AACR Annual Meeting.3

KEYNOTE-689 was a multicenter, open-label, active-controlled trial that enrolled 714 patients with stage III to IVA HNSCC.1 Patients were randomly assigned 1:1 to the investigational or active-controlled arms. In the investigational arm, patients received 2 cycles of preoperative pembrolizumab every 3 weeks (Q3W), followed by 3 cycles of adjuvant pembrolizumab within 6 weeks of surgery in combination with radiation with or without 3 cycles of cisplatin for those with and without high-risk pathological features, respectively, and as monotherapy for up to 12 weeks thereafter. Patients in the active-controlled arm proceeded straight to surgery, receiving radiation with or without the same dose and schedule of cisplatin no more than 6 weeks thereafter.

Pembrolizumab was administered at a dose of 200 mg and cisplatin was administered at a dose of 100 mg/m2 Q3W for patients with high-risk pathological features. High-risk pathological features were defined by the presence of positive margins or extranodal extension after surgical resection.

Treatment with pembrolizumab was continued for up to the 17 intended cycles, unacceptable toxicity, or evidence of disease progression that prevented definitive surgery, disease recurrence in the adjuvant setting, or disease progression in patients who did not undergo surgery or who had incomplete resection and entered the adjuvant setting.

Patients were stratified according to primary tumor site (oropharynx/oral cavity vs larynx vs hypopharynx), tumor stage (III vs IVA) and PD-L1 status (tumor proportion score [TPS] ≥ 50% vs TPS < 50%).

The primary end point was EFS by blinded independent central review. Secondary end points included major pathologic response, overall survival, pathological complete response, changes from baseline global health status/quality of life scores, and safety.4

With respect to safety, the most frequent treatment-related adverse effects that occurred in at least 20% of patients who received pembrolizumab in KEYNOTE-689 were radiation skin injury and stomatitis.1 The most common grade 3 to 5 TRAEs that occurred in at least 5% of patients were stomatitis (11.6%), decreased lymphocyte count (5.5%), and decreased neutrophil count (5.3%).

References

1. Health Canada approves Keytruda for patients with resectable locally advanced head & neck squamous cell carcinoma tumours that are PD-L1 (CPS) positive as neoadjuvant treatment, continued as adjuvant treatment combined with radiotherapy with or without cisplatin then as monotherapy. News release. Merck. August 13, 2025. Accessed August 13, 2025. https://www.biospace.com/press-releases/health-canada-approves-keytruda-for-patients-with-resectable-locally-advanced-head-neck-squamous-cell-carcinoma-tumours-that-are-pd-l1-cps-positive-as-neoadjuvant-treatment-continued-as-adjuvant-treatment-combined-with-radiotherapy-with-or-without-cisplatin-then-as-monotherapy
2. FDA approves Keytruda (pembrolizumab) for PD-L1+ resectable locally advanced head & neck squamous cell carcinoma as neoadjuvant treatment, continued as adjuvant treatment combined with radiotherapy with or without cisplatin then as a single agent. News release. Merck. June 13, 2025. Accessed August 13, 2025. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-pd-l1-resectable-locally-advanced-head-neck-squamous-cell-carcinoma-as-neoadjuvant-treatment-continued-as-adjuvant-treatment-combined-with-radiother/
3. Uppaluri R, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab plus standard of care (SOC) in resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): phase 3 KEYNOTE-689 study. Cancer Res. 2025;85(suppl 2):CT001. doi:10.1158/1538-7445.AM2025-CT001
4. 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 February 7, 2025. Accessed August 13, 2025. https://clinicaltrials.gov/study/NCT03765918