Health Canada Approves Pembrolizumab/Surgery in Locally Advanced HNSCC

Results from the phase 3 KEYNOTE-689 trial supported the agency’s approval of the pembrolizumab/surgery regimen in PD-L1–positive head and neck cancer.

Health Canada has approved pembrolizumab (Keytruda) as a therapy for adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) as a monotherapy neoadjuvant treatment, then continued as adjuvant treatment in combination with radiotherapy with or without cisplatin, and then as monotherapy, according to a press release from the developer, Merck.1

In June 2025, the FDA approved pembrolizumab in the same indication for HNSCC.2

Supporting results for the approval came from the randomized, active-controlled, open-label phase 3 KEYNOTE-689 trial (NCT03765918) that compared the approved regimen with standard of care therapies in patients with locally advanced HNSCC.3

In the overall patient population, the median EFS was 51.8 months (95% CI, 37.5-not reached [NR]) in the experimental group vs 30.4 months (95% CI, 21.8-50.1) in the control group (HR, 0.73; 95% CI, 0.58-0.92; P = .008). The estimated 36-month EFS rate was 57.6% (95% CI, 51.5%-63.3%) vs 46.4% (95% CI, 40.0%-52.5%), respectively. Major pathologic responses occurred in 9.4% (95% CI, 6.6%-12.8%) of the experimental group and 0% (95% CI, 0.0-1.0) of the control group (P <.001); pathologic complete responses (pCRs) occurred in 3.0% (95% CI, 1.5%-5.4%) and 0.0% (95% CI, 0.0%-1.0%).

In those with a PD-L1 combined positive score (CPS) of 1 or higher, the median EFS was 59.7 months (95% CI, 37.9-NR) in the experimental group vs 29.6 months (95% CI, 19.5-41.9) in the control group (HR, 0.70; 95% CI, 0.55-0.89; P = .003). The estimated 36-month EFS rate was 58.2% (95% CI, 51.9%-64.0%) vs 44.9% (95% CI, 38.4%-51.2%), respectively. Major pathologic responses occurred in 9.8% (95% CI, 6.9%-13.3%) vs 0.0% (95% CI, 0.0-1.1) of the control group (P <.001); pCRs occurred in 3.2% (95% CI, 1.6%-5.6%) vs 0.0% (95% CI, 0.0%-1.1%).

In the group of patients with a CPS of 10 or higher, the median EFS was 59.7 months (95% CI, 51.1-not reached) in the experimental group vs 26.9 months (95% CI, 18.3-51.5) in the control group (HR, 0.66; 95% CI, 0.49-0.88; P = .004). The estimated 36-month EFS rate was 59.8% (95% CI, 52.3%-66.5%) vs 45.9% (95% CI, 38.0%-53.4%), respectively. Major pathologic responses occurred in 9.4% (95% CI, 6.6%-12.8%) vs 0.0% (95% CI, 0.0-1.1) of the control group (P <.001). Major pathologic responses occurred in 13.7% (95% CI, 9.5%-18.8%) vs 0.0% (95% CI, 0.0-1.6) of the control group (P <.001); pCRs occurred in 4.3% (95% CI, 2.1%-7.7%) and 0.0% (95% CI, 0.0%-1.6%).

"We know that head and neck squamous cell carcinomas present significant treatment challenges because of their complexity," stated André Galarneau, PhD, executive director and vice president of the Oncology Business Unit at Merck Canada.1 "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."

KEYNOTE-689 randomly assigned 714 patients to either the experimental group (n = 363) or the control group (n = 351). In the experimental group, patients were planned to receive 2 cycles of intravenous neoadjuvant pembrolizumab at 200 mg every 3 weeks, then radiotherapy at 2 Gy per fraction daily in 30 fractions for low-risk disease or concomitant chemoradiotherapy at 2 Gy in 33 fractions plus cisplatin at 100 mg/m2 every 3 weeks for 3 cycles for high-risk disease, then postoperative pembrolizumab at 200 mg every 3 weeks, with 3 cycles concomitant with radiotherapy or chemoradiotherapy starting on day 1 of radiotherapy, followed by 12 cycles on an adjuvant basis. In the standard of care arm, patients received no neoadjuvant treatment prior to surgery, and within 6 weeks of surgery, either radiation plus 3 cycles of cisplatin at 100 mg/m2 every 3 weeks for those with high-risk pathological features after surgery or radiation alone for patients without high-risk pathological features after surgery.

Eligible patients were 18 years or older with newly diagnosed, nonmetastatic, resectable, locally advanced HNSCC, and had an ECOG performance status of 0 or 1, were eligible for primary surgery, and provided tumor tissue for PD-L1 and human papillomavirus analysis.

The trial’s primary end point was EFS assessed by blinded independent central review (BICR) via RECIST v1.1, in patients with a PD-L1 CPS of 10 or higher, with a PD-L1 CPS of 1 or higher, and all patients. Key secondary end points were major pathologic response, pCR, overall survival, and safety.

Regarding safety, treatment-related adverse effects (TRAEs) occurred in 81.4% of the experimental group and 81.9% of the control group; grade 3 or higher TRAEs occurred in 44.6% and 42.9%. The most common grade 3 or higher TRAEs were stomatitis (11.6% vs 13.3%), radiation skin injury (4.2% vs 5.7%), and neutrophil count decreased (5.3% vs 11.7%). Treatment-related serious AEs occurred in 19.1% and 10.5%; serious AEs of any cause occurred in 49.6% and 39.8%, respectively.

TRAEs led to treatment discontinuation in 17.7% and 12.4%, and death due to an AE occurred in 1.1% and 0.3%.

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. August 13, 2025. Accessed August 15, 2025. https://tinyurl.com/bdh44ntu
2. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. News release. FDA. June 12, 2025. Accessed August 15, 2025. https://tinyurl.com/yt9p66xz
3. 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