Regulatory Decision Summary for Keytruda

The purpose of this Supplement to a New Drug Submission (SNDS) was to seek market authorization for Keytruda (pembrolizumab) for the treatment of adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC).

After evaluation of the submitted data package, Health Canada authorized Keytruda for the treatment of adult patients with resectable locally advanced HNSCC whose tumours express PD-L1 (Combined Positive Score [CPS] ≥ 1), as determined by a validated test, as neoadjuvant treatment as monotherapy, continued as adjuvant treatment in combination with radiotherapy (RT) with or without cisplatin and then as monotherapy.

This SNDS was filed as part of Project Orbis.

Authorization was based on the results of KEYNOTE-689, a phase 3, randomized, open-label trial investigating the use of Keytruda in adult patients with resectable locally advanced head and neck squamous cell carcinoma (HNSCC) (N = 714). Patients were randomized (1:1) to one of the following treatment regimens:

• Neoadjuvant Keytruda (200 mg every 3 weeks) for 2 cycles prior to surgical resection, followed by adjuvant Keytruda (200 mg every 3 weeks) for 3 cycles in combination with either radiation plus cisplatin for patients with high-risk pathological features after surgery or radiation alone for patients without high-risk pathological features after surgery, followed by Keytruda (200 mg every 3 weeks) for up to 12 cycles.

• No neoadjuvant treatment prior to surgery, followed by adjuvant radiation plus 3 cycles of cisplatin for patients with high risk pathological features after surgery or radiation alone for patients without high-risk pathological features after surgery.

High risk pathological features were defined as the presence of positive margins or extranodal extension following surgical resection.

The primary efficacy endpoint was Event Free Survival (EFS) assessed by blinded independent central review. The study demonstrated a statistically significant and clinically meaningful improvement in EFS in the Keytruda treatment arm compared to the control arm for patients whose tumours express PD-L1 with a Combined Positive Score (CPS) ≥ 1 (N = 682). The EFS hazard ratio was 0.70 (95% confidence interval: 0.55, 0.89), representing a 30% reduction in the risk of disease progression that precludes surgery, local or distant disease progression or recurrence, or death due to any cause. The median EFS was 59.7 months in the Keytruda treatment arm compared to 29.6 months in the control arm.

The safety profile of Keytruda was consistent with the known safety profiles of Keytruda and the components of the treatment regimen. The most common treatment-related adverse events (reported in at least 20% of patients) included radiation skin injury and stomatitis. No new safety signals were identified. The safety findings and risk mitigation measures are described in the Keytruda Product Monograph.

Overall, the benefit-risk is positive for the recommended indication. The safety profile is considered acceptable in the context of the prognosis of the patient population and when used according to the instructions in the Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

The recommended dose of Keytruda is either 200 mg every 3 weeks or 400 mg every 6 weeks. For neoadjuvant treatment, Keytruda is administered as monotherapy for 2 doses of 200 mg every 3 weeks or 1 dose of 400 mg every 6 weeks or until disease progression that precludes definitive surgery or unacceptable toxicity. For adjuvant treatment, Keytruda is administered in combination with radiation with or without cisplatin for 3 doses of 200 mg every 3 weeks or 2 doses of 400 mg every 6 weeks followed by 12 doses of Keytruda as monotherapy at 200 mg every 3 weeks or 6 doses of 400 mg every 6 weeks or until disease recurrence or unacceptable toxicity.

Health Canada granted priority review status to this submission.

An updated Risk Management Plan (RMP) for Keytruda was reviewed by Health Canada and considered acceptable. 

The labelling information met all applicable regulations and guidance.

For further details about Keytruda, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.