Regulatory Decision Summary for Keytruda

Authorization was based on one international, multicentre, randomized, double-blind, placebo-controlled clinical trial, KEYNOTE-522. Patients (n=1174) with high-risk, early-stage triple-negative breast cancer (TNBC) received either Keytruda (n=669) or placebo (n=333) in combination with chemotherapy (containing carboplatin, paclitaxel, doxorubicin or epirubicin, and cyclophosphamide) as neoadjuvant treatment and then as monotherapy as adjuvant treatment following surgery. Treatment with Keytruda (200 mg every 3 weeks) or placebo continued for 17 cycles, or until disease recurrence or unacceptable toxicity. The co-primary efficacy endpoints were event-free survival (EFS) and pathological complete response (pCR) rate. Overall survival (OS) was a key secondary endpoint.

The study demonstrated a statistically significant improvement in EFS in the Keytruda group compared to the placebo group (hazard ratio [HR] 0.63, 95% confidence interval [CI]: 0.48. 0.82), representing a 37% reduction in the risk of disease progression that precludes definitive surgery, local or distant disease recurrence, second primary malignancy, or death due to any cause. The magnitude of EFS improvement in the Keytruda group is clinically meaningful. The pCR rate was statistically higher in the Keytruda group than in the placebo group with a difference of 13.6% (95% CI: 5.4, 21.8). The pCR result supports the EFS result. OS data were immature, and there was not a detrimental effect on OS in the Keytruda group.

The safety profile of Keytruda in combination with the chemotherapy neoadjuvant regimen and then as monotherapy as adjuvant treatment is generally consistent with the known safety profiles of Keytruda and the chemotherapy agents. Almost all patients experienced at least one treatment-related adverse event. Treatment-related adverse events in ≥ 20% of patients in the Keytruda group were nausea, alopecia, anemia, neutropenia, fatigue, diarrhea, alanine aminotransferase increased, vomiting, asthenia, rash, constipation, neutrophil count decreased, aspartate aminotransferase increased, neuropathy peripheral, and decreased appetite. Treatment-related serious adverse events occurred in 34% of patients in the Keytruda group and 20% of patients in the placebo group. Treatment-related serious adverse events in ≥ 2% of patients in the Keytruda group included febrile neutropenia (14.7%), pyrexia (2.6%), and anemia (2.4%). Fatal adverse events were reported in 7 patients (0.9%) and 1 patient (0.3%) in the Keytruda and placebo groups, respectively.

Patients with high-risk, early-stage TNBC require new options of neoadjuvant and adjuvant treatment to reduce the risk of disease recurrence (including metastasis) following definitive surgery and improve prognosis. In this context, the benefit of Keytruda in combination with chemotherapy as neoadjuvant treatment and then as monotherapy as adjuvant treatment after surgery is considered to outweigh its associated risk for adult patients with high-risk, early-stage TNBC. Key safety findings and related risk management recommendations are adequately described in the Product Monograph (PM). An updated Risk Management Plan (RMP) for Keytruda was reviewed by the Health Canada and considered acceptable.

The recommended dose of Keytruda is 200 mg every 3 weeks or 400 mg every 6 weeks. View the PM for details.

Health Canada granted the priority review status to this submission.