Regulatory Decision Summary for Enhertu

Authorization was based on one multicentre, randomized, active-controlled phase 3 clinical trial U302 (DESTINY-Breast03). Study U302 compared Enhertu with trastuzumab emtansine (T-DM1) in adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who had received at least one prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. Eligible patients were randomized 1:1 to receive either Enhertu 5.4 mg/kg (n = 261) or T-DM1 3.6 mg/kg (n = 263) by intravenous infusion (IV) every 3 weeks (Q3W). Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The primary efficacy endpoint was progression-free survival (PFS) as assessed by a blinded independent central review (BICR) based on the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Overall survival (OS) was a key secondary endpoint.

The study met the primary efficacy endpoint and demonstrated a statistically significant improvement in PFS in the Enhertu arm compared to the T-DM1 arm. The hazard ratio (HR) was 0.28, corresponding to a 72% reduction in the risk of disease progression or death in patients receiving Enhertu compared to patients receiving T-DM1. The magnitude of the PFS improvement is clinically meaningful. OS was not mature with 12.6% and 20.2% of patients died in the Enhertu and T-DM1 arms, respectively, at the time of analysis.

The safety of Enhertu was evaluated in 257 patients with unresectable or metastatic HER2-positive BC in Study U302. The most common adverse reactions (frequency ≥20%) were nausea, fatigue, vomiting, neutropenia, alopecia, constipation, anemia, transaminases increased, musculoskeletal pain, leukopenia, decreased appetite, diarrhea, thrombocytopenia, headache, and abdominal pain. The most common serious adverse reactions (frequency >1%) were interstitial lung disease and vomiting. Fatalities due to adverse events occurred in 0.8% of patients including COVID-19 and sudden death (one patient each). The safety findings in U302 are generally consistent with the known safety profile of Enhertu, and the adverse reactions appeared manageable in most patients by close monitoring, symptomatic treatment, and modification of Enhertu treatment (e.g., dose interruption, reduction or discontinuation).

Unresectable or metastatic HER2-positive breast cancer after at least one prior anti-HER2-based regimen is serious, incurable disease. New effective therapies are needed for the management of the disease and to improve clinical outcomes. In this context, the benefit/risk ratio of Enhertu is considered positive. Key safety findings and related risk management recommendations are adequately described in the final Product Monograph (PM). An updated Risk Management Plan (RMP) for Enhertu was reviewed by the Marketed Health Products Directorate (MHPD) and considered acceptable.

The recommended dose of Enhertu is 5.4 mg/kg IV Q3W. View the PM for details.

Health Canada granted the priority review status to this submission.