Regulatory Decision Summary for Enhertu

Authorization was based on one multicentre, randomized, active-controlled phase 3 clinical trial. The study compared Enhertu with a treatment of physician’s choice (TPC; single agent eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel) in adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low breast cancer who had received at least one prior line of chemotherapy in the metastatic setting, or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

Eligible patients were randomized 2:1 to receive either Enhertu 5.4 mg/kg (n=373) by intravenous infusion (IV) once every 3 weeks (Q3W) or a TPC. Treatment was administered until disease progression or unacceptable toxicity.

The major efficacy measures were progression-free survival (PFS) and overall survival (OS). The study demonstrated a statistically significant, clinically meaningful improvement in both PFS and OS in the Enhertu arm compared to the TPC arm. In all randomized patients, the median PFS was longer in the Enhertu arm vs. the TPC arm (9.9 months vs. 5.1 months), with a hazard ratio [HR] of 0.5 which corresponds to a 50% reduction in the risk of disease progression or death. The median OS was also longer in the Enhertu arm vs. the TPC arm (23.4 months vs. 16.8 months), with an HR of 0.64 which corresponds to a 36% reduction in the risk of death.

The safety of Enhertu was evaluated in 371 patients with unresectable or metastatic HER2-low BC treated with Enhertu. The most common adverse reactions (frequency ≥10%) were nausea, fatigue, alopecia, vomiting, neutropenia, anemia, decreased appetite, thrombocytopenia, respiratory infections, transaminases increased, leukopenia, diarrhea, constipation, weight decreased, abdominal pain, interstitial lung disease (ILD), stomatitis, and musculoskeletal pain. The most common serious adverse reactions (frequency ≥ 1%) were ILD, dyspnea, musculoskeletal pain, anemia, febrile neutropenia, nausea, pyrexia, and vomiting. There were 5 (1.3%) patients with adverse reactions leading to death, 3 attributed to ILD (0.8%) and 1 (0.3%) each for dyspnea and febrile neutropenia. The risk of ILD was higher in the subgroup of patients with moderate renal impairment at baseline. In general, the safety findings were consistent with the known safety profile of Enhertu, and the adverse reactions appeared to be manageable in most patients by close monitoring, symptomatic treatment, and modification of Enhertu dosage (e.g., dose interruption, reduction or discontinuation).

Unresectable or metastatic HER2-low BC after at least one prior line of chemotherapy is serious, incurable disease. New effective therapies are needed to improve the clinical outcome. 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) including the Patient Medication Information. An updated Risk Management Plan for Enhertu was reviewed by the Marketed Health Products Directorate 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.

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