Enhertu Approved by Health Canada as the First HER2-Directed Therapy for Patients with HER2-Low Metastatic Breast Cancer

On January 6, 2023, Health Canada approved Enhertu (trastuzumab deruxtecan) for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. Patients with hormone receptor positive (HR+) breast cancer should have received at least one and be no longer considered eligible for endocrine therapy.

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. The approval by Health Canada was based on the DESTINY-Breast04 Phase III trial results presented at the presidential plenary session of the 2022 American Society of Clinical Oncology (ASCO) Annual meeting and simultaneously published in The New England Journal of Medicine (NEJM).

“Since the approval of HER2-targeted therapies in breast cancer more than twenty years ago, only patients with HER2-positive disease have been eligible for these therapies – leaving those with tumours with lower levels of HER2 expression with limited effective treatment options,” said Dr. Jan-Willem Henning, Medical Oncologist, Tom Baker Cancer Centre, and Clinical Associate Professor, Cumming School of Medicine, University of Calgary. “The recent Health Canada approval of Enhertu in the HER2-low patient population is a significant milestone in the treatment of metastatic breast cancer, and is the first anti-HER2 molecule to demonstrate efficacy outside of traditional HER2-positive breast cancer. Based on the promising data from the DESTINY-Breast04 trial, we’re now able to differentiate levels of HER2 expression to redefine how we classify and treat metastatic breast cancer, providing additional patients with the opportunity to benefit from HER2-directed therapy.”

In Canada, 10 per cent of newly diagnosed breast cancers are metastatic, and for those initially diagnosed with early-stage breast cancer, approximately 30 per cent will progress to metastatic disease. HER2 expression is currently defined as either positive or negative, and is determined by an IHC test which estimates the amount of HER2 protein on a cancer cell, and/or an ISH test, which counts the copies of the HER2 gene in cancer cells.  However, approximately half of all breast cancers are HER2-low, and previously these patients had limited effective treatment options following progression on endocrine (hormone) therapy.

“A diagnosis of metastatic breast cancer is often accompanied by a fear of running out of options. This is especially true for those with HER2-low metastatic breast cancer, as available treatments have been limited – and targeted options non-existent for them,” said MJ DeCoteau, Founder and Executive Director, Rethink Breast Cancer. “The ability to now identify patients that are HER2-low and provide them with an effective and targeted treatment option is significant, and we hope that patients will be able to access this treatment without uncertainty or delay.”

In the DESTINY-Breast04 Phase III trial, Enhertu has shown to reduce the risk of disease progression or death by 49 per cent versus physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer with hormone receptor (HR)-positive disease, with a median progression-free survival (PFS) per blinded independent central review (BICR) of 10.1 months (95% confidence interval [CI]9.5, 11.5) for Enhertu versus 5.4 months (95% CI 4.4, 7.1) for those treated with chemotherapy (hazard ratio 0.51; 95% CI 0.40-0.64; p<0.0001). A median overall survival (OS) of 23.9 months (95% CI 20.8, 24.8) was seen in patients randomized to Enhertu versus 17.5 months (95% CI 15.2, 22.4) in those randomized to chemotherapy, a 36 per cent reduction in the risk of death (hazard ratio 0.64; 95% CI 0.48-0.86; p=0.0028).¹ 

In the overall population of patients with HER2-low metastatic breast cancer with HR-positive or HR-negative disease, Enhertu has shown to reduce the risk of disease progression or death by 50 per cent versus physician’s choice of chemotherapy, with a median PFS per BICR of 9.9 months (95% CI 9.0, 11.3) for Enhertu versus 5.1 months (95% CI 4.2, 6.8) in those treated with chemotherapy (hazard ratio 0.50; 95% CI 0.40-0.63; p<0.0001). A median OS of 23.4 months (95% CI 20.0, 24.8) was seen in patients randomized to Enhertu versus 16.8 months (95% CI 14.5, 20.0) in those randomized to chemotherapy, a 36 per cent reduction in the risk of death (hazard ratio 0.64; 95% CI 0.49-0.84; p=0.0010).¹

“The approval of Enhertu as the first HER2-targeted treatment approved in the HER2-low patient population is an important advancement for Canadian women impacted by this form of  breast cancer,” said Cathy Ammendolea, Chair of the Board, Canadian Breast Cancer Network. “We’re thrilled to see a new option available that will provide patients with a renewed sense of hope to live full and longer lives with their loved ones.”

The review and approval of Enhertu for this indication was conducted by Health Canada under the Priority Review and Project Orbis FDA collaboration pathways in seven months from filing, enabling the timely availability to bring this new treatment option to HER2-low breast cancer patients as quickly as possible.