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

Approval based on the DESTINY-Breast04 results which showed Enhertu reduced risk of disease progression or death by 50 per cent and increased overall survival by more than six months versus chemotherapy¹

MISSISSAUGA, ON, Jan. 12, 2023 /CNW/ - 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.¹ 

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).²

"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.³ 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.^4,5  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.^6,7

"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. 

About DESTINY-Breast04
DESTINY-Breast04 is a global, randomized, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) versus physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive or HR-negative, HER2-low unresectable or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either Enhertu or chemotherapy.¹ 

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on BICR. Key secondary endpoints include PFS based on BICR in all randomized patients (HR-positive and HR-negative disease), OS in patients with HR-positive disease and OS in all randomized patients (HR-positive and HR-negative disease). Other secondary endpoints include objective response rate based on BICR, and duration of response based on BICR and safety.¹ 

The safety profile of Enhertu was consistent with previous clinical trials with no new safety concerns identified. The most common adverse reactions (frequency ≥20%) were nausea, fatigue, vomiting, alopecia, anemia, constipation, neutropenia, transaminases increased, decreased appetite, diarrhea, musculoskeletal pain, thrombocytopenia, and leukopenia. The most common serious adverse reactions (frequency >1%) were ILD/pneumonitis, dyspnea, musculoskeletal pain, anemia, febrile neutropenia, nausea, pyrexia, and vomiting. Interstitial lung disease (ILD) or pneumonitis rates were consistent with those observed in late-line HER2-positive breast cancer trials of Enhertu. 12.1 per cent of patients had confirmed ILD or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events in the Enhertu arm were Grade 1 (3.5%) or 2 (6.5%), with five Grade 3 (1.3%) events reported. No Grade 4 events were reported in the Enhertu arm. There were three (0.8%) ILD-related deaths (Grade 5).¹ 

DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and North America.

About Enhertu
Enhertu (trastuzumab deruxtecan) is a HER2-directed antibody-drug conjugate. Designed using Daiichi Sankyo's proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca's ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker. Enhertu was first approved in Canada in 2021 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior treatment with trastuzumab emtansine based on the results from the DESTINY-Breast01 trial. In June 2022, Enhertu was approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have 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 six months of completing neoadjuvant or adjuvant therapy.  

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialize Enhertu in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

About AstraZeneca 
AstraZeneca is a global, innovation-driven biopharmaceutical business with a focus on the discovery, development, and commercialization of medicines that transform lives. Our core scientific focus is in the areas of Cardiovascular, Renal and Metabolic (CVRM) disease; Oncology; Rare Disease; Respiratory & Immunology; and Vaccine & Immune Therapies. AstraZeneca operates in more than 100 countries and its innovative medicines are used by millions of patients worldwide. In Canada, the company employs more than 1,200 people across Canada, including roughly 700 employees at our head office and clinical research hub in Mississauga, Ontario. For more information, please visit the company's website at www.astrazeneca.ca.

About Daiichi Sankyo
Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose "to contribute to the enrichment of quality of life around the world." In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an "Innovative Global Healthcare Company Contributing to the Sustainable Development of Society." For more information, please visit www.daiichi-sankyo.eu.

References

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1	Enhertu Product Monograph, January 6, 2023.
2	Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022; 387:9-20. Available at: https://www.nejm.org/doi/10.1056/NEJMoa2203690?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed Accessed October 5, 2022.
3	Canadian Breast Cancer Network. Metastatic Breast Cancer in Canada Infographic. Available at: https://www.cbcn.ca/en/metastatic_infographic  Accessed October 11, 2022.
4	Iqbal N, et al. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;852748.
5	Wolff A, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018;142(11):1364-1382.
6	Schettini F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. npj Breast Cancer. 2021; 7:1; https://doi.org/10.1038/s41523-020-00208-2.
7	Matutino A, et al. Current Oncology. Hormone receptor-positive, HER2-negative metastatic breast cancer: redrawing the lines. 2018; 25(S1):S131-S141.

SOURCE AstraZeneca

Vanessa Principe, AstraZeneca Canada, Email: [email protected]; Simone Jendsch-Dowé, Daiichi Sankyo Pharma Canada Ltd., Email: [email protected]