AstraZeneca and Daiichi Sankyo have received notification of acceptance of the supplemental Biologics License Application (sBLA) of Enhertu (trastuzumab deruxtecan) for the treatment of adult patients in the US with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [ISH]-negative) breast cancer who have received a prior therapy in the metastatic setting. The application has been granted Priority Review.
Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.
The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is during the fourth quarter of 2022.
The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) programme and Project Orbis, two initiatives of the FDA which are designed to bring safe and effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines among participating international partners.
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “The data from DESTINY-Breast04 represent the first time a HER2-targeted therapy has shown a survival benefit in patients with HER2-low metastatic breast cancer. For more than two decades, only patients with HER2-positive breast cancer have been able to benefit from HER2-targeted therapies. If approved, Enhertu will redefine how we classify and treat metastatic breast cancer, enabling patients whose tumours have lower levels of HER2 expression the opportunity to benefit from a HER2-directed therapy.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: “The results seen in the DESTINY-Breast04 trial represent a significant advance and reinforce the potential for Enhertu to become a new standard of care for patients with previously treated HER2-low metastatic breast cancer. The prioritisation of this application by the FDA and inclusion in both the Real-Time Oncology Review and Project Orbis initiatives support the importance of these data, and we look forward to working with the FDA to potentially bring Enhertu to patients with HER2-low metastatic breast cancer as quickly as possible.”
The sBLA is based on data from the Phase III trial that were presented at the presidential plenary session of the 2022 American Society of Clinical Oncology Annual Meeting and simultaneously published in .1
In the trial, Enhertu demonstrated superior and clinically meaningful efficacy in progression-free survival (PFS) and overall survival (OS) in previously treated patients with HER2-low metastatic breast cancer with hormone receptor (HR)-positive or HR-negative disease versus standard of care physician’s choice of chemotherapy.
The safety profile of Enhertu was consistent with previous clinical trials with no new safety concerns identified. Interstitial lung disease or pneumonitis rates were consistent with that observed in late-line HER2-positive breast cancer trials of Enhertu, as determined by an independent adjudication committee. The majority (10%) were primarily low Grade (Grade 1 or 2) with five Grade 3 (1.3%), no Grade 4 and three Grade 5 (0.8%) events reported.
This Priority Review follows receipt of (BTD) in the US in April 2022 in metastatic HER2-low breast cancer, the fifth BTD in the US for Enhertu.
Regulatory reviews for Enhertu in the HER2-low patient population are also underway in the European Union (EU) and Japan, and Enhertu is already approved in the US, the EU and many other countries across the globe for patients with previously treated HER2-positive (IHC 3+ or IHC 2+/ISH-positive) metastatic breast cancer.
Notes
Breast cancer and HER2 expression
Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide and in the US.2,3 More than two million cases of breast cancer were diagnosed in 2020 resulting in nearly 685,000 deaths globally.2 In the US, more than 290,000 new cases are expected to be diagnosed in 2022, resulting in more than 43,000 deaths.4
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumours.5 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.5,6
HER2-positive cancers are defined as IHC 3+, IHC 2+/ISH+, and HER2-negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.5 Approximately half of all patients with breast cancer have tumours with low HER2 expression, with a HER2 IHC score of 1+, or a HER2 IHC score of 2+ in combination with a negative ISH test, an expression level not currently eligible for HER2-targeted therapy.7-10Low HER2 expression occurs in both HR-positive and HR-negative disease.11
DESTINY-Breast04
DESTINY-Breast04 is a global, randomised, 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 and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomised 2:1 to receive either Enhertu or chemotherapy.
The primary endpoint of DESTINY-Breast04 is PFS in patients with HR-positive disease based on blinded independent central review (BICR). Key secondary endpoints include PFS based on BICR in all randomised patients (HR-positive and HR-negative disease), OS in patients with HR-positive disease and OS in all randomised patients (HR-positive and HR-negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety.
