25 July 2022 - - Japanese pharmaceutical company Daiichi Sankyo (TSX: 4568) and British-Swedish multinational pharmaceutical and biotechnology company AstraZeneca (LSE: AZN) (STO: AZN) (NASDAQ: AZN) have received notification of acceptance by the US Food and Drug Administration of the supplemental Biologics License Application of Enhertu (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients with unresectable or metastatic HER2 low (immunohistochemistry 1+ or IHC 2+/in-situ hybridization -negative) breast cancer who have received a prior therapy in the metastatic setting, the companies said.

The application has been granted Priority Review.

Enhertu is a specifically engineered HER2 directed antibody drug conjugate being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.

The 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 (PDUFA), the FDA action date for their regulatory decision, is during the fourth quarter of the 2022 calendar year.

The Priority Review follows receipt of Breakthrough Therapy Designation, granted by the FDA in April 2022 for Enhertu in metastatic HER2 low breast cancer.

The sBLA is being reviewed under the Real-Time Oncology Review program 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.

The sBLA is based on data from the DESTINY-Breast04 phase 3 trial recently presented at the presidential plenary session of the American Society of Clinical Oncology (#ASCO22) annual meeting and simultaneously published in The New England Journal of Medicine.

In DESTINY-Breast04, Enhertu demonstrated superior and clinically meaningful efficacy in progression-free survival and overall survival in previously treated patients with HER2 low unresectable and/or metastatic breast cancer with hormone receptor 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 those observed in other late-line HER2 positive breast cancer trials of Enhertu, as determined by an independent adjudication committee.

DESTINY-Breast04 is a global, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of Enhertu (5.4 mg/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 randomized 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. 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 PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety. DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and North America.

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.

More than two m cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.

In the US, more than 290,000 new cases are expected to be diagnosed in 2022, with more than 43,000 deaths.

Approximately one in five cases of breast cancer are considered HER2 positive.

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumors.

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.

HER2 positive cancers are defined as IHC 3+, IHC 2+/ISH+.4 HER2 negative cancers are currently defined as IHC 0, IHC 1+ or IHC 2+/ISH-.

Approximately half of all patients with breast cancer have tumors 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.

Low HER2 expression occurs in both HR positive and HR negative disease.

HER2 testing is routinely used to determine appropriate treatment options for patients with metastatic breast cancer.

Targeting the lower range of expression in the HER2 spectrum may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.

Currently, patients with low HER2 expression with HR positive tumors have limited treatment options following progression on endocrine (hormone) therapy.

Few targeted options are available for those who are HR negative.

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US only) is a HER2 directed ADC.

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 (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy, based on results from the DESTINY-Breast03 trial.

Enhertu also is approved in several countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

Enhertu (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

A global development program is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers.

Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

Regulatory applications for Enhertu are currently under review in China, Japan and several other countries for the treatment of adult patients with HER2 positive unresectable or metastatic breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

Enhertu is under review in Europe and Japan for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy, based on the results from the DESTINY-Breast04 trial.

Patients with HR positive breast cancer must additionally have received or be ineligible for endocrine therapy.

Enhertu also is currently under review in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy based on the results from the DESTINY-Lung01 trial, and in Europe for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2-based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

Daiichi Sankyo company, Ltd. (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.