AstraZeneca's (AZN) ENHERTU Granted Priority Review in the US for Patients with HER2 Positive Metastatic Breast Cancer Treated with a Prior Anti-HER2-Based Regimen

Daiichi Sankyo Company, Limited and AstraZeneca (Nasdaq: AZN) have received notification of acceptance by the U.S. Food and Drug Administration (FDA) of the supplemental Biologics License Application (sBLA) of ENHERTU® (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients in the U.S. with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen. The application has also been granted Priority Review.

ENHERTU is a HER2 directed antibody drug conjugate (ADC) being jointly developed 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 second quarter of the 2022 calendar year.

The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) program and Project Orbis, two initiatives of the FDA which are designed to bring 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.

Breast cancer is the most common cancer worldwide, with more than two million cases diagnosed in 2020, resulting in nearly 685,000 deaths globally.1 Approximately one in five cases of breast cancer are considered HER2 positive.2 Despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer will often experience disease progression.3 More treatment options are needed to further delay progression and extend survival.3,4,5

“This regulatory review of ENHERTU in the U.S. marks the first time this medicine is participating in both the Real-Time Oncology Review and Project Orbis programs,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “The FDA’s prioritization of our application underscores the potential of this medicine and the continued need to expedite the availability of new treatment options, while making it possible to potentially receive approvals in several countries concurrently.”

“This review across geographies and the priority review in the U.S. as part of Project Orbis is so important because it speaks to the transformative potential of ENHERTU based on the unprecedented progression-free survival benefit in this setting,” said Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca. “The news reinforces the importance of bringing this potential new option to patients as quickly as possible.”

The sBLA is based on data from the pivotal DESTINY-Breast03 phase 3 trial that were presented at the 2021 European Society for Medical Oncology (ESMO) Congress. In the trial, ENHERTU demonstrated a 72% reduction in the risk of disease progression or death compared to T-DM1 (hazard ratio [HR] = 0.28; 95% confidence interval [CI]: 0.22-0.37; p=7.8x10-22) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The median progression-free survival (PFS) for patients treated with ENHERTU was not reached (95% CI: 18.5-NE) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review (BICR). In the secondary endpoint analysis of PFS assessed by investigators, patients treated with ENHERTU experienced an improvement in PFS of 25.1 months (95% CI: 22.1-NE) compared to 7.2 months (95% CI: 6.8-8.3) for T-DM1 (HR=0.26; 95% CI: 0.20-0.35). There was a strong trend towards improved overall survival (OS) with ENHERTU (HR=0.56; 95% CI: 0.36-0.86; p=0.007172), however, this analysis is not yet mature and is not statistically significant. Nearly all patients treated with ENHERTU during the trial were alive at one year (94.1%; 95% CI: 90.3-96.4) compared to 85.9% of patients treated with T-DM1 (95% CI: 80.9-89.7). Confirmed objective response rate (ORR) was more than doubled in the ENHERTU arm versus the T-DM1 arm (79.7%; n=208; 95% CI: 74.3-84.4) versus 34.2% (n=90; 95% CI: 28.5-40.3; p<0.0001).

The safety profile of the most common adverse events with ENHERTU in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher drug-related treatment emergent adverse events in the ENHERTU arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in ALT (1.6%), decreased appetite (1.2%), increase in AST (0.8%), diarrhea (0.4%) and alopecia (0.4%). Overall, 10.5% of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (9.7%) were low grade (grade 1 (2.7%) or grade 2 (7.0%)) with two grade 3 (0.8%) events reported. No grade 4 or grade 5 ILD or pneumonitis events occurred.

In September 2021, ENHERTU received its fourth Breakthrough Therapy Designation (BTD) in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received one or more prior anti-HER2-based regimens.

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