AstraZeneca and Daiichi Sankyo’s Enhertu Receives FDA Priority Review for New Indication in HER2-Positive Metastatic Breast Cancer

On January 17, AstraZeneca and Daiichi Sankyo announced that they had received notification from the U.S. FDA accepting their supplemental Biologics License Application (sBLA) for Enhertu (trastuzumab deruxtecan), an antibody-drug conjugate (ADC), for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received anti-HER2 therapy. The sBLA has also been granted Priority Review, with a PDUFA date set for the second quarter of 2022.

Breast cancer is the most common cancer globally, with over 2 million confirmed cases in 2020, resulting in nearly 685,000 deaths worldwide. Approximately one in five breast cancer cases are considered HER2-positive. HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various types of tumors, including breast cancer. Overexpression of the HER2 protein may be the result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer. Despite initial treatment with trastuzumab and taxane drugs, patients with HER2-positive metastatic breast cancer often experience disease progression, necessitating additional treatment options to further delay progression and prolong survival.

This new indication sBLA is under review in the Real-Time Oncology Review (RTOR) program and the Orbis program. The RTOR program allows the U.S. FDA to review components of an application before the complete application is submitted, while the Orbis program provides a framework for participating international partners (including Japan, the European Union, and other countries/regions) to simultaneously submit and review oncology drugs. This sBLA is based on data from the pivotal Phase 3 trial DESTINY-Breast03, which was 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 the active comparator in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane (Hazard Ratio [HR]=0.28; 95% Confidence Interval [CI]: 0.22-0.37; p=7.8 x 10⁻²²). According to blinded independent central review (BICR), the median progression-free survival (PFS) was not reached in the Enhertu-treated group (95% CI: 18.5-NE), compared to 6.8 months (95% CI: 5.6-8.2) in the active comparator group. In the secondary endpoint analysis of investigator-assessed PFS, patients treated with Enhertu showed a PFS improvement of 25.1 months (95% CI: 22.1-NE), versus 7.2 months (95% CI: 6.8-8.3, HR=0.26; 95% CI: 0.20-0.35) in the active comparator group.

Enhertu Showed a Clear Trend of Improvement in Overall Survival (OS) (HR=0.56; 95%CI: 0.36-0.86; p=0.007172), but the Analysis is Not Yet Mature and Lacks Statistical Significance. At One Year, Nearly All Patients Treated with Enhertu Were Alive (94.1%; 95%CI: 90.3-96.4), Compared to 85.9% (95%CI: 80.9-89.7) for Those Receiving Active Comparator. The Confirmed Objective Response Rate (ORR) Was More Than Double in the Enhertu Group (79.7%; n=208; 95%CI: 74.3-84.4) Versus the Active Comparator Group (34.2%; n=90; 95%CI: 28.5-40.3; p<0.0001).

Ken Takeshita, MD, Global Head of R&D at Daiichi Sankyo, said: "This regulatory review of Enhertu in the United States marks the first time this medicine has been involved in both the Real-Time Oncology Review and the Orbis Project. The FDA's priority on our application underscores the potential of this drug and the ongoing need to accelerate the availability of new treatment options, potentially gaining approval in several countries simultaneously."

In March 2019, AstraZeneca and Daiichi-Sankyo reached a global collaboration to jointly develop and commercialize Enhertu. The drug is an ADC designed using Daiichi-Sankyo’s proprietary DXd ADC technology platform, consisting of a humanized monoclonal antibody targeting HER2 linked to a topoisomerase I inhibitor payload via a cleavable tetrapeptide linker. Enhertu has already received FDA approval as a third-line treatment for patients with HER2-positive unresectable or metastatic breast cancer who have been previously treated, as well as for patients with HER2-positive locally advanced or metastatic gastric cancer and gastroesophageal junction (GEJ) adenocarcinoma who have received trastuzumab-based therapy. In September 2021, Enhertu received its fourth Breakthrough Therapy Designation (BTD) in the United States for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received one or more anti-HER2 regimens.

References:

[1] ENHERTU® Granted Priority Review in the U.S. for Patients with HER2 Positive Metastatic Breast Cancer Treated with a Prior Anti-HER2-Based Regimen. Retrieved 2022-01-17, from https://www.businesswire.com/news/home/20220114005456/en

(Original text has been abridged)