FDA Grants Priority Review to AstraZeneca and Daiichi Sankyo's Enhertu for HER2+ Solid Tumors

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The FDA has granted Priority Review to a supplemental Biologics License Application (sBLA) from AstraZeneca and Daiichi Sankyo's for Enhertu (trastuzumab deruxtecan [DXd]) to treat adults with previously treated unresectable or metastatic human epidermal growth factor 2 (HER2)-positive (immunohistochemistry [IHC] 3+) solid tumors with no satisfactory alternative therapeutic options.¹ Enhertu is a HER2-directed antibody-drug conjugate (ADC) with approved indications in breast cancer, non-small cell lung cancer (NSCLC), and gastroesophageal junction (GEJ) adenocarcinoma.

“Today’s Priority Review for the first tumor-agnostic submission for Enhertu reflects the potential of this medicine to redefine the treatment of HER2-expressing cancers,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in a press release. “Biomarkers for HER2 expression are already established in breast and gastric cancers, but we must now define them across tumor types. We will continue working closely with the FDA to bring this potential first tumor-agnostic HER2-targeted medicine and biomarker to patients as quickly as possible.”¹

Enhertu’s mechanism of action involves the humanized anti-HER2 IgG1 antibody trastuzumab attaching by a cleavable linker to the small molecule DXd. Trastuzumab then attaches to HER2 on tumor cells to halt growth, which causes the antibody to be internalized as lysosomal enzymes cleave off DXd. Subsequently, DXd causes DNA damage as it replicates and apoptotic cell death as a topoisomerase I inhibitor.^2,3

The Priority Revew designation was granted based on findings from the ongoing, global, multicenter, multi-cohort, open-label Phase II DESTINY-PanTumor02 trial, which enrolled 267 patients. The study is analyzing the efficacy and safety of Enhertu at a dose of 5.4 mg/kg for patients with previously treated HER2-expressing tumors, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, and other tumor types.

The data show Enhertu produced clinically meaningful and durable responses for a survival benefit in patients previously administered treatment for HER2-expressing metastatic solid tumors. The submission also include data from supporting trials, including DESTINY-Lung01 and DESTINY-CRC02, in patients with HER2-positive IHC3+ tumors.¹

In prior trials, the most common adverse events associated with Enhertu (incidence 20% or greater) were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, increased aspartate aminotransferase, fatigue, decreased lymphocyte count, vomiting, decreased platelet count, increased blood alkaline phosphatase, alopecia, constipation, hypokalemia, decreased appetite, and diarrhea.³

Enhertu has been FDA-approved for adults with unresectable or metastatic HER2-positive breast cancer previously administered an anti-HER2-based regimen; adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer; adults with unresectable or metastatic NSCLC; and adults with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma.³

“The clinical benefit seen across HER2-expressing metastatic solid tumors in the DESTINY-PanTumor02 trial and ongoing data from the Enhertu clinical development program continues to demonstrate the potential of this medicine beyond its approved indications,” said Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, in a press release. “If approved, Enhertu could become the first HER2-directed therapy and antibody drug conjugate with a tumor-agnostic indication, providing patients with a potential new treatment option.”¹

References

1. Enhertu granted Priority Review in the US for patients with metastatic HER2-positive solid tumours. AstraZeneca. News release. January 29, 2024. Accessed January 29, 2024.

https://www.astrazeneca.com/media-centre/press-releases/2024/enhertu-granted-priority-review-in-the-us-for-patients-with-metastatic-her2-positive-solid-tumours.html

2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available. Accessed May 22, 2022.

3. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed January 29, 2024.