Priority Review Granted for Trastuzumab Deruxtecan; Would Be First Tumor-Agnostic ADC

A tumor-agnostic approval would be a significant development in the advance of antibody-drug conjugates (ADCs), which are designed to deliver a potent, cancer-fighting payload into a tumor while sparing nearby tissues.

January 30, 2024 9:00 am

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Clearity’s Perspective: Most drugs are tested and approved to treat cancers based on where in the body the cancer started and the type of tissue from which it developed. Enhertu (Trastuzumab Deruxtecan, T-Dxd), a HER2-targeted antibody drug conjugate (ADC), already approved for treatment of breast, gastric, and colon cancer, recently demonstrated encouraging activity in multiple other types of cancers when the tumor biomarker HER2 (IHC 3+) was present, no matter where the cancer originated. The FDA has granted the developers of Enhertu priority review for their application for tumor-agnostic approval of Enhertu meaning that access to the drug would be solely dependent on the presence of the HER2 (IHC3+) biomarker. If approved, Enhertu will be the first tumor-agnostic ADC on the market. 

By Mary Caffrey

Enhertu (trastuzumab deruxtecan) product packaging | AstraZeneca photo
Enhertu (trastuzumab deruxtecan) product packaging | AstraZeneca photo

FDA has granted priority review status to trastuzumab deruxtecan (Enhertu) for the treatment of adults with HER2-positive (HER2+) solid tumors who previously received treatment or have no other options, AstraZeneca and Daiichi Sankyo announced Monday.

If granted, this would be the first tumor-agnostic approval for an antibody drug conjugate (ADC) and the first for a HER2-directed targeted therapy. The tumor agnostic indication would apply to patients with unresectable or metastatic HER2+, immunohistochemistry (IHC) 3+ solid tumors.1 The deadline for FDA action is May 30, 2024.2

A tumor-agnostic approval would be a significant development in the advance of ADCs, which are designed to deliver a potent, cancer-fighting payload into a tumor while sparing nearby tissues. Trastuzumab deruxtecan consists of a HER2 monoclonal antibody with topoisomerase I inhibitor payloads, delivered through a tetrapeptide-based cleavable linker.1

Current FDA Approvals for Trastuzumab Deruxtecan

Trastuzumab deruxtecan currently has FDA approval as a second-line treatment for the treatment of certain patients with relapsed or refractory (R/R) unresectable or metastatic HER2+ breast cancer,3 for certain patients with R/R HER2-low unresectable or metastatic breast cancer, with IHC 1+ or IHC 2+/in situ hybridization (ISH),4 and for patients with HER2+ gastric or gastroesophageal junction adenocarcinoma who were previously treated with trastuzumab.5

In addition, FDA has granted accelerated approval for patients with metastatic non–small cell lung cancer if tumors have activating HER2 (ERBB2) mutations; this approval is contingent on a confirmatory trial.6

Evidence in Support of Tumor-Agnostic Approval

The supplemental biologics license application follows the presentation of data from the DESTINY-PanTumor02 trial (NCT04482309), a phase 2 study presented in October 2023 at the European Society for Medical Oncology Congress.7 Findings showed clinically meaningful and durable responses in previously treated patients who had HER2+ metastatic solid tumors in multiple sites, including biliary tract, bladder, cervical, endometrial, and ovarian cancers. In addition, the submission includes data involving HER2+ IHC3+ tumors from other trials, including DESTINY-Lung01 (NCT03505710)8 and DESTINY-CRC02 (NCT04744831).9

“Today’s priority review for the first tumor-agnostic submission for [trastuzumab deruxtecan] reflects the potential of this medicine to redefine the treatment of HER2-expressing cancers,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, said in a statement.1 “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.”

Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, said in his statement, “The clinical benefit seen across HER2-expressing metastatic solid tumors in the DESTINY-PanTumor02 trial and ongoing data from the [trastuzumab deruxtecan] clinical development program continues to demonstrate the potential of this medicine beyond its approved indications.”2


  1. Enhertu granted priority review in the US for patients with metastatic HER2-positive solid tumors. News release. AstraZeneca. January 29, 2024. January 30, 2024.
  2. Enhertu granted priority review in the US for patients with metastatic HER2-positive solid tumors. News release. Daiichi Sankyo. January 29, 2024. Accessed January 30, 2024.
  3. FDA grants regular approval in fam-trastuzumab deruxtean-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed January 30, 2024.
  4. Enhertu is approved in the US for HER2-low metasatic breast cancer. News release. AstraZeneca. August 6, 2022. Accessed January 30, 2024.
  5. FDA approves fam-trastuzumab deruxtcan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed January 30, 2024.
  6. FDA grants accelerated approval to fam-trastuzumab-deruxtecan-nxki for HER2-mutant non-small cell lung cancer. News release. FDA newsroom. August 11, 2022. Accessed January 30, 2024.
  7. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase 2 trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
  8. Li BT, Smit EF, Goto Y, et al for the DESTINY-Lung01 trial investigators. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. 2022;386:241-251. doi:10.1056/NEJMoa2112431
  9. Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019;20(4):518-530. doi:10.1016/S1470-2045(18)30904-5


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