EU approves Enhertu as first tumor-agnostic HER2 therapy

Edited by Robert McTiernan··2 min read

The European Commission has approved Enhertu (trastuzumab deruxtecan) as the first tumor-agnostic HER2-directed therapy and antibody drug conjugate in the EU, extending its use to adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior treatment and have no satisfactory remaining options.

The decision, which follows a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP), marks a structural shift in how HER2-directed therapy may be applied in Europe — moving from tumor-type-specific approvals toward a biomarker-defined, histology-agnostic model. AstraZeneca and Daiichi Sankyo co-develop and co-commercialise the agent globally, excluding Japan.

Enhertu is administered intravenously at 5.4 mg/kg and is indicated as monotherapy. The approval covers HER2-positive status defined by IHC 3+ scoring, a threshold that has been consistently associated with meaningful responses across tumor types in the supporting trials. Enhertu combines a HER2-targeting monoclonal antibody with Daiichi Sankyo’s DXd topoisomerase I inhibitor payload via a cleavable linker.

The approval is supported by data from three Phase II trials: DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. In DESTINY-PanTumor02, which enrolled patients with biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and other tumors, Enhertu demonstrated a confirmed objective response rate (ORR) of 52.3% (95% CI 42.6–61.8) and a median duration of response (DOR) of 21.1 months in 111 patients with IHC 3+ tumors, the largest patient dataset across the basket of trials.

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The biological rationale for a histology-agnostic approach rests on HER2 overexpression occurring across a broad range of solid tumor types — including lung, bladder, cervical, colorectal, endometrial, ovarian, salivary gland, and pancreatic cancers — where HER2-directed therapy had not previously been available in the EU. The IHC 3+ threshold functions as the unifying biomarker, and the consistency of response rates across histologically distinct tumor types in the DESTINY programme supports the premise that HER2 overexpression, rather than tissue of origin, is the primary driver of susceptibility to this ADC.

The approval establishes Enhertu as the only tumor-agnostic HER2-directed therapy currently approved in the EU. The most direct pipeline competitor is zanidatamab (Ziihera), a bispecific HER2-directed antibody developed by Jazz Pharmaceuticals, which received US FDA accelerated approval in November 2024 for previously treated HER2-positive (IHC 3+) biliary tract cancer. Jazz is also pursuing broader histology-agnostic use through the Phase II DiscovHER PAN-206 basket trial (NCT06695845), which enrolls patients with HER2 IHC 3+ solid tumors beyond biliary tract cancer. The approval also triggers a USD 25 million milestone payment from AstraZeneca to Daiichi Sankyo under their 2019 collaboration agreement, and represents Enhertu’s sixth approved indication in the EU.

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