Enhertu expands to first-line breast cancer in U.S.

Edited by Robert McTiernan··2 min read

The US FDA approved a new indication for AstraZeneca/Daiichi Sankyo’s antibody drug conjugate (ADC) Enhertu (fam-trastuzumab deruxtecan-nxki; T-DxD), for use in combination with pertuzumab as a first-line treatment in adults with unresectable or metastatic HER2-positive breast cancer. Enhertu becomes the first first-line treatment regimen for HER2+ metastatic disease to significantly outperform the current standard of care in over a decade.

New clinical standard from DESTINY-Breast09

The approval is grounded in results from the DESTINY-Breast09 Phase 3 trial (NCT04784715), a global, randomized, three-arm study enrolling 1,157 patients with HER2-positive metastatic disease. Patients without prior chemotherapy or HER2-targeted therapy (or whose prior therapy was >6 months before advanced disease) were randomized to receive:

  • T-DxD (5.4 mg/kg) + pertuzumab,
  • standard THP (taxane + trastuzumab + pertuzumab), or
  • an investigational regimen.

Key efficacy findings were:

  • Median progression-free survival (PFS): 40.7 months with the T-DxD + pertuzumab combo vs 26.9 months with THP (HR 0.56; p < 0.0001).
  • Confirmed objective response rate (ORR): 87% vs 81%.
  • Overall survival (OS): immature at interim analysis (16% deaths at cut-off).

Implications

Co-developed by Daiichi Sankyo and AstraZeneca, Enhertu originated from Daiichi Sankyo’s proprietary DXd ADC platform, designed to overcome limitations seen in earlier ADCs, including suboptimal potency, limited bystander effect, and premature payload release. The ADC combines targeted HER2 binding with a potent topoisomerase I inhibitor payload, delivering direct cytotoxicity after receptor-mediated internalization.

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The latest indication approval adds to prior approvals in later lines and HER2-low indications and reflects the maturation of ADC platforms into earlier treatment settings.

The FDA concurrently approved two companion diagnostics, the PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and the HER2 Dual ISH DNA Probe Cocktail, to identify eligible patients with HER2 IHC3+ or ISH+ tumors.

Regulatory support for this application included Priority Review and Breakthrough Therapy designation, underscoring the agency’s recognition of the combination’s substantial improvement over standard therapy.

R&D takeaways

  • This week’s approval demonstrates Enhertu’s progression from salvage settings into earlier treatment lines, a trend likely to influence R&D pipelines across oncology.
  • Biomarker-linked therapy optimization: Integration of companion diagnostics reaffirms precision medicine as a core driver in trial design and label strategy.
  • Benchmarking HER2+ treatment: Numeric superiority in PFS and ORR vs THP sets a new bar for emerging HER2-targeted combinations and next-gen modalities (e.g., bispecifics, TKIs) aiming to improve on or extend beyond these outcomes.