Regulatory & Policy

Enhertu plus pertuzumab breaks decade-long first-line HER2-positive breast cancer status quo

Edited by Robert McTiernan··2 min read
Enhertu plus pertuzumab breaks decade-long first-line HER2-positive breast cancer status quo

The European Commission has approved Enhertu (trastuzumab deruxtecan) in combination with pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive breast cancer — the first new regimen approved in this setting in more than a decade. The decision, granted to AstraZeneca and Japan-based Daiichi Sankyo, follows a positive opinion from the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) and, as previously reported, represents the second new EU indication for Enhertu within two months, following a tumor-agnostic approval earlier this year.

The approved regimen combines Enhertu at 5.4 mg/kg with pertuzumab, administered intravenously. Enhertu is a HER2-directed antibody-drug conjugate (ADC) comprising a HER2-targeting monoclonal antibody linked via a cleavable tetrapeptide linker to DXd, a topoisomerase I inhibitor payload, at a drug-to-antibody ratio of approximately 8. Adding pertuzumab, which blocks a distinct HER2 dimerization domain, provides complementary dual HER2 blockade.

The approval is supported by DESTINY-Breast09 (NCT04784715), a global, randomized, open-label Phase III trial enrolling 1,157 patients with HER2-positive metastatic breast cancer who had received no prior chemotherapy or HER2-targeted therapy in the metastatic setting. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Enhertu plus pertuzumab reduced the risk of disease progression or death by 44% versus the taxane, trastuzumab, and pertuzumab (THP) regimen (hazard ratio 0.56; 95% confidence interval 0.44–0.71; p<0.00001), with median PFS of 40.7 months versus 26.9 months for THP. Grade 3 or higher adverse events occurred in 63.5% of patients receiving Enhertu plus pertuzumab versus 62.3% with THP. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% versus 1.0%, including two grade 5 events in the Enhertu arm.

The results, presented at the 2025 American Society of Clinical Oncology Annual Meeting and published in The New England Journal of Medicine, led the European Society for Medical Oncology (ESMO) to include the combination as a Category IA first-line option in its Clinical Practice Guidelines, regardless of hormone receptor status.

The AllSci BriefSystematic R&D and deal news. Daily.

THP — pertuzumab plus trastuzumab plus a taxane — has been the standard of care for first-line HER2-positive metastatic breast cancer for more than a decade, with most patients progressing within approximately two years. The DESTINY-Breast09 data extend median first-line PFS by roughly 14 months against that comparator. Enhertu + pertuzumab therefore now directly displaces THP as a new first-line option after more than a decade of THP dominance.

The EU approval also triggers a USD 100 million milestone payment from AstraZeneca to Daiichi Sankyo under their 2019 collaboration agreement. Enhertu's EU expansion continues: a further submission for HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy, based on the DESTINY-Breast05 trial, remains under EMA review.

Spot something wrong? Report an issue with this article