Nature Medicine | Efficacy Study of Patritumab Deruxtecan (HER3-DXd) in HR+HER2− Advanced Breast Cancer

This study represents the first systematic evaluation of Patritumab Deruxtecan (HER3-DXd) efficacy and safety in HR+HER2− advanced breast cancer, while exploring potential predictive biomarkers to guide personalized antibody-drug conjugate (ADC) therapy strategies.

 

Literature Overview
The article titled 'Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial' published in Nature Medicine systematically evaluates HER3-DXd's therapeutic efficacy and safety in HR+HER2− advanced breast cancer patients. By analyzing baseline and on-treatment tumor samples, the study explores potential biomarkers for efficacy prediction and drug resistance mechanisms, establishing scientific foundations for personalized ADC applications.

Background Knowledge
Breast cancer remains one of the most prevalent malignancies in women. HR+HER2− advanced breast cancer patients typically receive CDK4/6 inhibitors combined with endocrine therapy as first-line treatment. However, approximately 50% of patients progress within two years and require chemotherapy, which is associated with significant toxicity and limited efficacy. Antibody-drug conjugates (ADCs) have demonstrated remarkable therapeutic potential in breast cancer by specifically delivering cytotoxic agents to tumor cells via monoclonal antibodies. Patritumab Deruxtecan (HER3-DXd), a HER3-targeted ADC, has shown preliminary activity in prior studies but lacked systematic investigations into its efficacy prediction and resistance mechanisms. This study addresses these critical gaps by characterizing HER3-DXd's therapeutic profile and biomarker landscape in HR+HER2− breast cancer, providing theoretical support for precision ADC treatment strategies.

 

 

Research Methods and Experiments
In the ICARUS-BREAST01 trial, 99 HR+HER2− advanced breast cancer patients progressing after CDK4/6 inhibitors and first-line chemotherapy received HER3-DXd treatment (5.6 mg/kg intravenous infusion every three weeks). Primary endpoint was investigator-assessed objective response rate (ORR), with secondary endpoints including progression-free survival (PFS), duration of response (DoR), and safety profile. Genomic, transcriptomic, and spatial distribution analyses were conducted on baseline (BL) and on-treatment tumor samples to identify potential biomarkers correlated with therapeutic response.

Key Conclusions and Perspectives

• HER3-DXd demonstrates robust antitumor activity in HR+HER2− advanced breast cancer with overall ORR of 53.5% and clinical benefit rate (CBR) reaching 62.6%.
• Subgroup analysis reveals differential efficacy between HER2-low (1+ or 2+) and HER2-0 populations, showing ORR of 60% vs 48.7%, and PFS of 12.8 months vs 9.1 months respectively.
• Baseline HER3 high expression correlates with prolonged PFS but not significant ORR differences. Spatial distribution analysis identifies cluster 0 (characterized by HER3+ cells surrounded by connective tissue with low immune infiltration) as a spatial biomarker associated with treatment response.
• On-treatment analysis demonstrates significant correlation between HER3-DXd+ cell proportion and tumor shrinkage, with IFN signaling pathway activation observed in HER3-DXd+ tumors.
• Safety profile analysis shows common treatment-related adverse events including fatigue (83%), nausea (75%), diarrhea (53%), and alopecia (40%), with low-grade interstitial lung disease (ILD) incidence at 8.1%.
• ESR1-mutant patients exhibit reduced HER3-DXd efficacy, suggesting potential involvement in drug resistance mechanisms.

Research Significance and Prospects
HER3-DXd demonstrates promising efficacy with manageable safety profile in HR+HER2− advanced breast cancer, establishing its potential as novel therapeutic option. The study suggests HER3 expression levels, spatial distribution patterns, ESR1 mutation status, and IFN response pathways as candidate predictive biomarkers. Phase III trials with larger cohorts are warranted to validate these findings and develop precision patient stratification strategies for optimized ADC therapy.

 

 

Conclusion
This systematic evaluation of HER3-DXd in HR+HER2− advanced breast cancer demonstrates over 50% objective response rate with favorable tolerability. Exploratory biomarker analyses identify spatial HER3 distribution patterns, ESR1 mutation status, and IFN signaling activation as potential response predictors, providing critical directions for future research. The study expands clinical evidence for ADC applications in breast cancer, supporting their therapeutic potential in specific molecular subtypes while highlighting the importance of precision medicine approaches.

 

Barbara Pistilli, Fernanda Mosele, Noemie Corcos, Dalila Sellami, and Guillaume Montagnac. Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial. Nature Medicine.