Nature Medicine | Patritumab deruxtecan demonstrates clinical efficacy in HR+HER2− advanced breast cancer

This study provides the first evaluation of patritumab deruxtecan (HER3-DXd) efficacy and safety in HR+HER2− advanced breast cancer patients, while exploring potential biomarkers to offer new insights for personalized antibody-drug conjugate (ADC) therapy.

 

Literature Overview
This article titled 'Patritumab deruxtecan in HR+HER2− advanced breast cancer: a phase 2 trial', published in Nature Medicine, reviews and summarizes the efficacy, safety, and biomarker analysis of HER3-DXd in HR+HER2− advanced breast cancer. The study enrolled 99 patients who progressed after prior CDK4/6 inhibitor and first-line chemotherapy treatments, evaluating ORR, PFS, adverse events, and conducting exploratory biomarker analysis of baseline and on-treatment tumor samples to establish foundation for larger trials.

Background Knowledge
Breast cancer is the most common female malignancy, with HR+HER2− subtype comprising a significant proportion. While CDK4/6 inhibitors combined with endocrine therapy have improved outcomes, most patients eventually develop resistance requiring second-line treatment. As an emerging therapeutic modality, ADCs have shown remarkable efficacy in HER2+ breast cancer but remain understudied in HER2− populations. HER3-DXd targets HER3 while delivering topoisomerase I inhibitors, with potential efficacy linked to HER3 expression levels, spatial distribution, and ERBB2/ERBB3 pathway activity. However, predictive biomarkers for ADC efficacy remain undefined due to limitations in dynamic mechanism evaluation. This study employs multi-omics analysis, spatial protein localization, and gene expression profiling to explore HER3-DXd mechanisms, providing potential frameworks for personalized therapy.

 

 

Research Methods and Experiments
ICARUS-BREAST01 was a phase 2 trial enrolling 99 HR+HER2− advanced breast cancer patients treated with HER3-DXd (5.6 mg/kg) every 3 weeks. Primary endpoint was independently assessed ORR, with secondary endpoints including PFS, DoR, OS, and safety. The study collected tumor samples, whole blood, and serum at baseline, during treatment, and trial completion for whole-exome sequencing, RNA sequencing, spatial protein expression analysis (IHC+H&E with image processing), immune cell density quantification, and pharmacokinetic evaluation.

Key Conclusions and Perspectives

• HER3-DXd demonstrated moderate ORR (53.5%) with CBR of 62.6% and median PFS of 9.2 months in HR+HER2− advanced breast cancer, with comparable efficacy between HER2-low and HER2-0 subgroups.
• Common TRAEs included fatigue (83%), nausea (75%), diarrhea (53%), and alopecia (40%), with over 50% experiencing ≥grade 3 adverse events, though no fatal TRAEs were reported.
• Baseline HER3 membrane expression showed no significant correlation with efficacy, but HER3-high expressing patients demonstrated trend toward longer PFS (10.9 vs 6.7 months).
• Spatial analysis identified cluster 0 (moderate HER3+ cells surrounded by connective tissue without necrosis) as positively correlated with efficacy (OR=1.527), suggesting tumor microenvironment influences ADC distribution and response.
• Genomic analysis revealed higher ESR1 mutation prevalence in non-responders (52.9% vs 23.1%), indicating potential resistance biomarker.
• On-treatment samples showed significant HER3 downregulation and IFN pathway activation in responders, suggesting immune modulation enhances ADC efficacy.

Research Significance and Prospects
This study represents the first systematic assessment of HER3-DXd in HR+HER2− advanced breast cancer, demonstrating potential efficacy in HER2-low/HER2-0 populations. While limited by small sample size, exploratory biomarker analysis supports HER3 expression, spatial distribution, and ESR1 mutations as predictive factors. Future phase 3 trials should validate efficacy while investigating microenvironmental and genomic mechanisms influencing ADC penetration and pharmacodynamics to enable personalized treatment strategies.

 

 

Conclusion
HER3-DXd shows manageable safety profile and moderate efficacy in HR+HER2− advanced breast cancer, achieving 53.5% ORR with ~9-month PFS. Exploratory analyses suggest HER3 spatial distribution and ESR1 mutations may influence treatment outcomes, while IFN pathway activation correlates with response. Despite II期 design and limited cohort size, findings identify potential biomarkers and therapeutic strategies for future research. Cyagen offers gene-edited animal models, tumor efficacy evaluation, and biomarker validation services to support ADC mechanism studies and personalized therapy development.

 

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.