Nature Communications | Neoadjuvant anti-HER2 antibody-drug conjugate SHR-A1811 in Hormone Receptor-positive, HER2-low Breast Cancer: A Phase 2 Clinical Trial (HELEN-015)

This study reveals a new precision therapy strategy for HER2-low expressing breast cancer, providing critical clinical data support for optimizing neoadjuvant treatment regimens in breast cancer.

 

Literature Overview

This article, "Neoadjuvant anti-HER2 antibody-drug conjugate SHR-A1811 in Hormone Receptor-positive, HER2-low Breast Cancer: A Phase 2 Clinical Trial (HELEN-015)", published in Nature Communications, systematically explores the efficacy and safety of the third-generation HER2-targeted antibody-drug conjugate (ADC) SHR-A1811 in the neoadjuvant treatment of hormone receptor-positive (HR+), HER2-low expressing breast cancer. Through a single-arm Phase II clinical trial, the study confirms significant anti-tumor activity of this drug in this specific subgroup, offering a new treatment option for patients with poor responses to traditional chemotherapy.

Background Knowledge

This study aims to address the critical unmet needs faced by the large population of patients with HR+/HER2-low breast cancer in the neoadjuvant setting. Currently, such patients primarily rely on chemotherapy combined with endocrine therapy, but the pathological complete response (pCR) rate is typically below 10%, and chemotherapy is associated with significant toxicity. Although HER2-targeted therapies have shown potential in HER2-low advanced breast cancer, efficacy data in the neoadjuvant stage remains absent. Furthermore, existing HER2-targeted drugs like T-DXd carry safety concerns such as interstitial lung disease (ILD), limiting their widespread application in early curative settings. The focus of this study is to evaluate whether SHR-A1811, with its unique chemical structure (optimized linker-payload), can achieve a high objective response rate (ORR) while maintaining manageable toxicity in the neoadjuvant environment. Specifically, it explores whether the drug can effectively suppress the Ki-67 proliferation index without triggering ILD, thereby challenging the traditional paradigm that strongly correlates HER2 expression levels with efficacy.

 

 

Research Methods and Experiments

This study employed a single-arm, Phase II Simon two-stage design, enrolling 66 treatment-naïve female patients with HR+/HER2-low invasive breast cancer (cT2-3, cN0-3, Ki-67 > 14%). Patients received intravenous SHR-A1811 (6.4 mg/kg) every 3 weeks for a total of 8 cycles. Core experimental evidence included the objective response rate (ORR) assessed by enhanced MRI, as well as post-surgical pathological evaluation (pCR and Residual Cancer Burden, RCB). The study specifically focused on efficacy differences between HER2 IHC 1+ and 2+ subgroups and conducted paired pre- and post-treatment analyses of Ki-67 expression levels. Additionally, the study detailed adverse events, particularly hematologic toxicity, and observed the effectiveness of prophylactic PEG-rhG-CSF in controlling neutropenia.

Key Conclusions and Perspectives

• SHR-A1811 monotherapy in the neoadjuvant setting achieved an objective response rate (ORR) of 81.5%, significantly exceeding the prespecified threshold of 66%, indicating potent anti-tumor activity in HR+/HER2-low breast cancer.
• Although the pCR rate was 3.1%, the RCB 0-1 rate reached 9.2%, and Ki-67 expression decreased by an average of 35.6%, confirming the drug's potent inhibitory effect on tumor cell proliferation. This suggests that pCR may not be the optimal endpoint for evaluating efficacy in this subgroup.
• In terms of safety, no treatment-related interstitial lung disease (ILD) or deaths were observed. The main adverse events were hematologic toxicities (e.g., neutropenia), which could be effectively managed with prophylactic colony-stimulating factors, offering a safer HER2-targeted option for early breast cancer treatment.
• Subgroup analysis showed that the ORR in HER2 IHC 1+ patients (94.1%) was even higher than in IHC 2+ patients (77.1%), challenging the conventional notion that HER2 expression levels dictate efficacy. This suggests that ADC efficacy may depend more on the bystander effect and membrane permeability of the payload.

Research Significance and Prospects

These findings hold significant importance for the field of drug development, demonstrating the immense potential of third-generation HER2-targeted ADCs in neoadjuvant treatment for early breast cancer, potentially becoming a new standard to replace traditional chemotherapy. For clinical monitoring, the study suggests a greater focus on dynamic changes in RCB and Ki-67 rather than solely pursuing pCR. In terms of disease modeling, these results encourage the development of more precise biomarkers to predict ADC efficacy, particularly for the heterogeneous HER2-low population. Future research needs to further validate long-term survival benefits through large-scale randomized controlled trials and explore combination strategies with endocrine therapy or immunotherapy.

 

 

Conclusion

The HELEN-015 study brings a breakthrough to the treatment landscape of HR+/HER2-low breast cancer. As a neoadjuvant monotherapy, SHR-A1811 not only demonstrated an exceptional objective response rate but also showed potential for superior safety compared to similar drugs, particularly by avoiding the fatal risk of interstitial lung disease. From the perspective of laboratory-to-clinical translation, this study establishes a new status for HER2-targeted ADCs in early breast cancer treatment, providing critical survival hope for patients who respond poorly to traditional chemotherapy. This discovery not only optimizes the existing breast cancer care system but also provides a solid clinical basis for future exploration of combination therapy strategies and precision medicine, marking the entry of HER2-low breast cancer treatment into a new era of precise targeting.

 

Dechuang Jiao, Jiujun Zhu, Xianfu Sun, Yijia Wu, and Zhenzhen Liu. Neoadjuvant anti-HER2 antibody-drug conjugate SHR-A1811 in Hormone Receptor-positive, HER2-low Breast Cancer: A Phase 2 Clinical Trial (HELEN-015). Nature Communications.