This study provides a novel immunotherapy-combined antibody-drug conjugate (ADC) strategy for HR-negative, HER2-low advanced breast cancer, demonstrating durable responses even in PD-L1 unselected populations. It offers direct reference value for the design of clinical immunotherapy regimens in oncology.
Literature Overview
The article titled 'First-line durvalumab in combination with trastuzumab deruxtecan in women with locally advanced unresectable or metastatic, hormone-receptor-negative, HER2-low breast cancer: multicenter, open-label, phase 1b/2 BEGONIA platform trial,' published in Nature Cancer, systematically investigates the efficacy and safety of durvalumab combined with trastuzumab deruxtecan (T-DXd) as first-line treatment in patients with HR-negative, HER2-low advanced breast cancer. Based on cohort 6 of the BEGONIA platform trial, 58 patients were enrolled to evaluate objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS), along with safety profiles. The results show that although the prespecified ORR target (66.6%) was not met, the observed ORR of 62.1% and median DoR of 15.2 months indicate clinically meaningful activity, offering a treatment option beyond conventional chemotherapy for the HER2-low population.Background Knowledge
Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of all breast cancers and is characterized by the absence of ER, PR, and HER2 overexpression, resulting in limited treatment options and poor prognosis. Although immune checkpoint inhibitors combined with chemotherapy have achieved some success in PD-L1-positive TNBC, most patients remain PD-L1 negative and experience rapid disease progression. In recent years, HER2-low has been widely recognized as a new therapeutic target, defined as IHC 1+ or 2+ without ERBB2 amplification. Trastuzumab deruxtecan (T-DXd), a novel antibody–drug conjugate (ADC), exhibits activity in HER2-low and even HER2-ultralow (IHC 0) tumors due to its 'bystander effect.' However, the efficacy of ADCs in TNBC is currently limited by insufficient durability of monotherapy responses and unclear resistance mechanisms, necessitating combination strategies to enhance antitumor immunity. This study is based on preclinical evidence that T-DXd upregulates CD8+ T-cell infiltration and PD-L1 expression in the tumor microenvironment, proposing a rational combination with the PD-L1 inhibitor durvalumab to overcome immunosuppressive conditions and achieve synergistic antitumor effects.
Research Methods and Experiments
The study employed a multicenter, open-label, phase 1b/2 BEGONIA platform trial design, enrolling 58 women with locally advanced unresectable or metastatic HR-negative, HER2-low breast cancer, who received durvalumab (1120 mg Q3W) plus T-DXd (5.4 mg/kg Q3W) as first-line therapy. The primary endpoints were ORR and safety, while secondary endpoints included DoR, PFS, and OS. All patients underwent baseline imaging and were assessed every six weeks per RECIST v1.1. Safety monitoring focused on immune-related adverse events (irAEs) and drug-related interstitial lung disease (ILD) or pneumonitis. Additionally, central laboratory IHC testing for HER2 expression was performed retrospectively to assess concordance between local and central interpretation and its correlation with efficacy. With a median follow-up of 20.6 months, the ORR was 62.1% (95% CI: 48.4–74.5), including a complete response (CR) rate of 1.7% and partial response (PR) rate of 60.3%. The median DoR was 15.2 months, median PFS was 12.6 months, and median OS reached 30.3 months. Notably, even among PD-L1-negative patients (79.3% of the cohort), the ORR was 65.2%, suggesting efficacy independent of PD-L1 status. Central HER2 testing revealed that 62% of patients were reclassified as IHC 0 (with or without membrane staining), yet responses were still observed in these patients, indicating T-DXd retains activity in HER2-ultralow tumors.Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes a highly effective first-line treatment option for patients with HR-negative, HER2-low advanced breast cancer, overcoming the limitations of traditional TNBC therapies that rely on chemotherapy and PD-L1 selection. The durable responses and prolonged survival suggest this combination could become a new standard of care. However, the heterogeneity in HER2 testing highlights inconsistencies in current biomarker interpretation, necessitating standardized IHC protocols and auxiliary technologies to improve accuracy. Although ILD risk is manageable, individualized management strategies are still required, particularly in elderly patients or those with preexisting lung conditions. From a drug development perspective, this study supports further investigation into the synergistic mechanisms between ADCs and immune checkpoint inhibitors, such as using single-cell sequencing to analyze dynamic changes in the tumor microenvironment or humanized mouse models to validate combination effects.
Conclusion
This study establishes the significant role of durvalumab in combination with trastuzumab deruxtecan as a first-line treatment for HR-negative, HER2-low advanced breast cancer. The high response rate, durable responses, and acceptable safety profile offer new hope for this difficult-to-treat population. Although the prespecified ORR endpoint was not met, the median OS of 30.3 months far exceeds historical controls, suggesting the regimen may substantially improve patient outcomes. The study also reveals the complexity of the HER2-low definition—central testing showed most patients were actually HER2 IHC 0, yet still derived benefit—challenging traditional HER2 classification boundaries and indicating the need for more precise molecular subtyping strategies. Moreover, the combination did not increase severe irAEs, though ILD incidence was slightly elevated, emphasizing the importance of enhanced clinical monitoring and patient education. From a translational medicine standpoint, this study provides high-quality clinical evidence for combining ADCs with immunotherapy, advancing the treatment paradigm from 'chemotherapy + immunotherapy' to 'targeted therapy + immunotherapy.' Future research should focus on optimizing biomarkers, elucidating resistance mechanisms, and exploring safer dosing regimens to enable personalized precision therapy. These findings have the potential to reshape the treatment landscape for HER2-low breast cancer, serving as a critical bridge between laboratory discoveries and clinical practice.
