Schettini Francesco, Nucera Sabrina, Pascual Tomás, Martínez-Sáez Olga, Sánchez-Bayona Rodrigo, Conte Benedetta, Buono Giuseppe, Lambertini Matteo, Punie Kevin, Cejalvo Juan Miguel, Arpino Grazia, Vigneri Paolo, Generali Daniele, Ciruelos Eva, Cortés Javier, Gennari Alessandra, Muñoz Montserrat, Vidal Losada Maria J, Tolaney Sara M, Prat Aleix, Villacampa Guillermo
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain; SOLTI Cancer Research Group, Barcelona, Spain.
Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Department of Human Pathology "G. Barresi", University of Messina, Messina, Italy.
Cancer Treat Rev. 2025 Jan;132:102865. doi: 10.1016/j.ctrv.2024.102865. Epub 2024 Dec 19.
Antibody-drug conjugates (ADCs) trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) provided significant progression-free survival (PFS) and overall survival (OS) improvements over chemotherapy (CT) in pretreated hormone receptor-positive (HR+) and triple-negative (TN)/HER2-low metastatic breast cancer (MBC). However, no direct comparison between the two exists, nor with the more recent datopotamab-deruxtecan (Dato-DXd).
We conducted a network meta-analysis (NMA) to compare efficacy and safety of T-DXd and SG in CT-pretreated HR+ and TN/HER2-low MBC and assess their benefit over standard CT, exploring also a comparison with Dato-DXd. Hazard ratios (HRs) with 95 % confidence intervals (CI) were calculated for PFS/OS. P-score was used for treatment ranking.
Three RCTs (956 patients) were included in the primary analysis and 5 (1,445) in the exploratory NMA with Dato-DXd. In HR+/HER2-low, T-DXd showed no significant difference in PFS and OS when compared to SG. Similarly, in TN/HER2-low, PFS and OS did not differ significantly between the two ADCs. The P-score analysis favored T-DXd over SG in HR+/HER2-low in PFS (0.90 vs. 0.60) and OS (0.89 vs. 0.60). SG was favored over T-DXd in OS in TN/HER2-low (0.80 vs. 0.69). Similar results were obtained for HR+ MBC when including Dato-Dxd, which showed the worst performance, while T-DXd was the only ADC significantly outperforming CT in OS. The ADCs showed significantly better PFS and OS than CT in HR+/HER2-low and TN/HER2-low (all p < 0.001). SG had higher rates of neutropenia, diarrhea and alopecia vs. T-DXd, which showed more thrombocytopenia, fatigue and nausea. Pneumonitis and cardiotoxicity were typically T-DXd-related, and T-DXd showed more toxicity-related discontinuations.
Similar efficacy with T-DXd and SG in HER2-low MBC was observed, regardless of HR status. Safety profile, local drug-approval criteria and guidelines, patients' preferences and overall quality of evidence should ultimately guide therapeutic decision-making. Dato-DXd role remains uncertain.
在经治的激素受体阳性（HR+）和三阴性（TN）/HER2低表达转移性乳腺癌（MBC）中，抗体药物偶联物（ADC）曲妥珠单抗-德曲妥珠单抗（T-DXd）和赛托珠单抗-戈维汀（SG）与化疗（CT）相比，显著改善了无进展生存期（PFS）和总生存期（OS）。然而，这两者之间以及与更新的达泊妥珠单抗-德曲妥珠单抗（Dato-DXd）之间均未进行直接比较。
我们进行了一项网状Meta分析（NMA），以比较T-DXd和SG在CT预处理的HR+和TN/HER2低表达MBC中的疗效和安全性，并评估它们相对于标准CT的获益，同时还探索了与Dato-DXd的比较。计算PFS/OS的风险比（HR）及其95%置信区间（CI）。使用P评分进行治疗排名。
三项随机对照试验（956例患者）纳入了主要分析，五项（1445例）纳入了包含Dato-DXd的探索性NMA。在HR+/HER2低表达组中，与SG相比，T-DXd在PFS和OS方面无显著差异。同样，在TN/HER2低表达组中，两种ADC在PFS和OS方面也无显著差异。P评分分析显示，在HR+/HER2低表达组的PFS（0.90对0.60）和OS（0.89对0.60）方面，T-DXd优于SG。在TN/HER2低表达组的OS方面，SG优于T-DXd（0.80对0.69）。纳入Dato-DXd的HR+MBC患者也得到了类似结果，Dato-DXd表现最差，而T-DXd是唯一在OS方面显著优于CT的ADC。在HR+/HER低表达和TN/HER2低表达组中，ADC的PFS和OS均显著优于CT（所有p<0.001）。与T-DXd相比，SG的中性粒细胞减少、腹泻和脱发发生率更高，而T-DXd的血小板减少、疲劳和恶心更为常见。肺炎和心脏毒性通常与T-DXd相关，且T-DXd因毒性导致的停药更多。
无论HR状态如何，在HER2低表达MBC中观察到T-DXd和SG具有相似的疗效。安全性、当地药物批准标准和指南、患者偏好以及总体证据质量最终应指导治疗决策。Dato-DXd的作用仍不确定。
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