抗體藥物複合體用於第二型人類表皮生長因子受體非過度表現之轉移性乳癌：系統性回顧及統合分析與臨床試驗計畫書

Abstract

背景：抗體藥物複合體（ADC）在第二型人類表皮生長因子受體（HER2）非過度表現的轉移性乳腺癌中，顯示出較化療更優的療效。然而，不同患者亞組的療效差異及最佳ADC選擇仍待釐清。

方法：本研究依據系統性回顧與統合分析首選報告項目（PRISMA）指引，系統檢索PubMed、Embase、Cochrane Library及ClinicalTrials.gov，納入截至2025年05月17日已完整出版的文獻，並輔以會議摘要進行亞組分析。主要療效指標包括ADC相較於化療的總反應率（ORR）勝算比（OR）、無進展生存期（PFS）及總生存期（OS）的風險比（HR）。

結果：共納入六項隨機分派臨床試驗（N=3,558），涵蓋三種核准上市之ADC。整體而言，所有ADC在ORR、PFS及OS三項療效指標均顯著優於化療。賀爾蒙受體陰性患者的ORR勝算比高於賀爾蒙受體陽性患者。在賀爾蒙受體陽性患者中，HER2低表達（HER2-low，定義為免疫組織化學染色[IHC] 1+至2+）疾病使用ADC的ORR（OR 3.40 vs. 2.12）及PFS（HR 0.56 vs. 0.65）療效優於HER2零表達（HER2-zero，IHC 0）疾病。反之，在賀爾蒙受體陰性患者中，ADC於HER2-zero疾病的療效較HER2-low更顯著（ORR OR 12.42 vs. 5.15；PFS HR 0.38 vs. 0.45）。無論賀爾蒙受體狀態，OS在不同HER2表現水平間無顯著差異。HER2-ADC與Trop2-ADC在各亞組的PFS及OS效益相近，但在賀爾蒙受體陽性患者的ORR中，HER2-ADC表現更佳（OR 3.83 vs. 1.70）。對於賀爾蒙受體陰性/HER2-zero患者，僅Trop2-ADC數據顯示顯著療效（ORR OR 12.42，PFS HR 0.38，OS HR 0.50）。

結論：ADC的療效因賀爾蒙受體狀態及HER2表現水平而異，ORR的差異尤為顯著。在賀爾蒙受體陽性患者中，HER2-ADC的ORR勝算比優於Trop2-ADC，顯示其潛在的優先應用價值。

Background: Antibody-drug conjugates (ADCs) have shown superior efficacy over chemotherapy in HER2 non-overexpressing metastatic breast cancer. However, efficacy across different patient subgroups and the optimal ADC choice remains undefined.

Methods: Literature search in PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline, and full paper publications up to 17 May, 2025 were enrolled. Additional conference abstracts were collected for subgroup analyses. Primary outcomes were odds ratio (OR) for overall response rate (ORR), hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) when ADCs were compared to chemotherapies.

Results: Six randomized trials (N=3,558) which consisted of three approved ADCs were enrolled; all showed superior efficacy of ADCs over chemotherapy. In general, higher OR for ORR was observed in hormone receptor-negative (HR-neg) patients than in hormone receptor-positive (HR-pos) patients. Among HR-pos patients, ADC efficacy in ORR (OR 3.40 vs. 2.12) and PFS (HR 0.56 vs. 0.65) was more prominent in HER2-low (immunohistochemical staining [IHC] 1+ to 2+) disease than in HER2-zero (IHC 0) disease. Conversely, among HR-neg patients, ADCs were preferentially better in HER2-zero disease (ORR OR 12.42 vs. 5.15 and PFS HR 0.38 vs. 0.45). Regardless of hormone receptor status, OS benefits remained consistent across HER2 expression levels. HER2-ADC and Trop2-ADCs provided similar benefit in PFS and OS. While HER2-ADC appeared to have superior ORR than Trop-2-ADCs in HR-pos patients (OR 3.83 vs. 1.70); for HR-neg/HER2-zero patients, available data were limited to Trop2-ADC only, with outstanding results (ORR OR 12.4, PFS HR 0.38 and OS HR 0.5).

Conclusions: Differential benefits of ADCs in ORR and PFS were observed across different patient subgroups defined by hormone receptor status and HER2 expression level. In HR-pos patients, HER2 ADC had superior odds in ORR than Trop2 ADCs.