新型治療相比化療治療用在HER2陽性晚期胃癌二線及以上治療系統性文獻回顧、統合分析及臨床試驗方案

Abstract

中文摘要 背景 胃癌是全球發病率第五高的惡性腫瘤，同時也是癌症相關死亡的第三大主因。 在不可切除的晚期胃癌中，人類表皮生長因子受體第2型（Human Epidermal Growth Factor Receptor 2, HER2） 被視為影響第一線化療反應的重要預後因子。研究指出，化療中合併使用 Trastuzumab（賀癌平） 可顯著延長 HER2 陽性患者的總存活期（Overall Survival,OS）。 除了 Trastuzumab，目前用於第二線治療 HER2 標靶選擇，尚包括針對血管內皮生長因子受體第2型（Vascular Endothelial Growth Factor Receptor 2, VEGFR2）的單株抗體 Ramucirumab（欣銳擇）。 近年來，抗體複合物（Antibody–Drug Conjugate,ADC） 作為新興的 HER2 標靶策略，在多項臨床試驗中展現良好療效，也逐漸被視為具發展潛力的創新療法。 方法 本研究依據系統性文獻回顧原則，於 PubMed、Embase與Cochrane Library 等資料庫進行全面檢索，並參閱美國臨床腫瘤醫學會（American Society of Clinical Oncology, ASCO）與歐洲腫瘤內科學會（European Society for Medical Oncology, ESMO）等國際腫瘤學年會之摘要資料，以搜尋探討 HER2 陽性胃癌患者接受第二線治療的隨機對照試驗（Randomized Controlled Trial, RCT）。 納入研究需為第二或第三期臨床試驗，並須報告主要療效與安全性指標，包括客觀緩解率（Objective Response Rate, ORR）、無惡化存活期（Progression-Free Survival, PFS）、總存活期（OS）及不良事件（Adverse Events, AE）。統合分析採用隨機效應模型進行，並以森林圖方式呈現合併效益；所有統計程序皆使用 R 軟體（版本 4.4.2）執行。篩選出76篇相關文獻，其中4篇RCT 符合條件並納入分析。 結果 整體分析結果顯示，與化療相比，HER2 標靶治療在 OS 方面並未達統計顯著差異，但各試驗結果間存在明顯不一致性。其中，DESTINY-Gastric01 試驗中接受 Trastuzumab deruxtecan（T-DXd）的患者表現出顯著的生存優勢（風險比〔Hazard Ratio, HR〕=0.59；95% 信賴區間〔Confidence Interval,CI〕0.37-0.94），然而 GATSBY、T-ACT 及 TyTAN試驗則未觀察到類似的生存效益，導致合併分析結果呈現高度異質性與統計不確定性。 在 PFS方面，整體合併 HR為0.82（95% CI：00.58-1.16），雖呈現改善趨勢，仍未達統計顯著，且異質性顯著（I²=77.1%；p=0.0044）。同樣地，僅有 DESTINY-Gastric01 試驗顯示 PFS 明顯延長（HR=0.47；95% CI:0.31–0.71），其餘研究未呈現一致的治療效果。 亞組分析依據 HER2 表現強度（免疫組織化學染色〔Immunohistochemistry, IHC〕2+ vs.3+）、年齡與性別進行探討，結果顯示HER2高表現（IHC 3+）患者與年長族群可能從HER2標靶治療中獲得較多存活效益，而女性患者的相對效益則較低。然而，這些交互作用皆未達統計顯著水準。 結論 本統合分析結果顯示，在現有的HER2標靶治療選項中，僅 T-DXd在HER2陽性晚期胃癌的第二線或更後線治療中展現出顯著的存活優勢。其他HER2標靶療法雖具潛力，但其臨床效益尚未在多項試驗中獲得一致驗證。 試驗結果間存在顯著差異與異質性，可能與HER2表現強度、患者年齡及性別等生物特徵相關。本研究結果突顯個別化治療策略的重要性，並支持未來進一步針對不同生物特徵進行分層分析與臨床試驗，以優化HER2陽性晚期胃癌患者的治療成效。

Abstract Background Gastric cancer (GC) ranks as the fifth most frequently diagnosed malignancy and remains the third leading cause of cancer-related mortality worldwide [1] . HER2 overexpression serves as a key biomarker in selecting first-line chemotherapy for patients with unresectable advanced gastric cancer. The addition of trastuzumab to chemotherapy has significantly improved overall survival (OS) in HER2-positive advanced GC patients [2] . Beyond trastuzumab, other HER2-directed agents have been approved. Ramucirumab, an anti-VEGFR2 monoclonal antibody, is frequently used as a second-line treatment. More recently, ADCs have shown encouraging clinical activity, representing a promising advance in the therapeutic landscape for HER2-positive advanced GC. Methods We conducted a thorough literature review across PubMed, Embase, and the Cochrane Library, complemented by manual searches of ASCO and ESMO conference abstracts, to identify relevant randomized controlled trials (RCTs) evaluating second-line HER2-targeted therapies in advanced GC. Eligible studies were phase II or III RCTs reporting on clinical outcomes such as objective response rate (ORR), progression-free survival (PFS), OS, and adverse events (AEs). Data synthesis was performed using random-effects models, and forest 6 plots were generated for visualization. All statistical analyses were completed using R software (version 4.4.2). Results A total of 76 studies were initially screened, and 4 RCTs met the eligibility criteria for inclusion in the meta-analysis. The pooled results did not indicate a statistically significant improvement in OS with HER2-targeted treatments compared to chemotherapy. However, individual trial outcomes were inconsistent. Notably, the DESTINY-Gastric01 trial demonstrated a significant OS benefit with tratuzumab deruxtecan (T-DXd) (HR = 0.59; 95% CI: 0.37–0.94), whereas GATSBY, T-ACT, and TyTAN trials failed to show survival advantages, contributing to overall heterogeneity and statistical uncertainty. For PFS, the combined HR under the random-effects model was 0.82 (95% CI:0.58–1.16), suggesting a non-significant trend in favor of HER2-targeted approaches. Consistent with OS findings, only the DESTINY-Gastric01 study reported a statistically significant improvement in PFS (HR = 0.47; 95% CI: 0.31–0.71). Subgroup analyses stratified by HER2 expression (IHC 2+ vs. 3+), age, and gender revealed potentially greater benefit in patients with high HER2 expression and in older individuals, though no subgroup interaction reached statistical significance. Conclusions Among the HER2-directed therapies evaluated, T-DXd is the only agent associated with a significant survival benefit in the second-line or later setting for HER2-positive advanced gastric cancer. Other regimens did not demonstrate comparable efficacy. The observed heterogeneity and inconsistent findings across studies suggest that factors such as HER2 status, age, and sex may influence treatment response. These results underscore the importance of patient stratification and advocate for future research on personalized HER2-targeted therapeutic strategies.