- 學位論文
抗PD-1/PD-L1抗體聯合療法與化學治療，適用順鉑的晚期泌尿道上皮癌患者第一線治療比較: 系統性回顧、網絡後設分析及臨床試驗計畫書
Anti-PD-1/ PD-L1-antibodies-based combination therapy versus chemotherapy as the first-line therapy in cisplatineligible patients with advanced urothelial cancer: A systematic review, network meta-analysis, and the clinical study protocol
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摘要
背景： 泌尿道上皮癌 (UC) 主要發生於膀胱，佔所有泌尿道上皮癌病例的 90-95%。在初診斷時，約有 10-20% 的 UC 患者已出現轉移，另有 30-40% 的患者為肌肉侵犯型腫瘤，其在治療後5年內的復發率高達 50%。由於腫瘤已廣泛擴散，手術切除通常不再可行，此時需要採取全身性治療。傳統上，含鉑類化療一直是轉移性 UC 的一線標準治療方案，總生存期中位數為 12-15 個月。然而，由於化療藥物的累積毒性，長期使用存在顯著限制。近年來，抗 PD-1/PD-L1 抗體和抗體藥物偶聯物 (ADC) 的發展有顯著進展。儘管取得了進展，這些免疫治療組合之間缺乏直接比較。 方法： 遵循系統性文獻回顧和統合分析首選報告項目(Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA)，使用PICO框架的檢索策略確定相關檢索關鍵字。在PubMed、EMBASE和Scopus中進行了全面的文獻檢索，包括主要腫瘤醫學會議（美國臨床腫瘤學會 [ASCO]、歐洲內科腫瘤學會 [ESMO]）的摘要。納入了針對晚期泌尿道上皮癌的第三期隨機對照試驗，評估抗PD-1/PD-L1抗體聯合療法與化學治療的對比。提取了總生存期（Overall survival, OS）、無疾病進展存活期（Progression free survival, PFS）和治療相關不良事件（Treatment-related adverse events, TRAEs）的數據，利用考科藍誤差風險評估工具 (Cochrane risk of bias tool) 進行文獻品質評估。為了比較不同治療間的療效與安全性評估，使用 Review Manager Web 進行了統合分析和森林圖，將組合療法分類為以 gemcitabine-cisplatin 為基礎與否的療法，以及以抗 PD-1 或抗 PD-L1 為基礎的療法，並與單獨使用化療進行比較。進一步使用 R 軟體版本 4.3.1 執行隨機效應模型的網絡統合分析（Network Meta-Analysis, NMA），對 Pembrolizumab 合併 Enfortumab Vedotin 與 Nivolumab 合併 Gemcitabine-Cisplatin 進行間接比較。 結果： 本研究納入5篇符合條件的第三期隨機對照試驗至網絡統合分析，共3734位受試者。在我的研究中納入目前已經有的5個第3期臨床試驗資料證據，分別提供幾個治療選擇：KEYNOTE-361 (Pembrolizumab plus Gemcitabine-Cisplatin or Carboplatin)、DANUBE (Durvalumab plus Tremelimumab)、IMvigor130 (Atezolizumab plus Gemcitabine-Cisplatin or Carboplatin)、CheckMate-901 (Nivolumab plus Gemcitabine-Cisplatin) 和 EV-302 (Pembrolizumab plus Enfortumab vedotin)。統合分析顯示，相較於標準化療，免疫組合療法顯著改善了總生存期（HR=0.74, 95% CI 0.60-0.92）和無疾病進展存活期（HR=0.75, 95% CI 0.59-0.96）。含化療的組合療法有較高的≥3級治療相關不良事件 (TRAEs) 發生率，而不含化療的組合則有較低的發生率（durvalumab 加 tremelimumab OR=0.25, 95% CI 0.18-0.35；pembrolizumab 加 enfortumab vedotin OR=0.73, 95% CI 0.53-0.99）。分組統合分析數據顯示，抗 PD-1 為基礎的組合療法在總生存期和無疾病進展存活期方面更具優勢。網絡統合分析 (NMA) 的間接比較顯示，pembrolizumab 加 enfortumab vedotin 在總生存期（HR=0.60, 95% CI 0.45-0.81）和無疾病進展存活期（HR=0.63, 95% CI 0.45-0.87）方面比 nivolumab 加化療更有效。 結論： 本研究進行了系統性文獻回顧、統合分析及網絡統合分析，結果顯示Nivolumab合併Gemcitabine-Cisplatin和Pembrolizumab合併Enfortumab vedotinn 相較於單獨使用化學治療，顯著改善總生存期，這與2024年3月的NCCN指南一致。特別是，本研究發現Pembrolizumab合併 Enfortumab vedotin在總生存期方面顯著優於其他組合。從CheckMate-901 (Nivolumab plus Gemcitabine-Cisplatin) 和 EV-302 (Pembrolizumab plus Enfortumab vedotin) 兩個療效顯著的臨床試驗結果觀察，次族群分析顯示，來自歐洲的數據最為可靠，而美國和亞洲的結果不一致且不穩定。因此，需要進一步補充美國及亞洲兩個地區的資料，以確認目前兩個第一線標準合併治療研究結果的療效差距。儘管結果顯示出這些發現，但目前我們已知沒有直接比較證明這些治療組合的差異。此外，不同地區的療效存在不一致現象，因此本研究的需進一步設計臨床試驗以驗證網絡統合分析的結果。
並列摘要
Background Urothelial carcinoma (UC), primarily originating in the bladder, constitutes 90-95% of urothelial cancers. At diagnosis, 10-20% of UC patients present with metastasis, and 30-40% have muscle-invasive tumors, with a high recurrence rate of up to 50% within five years post-treatment. Advanced stages often necessitate systemic therapies due to limited surgical options. Historically, platinum-based chemotherapy has been the first-line treatment for metastatic UC, achieving a median overall survival of 12-15 months but with significant toxicity. Recent advancements include anti-PD-1/PD-L1 antibodies and antibody-drug conjugates. Despite progress, direct comparisons among these immunotherapy combinations are lacking. Methods This study adhered to PRISMA guidelines, employing the PICO framework to identify relevant search terms. A comprehensive literature search was conducted in PubMed, EMBASE, and Scopus, including key oncology conference abstracts (ASCO, ESMO). Phase III RCTs of advanced urothelial carcinoma, evaluating anti-PD-1/PD-L1 combinations against chemotherapy, were included. Data on overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were extracted. Quality assessment used the Cochrane risk of bias tool. To compare the efficacy and safety of different treatments, meta-analyses and forest plots were conducted using Review Manager Web. Combination therapies were categorized based on whether they included gemcitabine-cisplatin or were anti-PD-1/PD-L1-antibodies-based, and these were compared to chemotherapy alone. Further, a network meta-analysis (NMA) using a random effects model was performed with R software version 4.3.1 to conduct indirect comparisons between pembrolizumab combined with enfortumab vedotin and nivolumab combined with gemcitabine-cisplatin. Results The systematic search identified five eligible phase III RCTs with a total of 3734 participants. The RCTs included in my study are providing several treatment options: KEYNOTE-361 (pembrolizumab plus gemcitabine-cisplatin or carboplatin), DANUBE (durvalumab plus tremelimumab), IMvigor130 (atezolizumab plus gemcitabine-cisplatin or carboplatin), CheckMate-901 (nivolumab plus gemcitabine-cisplatin), and EV-302 (pembrolizumab plus enfortumab vedotin). Meta-analyses revealed that compared to standard chemotherapy, immune-combination therapy significantly improved OS (HR=0.74, 95% CI 0.60-0.92) and PFS (HR=0.75, 95% CI 0.59-0.96). Chemotherapy combinations had higher rates of grade ≥3 TRAEs, while regimens without chemotherapy had lower rates (durvalumab plus tremelimumab OR=0.25, 95% CI 0.18-0.35; pembrolizumab plus enfortumab vedotin OR=0.73, 95% CI 0.53-0.99). The data from the grouping meta-analyses, indicated that OS and PFS were more favorable in the anti-PD-1-based combination group. NMA for indirect comparisons indicated pembrolizumab plus enfortumab vedotin was more effective than nivolumab plus chemotherapy for OS (HR=0.60, 95% CI 0.45-0.81) and PFS (HR=0.63, 95% CI 0.45-0.87). Conclusions This study performs the systematic review, meta-analyse and NMA, revealing that nivolumab with gemcitabine-cisplatin and pembrolizumab with enfortumab vedotin significantly improve overall survival compared to chemotherapy alone, aligning with the March 2024 NCCN guidelines. Notably, this study found that pembrolizumab combined with enfortumab vedotin was significantly superior in terms of OS compared to other combinations. Observing the significantly effective clinical trial results from CheckMate-901 (nivolumab plus gemcitabine-cisplatin) and EV-302 (pembrolizumab plus enfortumab vedotin), subgroup analysis shows robust data from Europe but inconsistent results from the US and Asia, highlighting the need for further regional data. Therefore, additional data from the US and Asia are needed to confirm the efficacy gap in the current first-line standard combination therapy study results. Despite these findings, there is currently no direct comparative evidence proving the differences between these treatment combinations. Furthermore, the efficacy varies across different regions, indicating the need for further clinical trial designs to validate the results of the NMA.
參考文獻
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