血管新生抑制劑合併抗PD-1/PD-L1抗體相比sunitinib作為晚期腎細胞癌病人一線治療：系統性回顧及網絡後設分析與臨床試驗計畫書

背景：作為晚期腎細胞癌患者的一線治療藥物，近年來許多研究支持血管新生抑製劑聯合抗PD-1/PD-L1抗體的療效優於sunitinib。然而，在這些治療方案之間尚未進行過直接比較。因此，本研究進行了系統性回顧和網絡後設分析，以評估血管新生抑製劑和抗 PD-1/PD-L1 抗體的組合作為晚期腎細胞癌的一線治療。此外，根據分析結果，設計並撰寫臨床試驗計畫書來比較bevacizumab加atezolizumab和lenvatinib加pembrolizumab的療效和安全性。方法：根據系统性回顧和後設分析首選報告項目 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA)，在MEDLINE、Cochrane Library、clinicaltrial.gov、PubMed和EMBASE中，系統性的檢索針對晚期腎細胞癌患者第一線治療使用血管新生抑制劑合併抗PD-1/PD-L1抗體的第三期隨機對照試驗。使用頻率學派的隨機效應模型(Frequentist methods in the random-effects model)進行網絡後設分析 (Network meta-analysis, NMA)。此外，在基於抗血管內皮生長因子(anti-vascular endothelial growth factor-based, anti-VEGF-based)的聯合治療與基於血管內皮生長因子酪胺酸激酶抑制劑( Vascular endothelial growth factor receptor tyrosine kinase inhibitor-based, VEGFR-TKI) 的聯合治療之間或基於抗PD-L1 (Anti-PD-L1-based)的聯合治療與基於抗 PD-1(Anti-PD1-based)的聯合治療之間進行了直接比較後設分析和調整後的間接比較。結果：本研究的網絡後設分析納入了五項第三期臨床試驗，包括 4025 名患者。與sunitinib相比，所有合併治療均顯著提高了無進展生存期（axitinib加avelumab：HR = 0.69，95% CI 0.58-0.83；axitinib加pembrolizumab：HR = 0.71，95% CI 0.60-0.84；bevacizumab加atezolizumab：HR = 0.83, 95% CI 0.71–0.98；cabozantinib加nivolumab：HR = 0.52, 95% CI 0.43–0.63；lenvatinib加pembrolizumab：HR = 0.39, 95% CI 0.32–0.48）。當比較的對照使用bevacizumab加atezolizumab，與其他治療相比，bevacizumab加atezolizumab有比較低的 3 級或更高治療相關不良事件的發生率（axitinib加avelumab：OR = 1.82，95% CI 1.25–2.65；axitinib加pembrolizumab：OR = 2.10, 95% CI 1.43–3.09；cabozantinib加nivolumab：OR = 2.55, 95% CI 1.69–3.85；lenvatinib加pembrolizumab：OR = 3.17, 95% CI 2.32–2.24；sunitinib：OR = 1.72, 95% CI 1.32-2.24）。當 lenvatinib 加 pembrolizumab 被用作網絡後設分析的對照時，在總生存期結果方面，lenvatinib 加 pembrolizumab 與其他四種組合沒有顯示出統計學上的顯著差異（axitinib加avelumab：HR = 1.21，95% CI 0.82–1.79；axitinib加 pembrolizumab：HR = 1.03 , 95% CI 0.72–1.48；bevacizumab加atezolizumab：HR = 1.41, 95% CI 0.99–2.01；cabozantinib加nivolumab：HR = 1.00, 95% CI 0.67–1.50）。根據調整後的間接比較，基於抗 PD-1 的聯合療法在總生存期方面的表現優於基於抗 PD-L1 的聯合療法（HR = 0.77, 95% Cl 0.62–0.98）。基於 VEGFR-TKI 的聯合治療在無進展生存期（HR = 0.69, 95% Cl 0.50–0.95）、總生存期（HR = 0.74, 95% Cl 0.58–0.95）與客觀緩解率（OR = 2.63, 95% Cl 1.81–3.83）優於基於抗 VEGF 的聯合治療，並具有 3 級或大於3級的治療相關不良事件發生率（OR = 2.31, 95% Cl 1.63–3.27)。結論：與sunitinib相比，所有合併治療均顯示出更好的無進展生存期，lenvatinib加pembrolizumab抗腫瘤作用最強，而bevacizumab加atezolizumab的抗腫瘤作用最弱。在間接比較的結果中顯示，lenvatinib 加 pembrolizumab 的總生存期似乎優於bevacizumab加 atezolizumab。然而，相比lenvatinib加pembrolizumab，bevacizumab加atezolizumab的毒性顯著降低。據我們所知，目前沒有直接比較的研究證明這種差異。因此，本文報告的研究結果需要在精心設計的比較試驗中得到驗證。此外，調整後的間接比較結果發現，VEGFR-TKI 加上抗 PD-1/PD-L1 抗體可能比抗 VEGF 抗體加上抗 PD-1/PD-L1 抗體具有更好的腫瘤學益處和更大的毒性。

關鍵字

一線治療；晚期腎細胞癌；血管新生抑制劑；抗 PD-1/PD-L1 抗體；合併治療；網絡後設分析

並列摘要

Background: As the first-line treatment in patients with advanced renal cell carcinoma, many studies have supported that the efficacy of angiogenesis inhibitors in combination with anti-PD-1/PD-L1 antibodies is superior to sunitinib in recent years. However, no direct comparisons have been performed among these treatment options. Therefore, a systematic review and network meta-analysis were performed to evaluate the combination of angiogenesis inhibitors and anti-PD-1/PD-L1 antibodies as the first-line therapy for advanced renal cell carcinoma. Additionally, according to the analysis results, bevacizumab plus atezolizumab and lenvatinib plus pembrolizumab were compared in a clinical trial protocol. Methods: Under the Preferred Reporting Items for Systematic Review statement, a systematic search of reported studies was performed in MEDLINE, the Cochrane library, clinicaltrial.gov, PubMed, and EMBASE to identify phase III randomized controlled trials of patients receiving first-line angiogenesis inhibitors plus anti-PD-1/PD-L1 antibodies therapy for advanced renal cell carcinoma. A network meta-analysis with frequentist methods in the random-effects model was performed. In addition, directed meta-analyses and adjusted indirect comparisons were conducted between anti-VEGF-based combination therapy and VEGFR-TKIs-based combination therapy or between anti-PD-L1-based combination therapy and anti-PD-1-base combination therapy. Results: Five trials were included in the network meta-analyses comprising 4025 patients. When compared with sunitinib, all combination treatments had significantly improved progression-free survival (axitinib plus avelumab: HR = 0.69, 95% CI 0.58–0.83; axitinib plus pembrolizumab: HR = 0.71, 95% CI 0.60–0.84; bevacizumab plus atezolizumab: HR = 0.83, 95% CI 0.71–0.98; cabozantinib plus nivolumab: HR = 0.52, 95% CI 0.43–0.63; lenvatinib plus pembrolizumab: HR = 0.39, 95% CI 0.32–0.48). When the comparison used bevacizumab plus atezolizumab as a reference. Bevacizumab plus atezolizumab was significantly associated with a lower risk of grade 3 or higher treatment-related adverse events when compared with the other treatments (axitinib plus avelumab: OR = 1.82, 95% CI 1.25–2.65; axitinib plus pembrolizumab: OR = 2.10, 95% CI 1.43–3.09; cabozantinib plus nivolumab: OR = 2.55, 95% CI 1.69–3.85; lenvatinib plus pembrolizumab: OR = 3.17, 95% CI 2.32–2.24; sunitinib: OR = 1.72, 95% CI 1.32–2.24). When lenvatinib plus pembrolizumab was used as the reference for the network meta-analyses. In terms of overall survival results, lenvatinib plus pembrolizumab did not show statistically significant differences from the other four combinations (axitinib plus avelumab: HR = 1.21, 95% CI 0.82–1.79; axitinib plus pembrolizumab: HR = 1.03, 95% CI 0.72–1.48; bevacizumab plus atezolizumab: HR = 1.41, 95% CI 0.99–2.01; cabozantinib plus nivolumab: HR = 1.00, 95% CI 0.67–1.50). Based on adjusted indirect comparisons, the anti-PD-1-based combination therapy performed better than the anti-PD-L1-based combination therapy in terms of overall survival (HR = 0.77, 95% Cl 0.62–0.98). The VEGFR-TKIs-based combination therapy had better than the anti-VEGF-based combination therapy in progression-free survival (HR = 0.69, 95% Cl 0.50–0.95), overall survival (HR = 0.74, 95% Cl 0.58–0.95), objective response rate (OR = 2.63, 95% Cl 1.81–3.83), and had associated with a higher risk of grade 3 or higher treatment-related adverse events (OR = 2.31, 95% Cl 1.63–3.27). Conclusions: All combination treatments showed better progression-free survival compared with sunitinib. Lenvatinib plus pembrolizumab showed the strongest antitumor effect, while bevacizumab plus atezolizumab had the weakest. As a result of indirect comparisons, overall survival appeared to be better with lenvatinib plus pembrolizumab than with bevacizumab plus atezolizumab. However, bevacizumab plus atezolizumab had significantly lower toxicity. To the best of our knowledge, no head-to-head comparative studies demonstrate the difference. Therefore, the findings reported herein need to be validated in well-designed comparative trials. The results of the adjusted indirect comparison found that VEGFR-TKI plus anti-PD-1/PD-L1 antibodies may have better oncological benefits and more toxicity than anti-VEGF antibodies plus anti-PD-1/PD-L1 antibodies.

並列關鍵字

First-line treatment ； Advanced renal cell carcinoma ； Angiogenesis inhibitors ； Anti-PD-1/PD-L1 antibodies ； Combination therapy ； Network meta-analysis

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