使用標靶治療或合併免疫治療之療效及安全性以肝細胞癌及腎細胞癌為例:統合分析與臨床試驗計畫書

Efficacy and Safety of Targeted Therapy or in Combination with Immunotherapy in Unresectable Hepatocellular Carcinoma and Advanced Renal Cell Carcinoma: A Meta-Analysis and Protocol

游雅芳(Ya-Fang Yu)

指導教授 ： 成佳憲

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2022年)

https://doi.org/10.6342/NTU202203447

摘要

背景：在過去三十年，癌症治療的方式已經從相對非特異性的細胞毒性藥物發展為選擇性的、針對作用機制之治療方法。標靶藥物主要為抑制癌細胞生長和維持重要的分子途徑，儘管腫瘤對靶向治療的初始反應可能很高，產生積極的反應率，並且提高大部分患者的生存率，但耐藥性通常會限制長期的療效，且腫瘤高復發率和藥物引起的相關副作用，仍常發生在肝細胞癌及腎細胞癌患者。免疫治療僅在少數晚期腎細胞癌患者表現出持久的效果。免疫檢查抑制劑單獨使用的治療不足以改善晚期肝細胞癌患者的整體存活期或疾病無惡化存活期。此外，日益漸增的臨床研究結果展現，合併使用標靶治療和免疫治療，對肝細胞癌及腎細胞癌患者可能帶來協同作用和持續的療效。
方法：本研究於電子資料庫，以無法切除肝細胞癌或晚期腎細胞癌為對象，使用關鍵字，隨機分派試驗、標靶治療或合併PD-1/PD-L1抑制劑治療進行文獻搜尋，並以RECIST1.1評估工具測得至少一個病灶、ECOG日常體能狀態為0-2分、柯氏體能表現狀態≥70分、Child-Pugh 評分≤7，及療效指標為整體存活期、疾病無惡化存活期、不良事件，列為納入條件，進行文獻分析。
結果：九篇為第二/三階段試驗研究論文（三篇為肝細胞癌，六篇為腎細胞癌）進行統合分析。在肝細胞癌風險比值為0.67（95% CI，0.50–0.91，p= 0.01)及腎細胞癌風險比值為0.73 (95% CI，0.62–0.86，p = 0.0002)，標靶治療單獨使用的整體存活期低於標靶治療合併PD-1/PD-L1抑制劑治療；而兩者於接受合併治療後，在疾病無惡化存活期的表現皆優於單獨標靶治療。在3-5 級治療相關不良事件，肝細胞癌勝算比為1.98（95% CI，1.13–3.48，p = 0.02）相較於單獨治療，合併治療有較高的勝算會發生；而在腎細胞癌接受單獨治療或合併治療則無明確差異，勝算比為1.03（95% CI，0.70–1.52，p = 0.88）。
結論：對於無法切除肝細胞癌和晚期腎細胞癌，與單獨治療相較下，合併治療顯著改善整體存活期或疾病無惡化存活期。然而，標靶治療合併 PD-1/PD-L1 抑制劑的不良事件發生率與單獨標靶治療在腎細胞癌未顯示差異，而在肝細胞癌則是合併治療有較高的勝算比會出現≥ 3級治療之不良事件。

關鍵字

標靶治療 ； 免疫治療 ； 晚期肝細胞癌 ； 晚期腎細胞癌 ； 系統性文獻回顧 ； 統合分析

並列摘要

Background
Over the past three decades, systemic cytotoxic chemotherapy for cancer treatment has evolved into selective and specific targeted therapies and mechanisms of action-based immunotherapy. Although targeted therapies have good initial response rates and can improve survival in some patients, targeted therapies have high recurrence rates and drug-related side effects in unresectable hepatocellular carcinoma (HCC) patients and advanced renal cell carcinoma (RCC) patients. It makes more effective and safer treatments urgently needed. Immunotherapy has shown the long-lasting effects in only a few patients with advanced RCC. Monotherapy with immune checkpoint inhibitors was not robust enough to improve overall survival (OS) and/or progression-free survival (PFS) in unresectable HCC patients. Besides, there is growing evidence that combining targeted therapy with immunotherapy can produce synergistic and sustained effects in patients with HCC and RCC.
Methods
We searched databases including PubMed, Web of Science, Cochrane Library, and EMBASE for the clinical randomized controlled trials (RCTs) reporting the comparison between targeted therapy alone and the combination of targeted therapy and PD-1/PD-L1 inhibitors in unresectable HCC and advanced RCC patients. Eligibility criteria were patients with unresectable HCC or advanced RCC; at least one lesion is present that, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST1.1), can measure; Eastern Cooperative Oncology Group performance status of 0 to 2; Karnofsky Performance Status Scale ≥70; Child-Pugh score ≤7. Outcome measurements include OS, PFS, and adverse event (AE).
Results
Nine studies were included, three for HCC and six for RCC. All these studies were phase II/III RCTs. Meta-analysis showed that targeted therapy alone was inferior to the combination of targeted therapy and PD-1/PD-L1 inhibitors, in terms of OS, in patients with HCC the hazard ratio (HR) was 0.67 (95% CI, 0.50–0.91, p = 0.01) and RCC the HR was 0.73 (95% CI, 0.62–0.86, p = 0.0002). Meta-analysis showed that all combined therapies had PFS advantages over targeted therapy alone. In the analysis of grade 3–5 TRAEs, the combination therapy was higher than monotherapy in HCC (OR= 1.98, 95% CI, 1.13–3.48, p = 0.02). The odds ratios were not different between combination therapy and monotherapy for grade 3–5 TRAEs, and were 1.03 (95% CI, 0.70–1.52, p = 0.88) in RCC.
Conclusion
For unresectable HCC and advanced RCC, the combination of targeted therapy with PD-1/PD-L1 inhibitors increased OS and PFS significantly compared to targeted therapy alone. However, in RCC, the incidence of AEs in combining targeted therapies with PD-1/PD-L1 inhibitors was not different from that with targeted therapy alone. In HCC, the incidence of AEs was higher with combination therapy than with monotherapy.

並列關鍵字

targeted therapy ； immunotherapy ； unresectable hepatocellular carcinoma ； advanced renal cell carcinoma ； systematic review ； meta-analysis

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