新輔助免疫檢查點抑制劑(抗程序性細胞死亡受體-1/程序性細胞死亡-配體1抗體)聯合化學治療用於可切除非小細胞肺癌：系統性回顧、統合分析及臨床試驗計畫書

Abstract

背景： 對於早期和局部晚期非小細胞肺癌（NSCLC），手術被視為主要的治療方法，以治癒為目的。手術的5年總體生存率從IA期的92％到IIIB期的26％不等。然而，約30%-55%的患者即使接受完整的切除手術，仍可能出現疾病復發，主要是遠端轉移。儘管加入新輔助或傳統輔助化學治療僅能提高5年生存率5%。具體而言，免疫檢查點抑制劑(ICIs)的程序性細胞死亡受體-1（PD-1）及其配體-1（PD-L1）已成為轉移性NSCLC的標準治療，顯示出比傳統細胞毒性化學治療有更高的治療反應率並改善總體生存。雖然在晚期NSCLC的免疫療法取得了顯著進展，但對於可切除的NSCLC，新輔助免疫療法的治療效果和安全性尚未明確證實。

方法： 研究透過檢索PubMed、Cochrane Library、ClinicalTrial.gov等數據庫，以及參考國際癌症會議(ASCO/AACR/ESMO)的摘要和報告，進行系統性檢索和統合分析， 比較新輔助免疫檢查點抑制劑(ICIs)聯合化學治療與單獨化學治療的療效和安全性。評估指標包括病理完全反應率(pCR)、主要病理反應率(MPR)、無事件存活率(EFS)、總體生存期(OS)、手術切除率以及3-4級不良事件(AE)。

結果： 納入4篇條件符合的隨機對照試驗進行統合分析。比較新輔助免疫檢查點抑制劑合併雙鉑化學治療和單獨化學治療，結果顯示，新輔助免疫檢查點抑制劑合併雙鉑化學治療顯著提高了病理完全反應率(pCR) (OR=10.16 [95% CI: 4.08 to 25.30], P < 0.00001 )、主要病理反應率(MPR) (OR=5.97 [95% CI: 3.45 to 10.31], P < 0.00001)以及延長了無事件生存期(EFS) (HR=0.57 [95% CI: 0.42 to 0.78], P=0.0004)。同時，相較於單獨化學治療，新輔助免疫檢查點抑制劑合併雙鉑化學治療在總體生存期(OS) (OR=0.56 [95% CI: 0.39 to 0.81], P=0.002)和手術切除率(OR=1.60 [95% CI: 1.02 to 2.53], P=0.04]方面也具有統計學的顯著差異。在安全性方面，合併化學治療與單獨化學治療相比沒有明顯的統計學差異，兩組治療的耐受性相當，沒有引起任何新的安全顧慮。

對於亞組(Subgroup) PD-L1表現的無事件生存期 (EFS based on PD-L1 expression level)和臨床分期的無事件生存期(EFS based on clinical stage)的結果，如上述的統合分析所示，新輔助免疫檢查點抑制劑合併雙鉑化學治療有較好的臨床結果。其中患者PD-L1表現≥ 1%在無事件生存期的表現優於PD-L1表現< 1%的患者; 在III期的患者中，比IB-II期的患者有較佳的臨床益處。

結論： 對於患有非小細胞肺癌且處於早期階段、可以透過手術進行治療的患者，新輔助免疫檢查點抑制劑合併雙鉑化學治療組合可以顯著提升病理完全反應率(pCR)及延長無事件生存期(EFS)，並且二組治療的比較並未產生新的安全性問題。

Background: Early and locally advanced non-small-cell lung cancer (NSCLC), surgery is considered the primary treatment approach with curative intent. This procedure has shown a 5-year overall survival rate ranging from 92% for stage IA to 26% for stage IIIB. However, despite the complete removal of the tumor, approximately 30% to 55% of patients experience a recurrence of the disease, primarily in distant locations.1 The utilization of neoadjuvant or adjuvant chemotherapy has only resulted in a modest 5% improvement in the 5-year survival rate.2 Immunotherapy has become an increasingly important systemic treatment option for non-small cell lung cancer (NSCLC) in recent years, surpassing the benefits provided by traditional chemotherapy regimens. Specifically, the use of immune checkpoint inhibitors (ICIs) targeting the programmed death 1 (PD-1) pathway and its ligand (PD-L1) has become the standard of care for metastatic NSCLC, showing higher response rates and improved overall survival compared to conventional cytotoxic chemotherapy. While significant progress has been made in immunotherapy for advanced NSCLC, the effectiveness and safety of neoadjuvant immunotherapy for resectable NSCLC have yet to be clearly demonstrated. 3

Methods: We conducted a thorough search across various databases, such as PubMed, Cochrane Library, ClinicalTrial.gov, and ASCO/AACR/ESMO abstracts, to identify randomized controlled trials that focused on patients with confirmed stage IB-IIIB cancer. Specifically, we explored the combination of neoadjuvant ICIs with chemotherapy and compared it to chemotherapy alone. The key measures analyzed in these trials included pathologic complete response (pCR), major pathologic response (MPR), event-free survival (EFS), overall survival (OS), resection rates, and the occurrence of adverse events (AE) graded 3-4. By analyzing these endpoints, we aimed to evaluate both the effectiveness and safety of the combined treatment approach.

Result: After conducting a screening and review process, a total of 106 articles were identified. Upon careful examination, 4 randomized controlled trials (RCTs) were chosen for meta-analysis as they met the inclusion criteria. The findings of the analysis indicate that combining neoadjuvant ICIs with chemotherapy leads to significant improvements in several key outcomes. Firstly, the combination therapy showed a significant enhancement in pCR (odds ration [OR]= 10.16 [95% CI: 4.08 to 25.30], P < 0.00001). Additionally, it resulted in longer EFS (hazard ratio [HR]=0.57, [95% CI: 0.42 to 0.78], P=0.0004)). Furthermore, the combination therapy demonstrated benefits in terms of MPR (OR=5.97 [95% CI: 3.45 to 10.31], P < 0.00001), OS (HR=0.56 [95% CI:0.39 to 0.81], P=0.002 ), resection rate (OR=1.60 [95%:1.02 to 2.53], P=0.04 ), and the occurrence of AE of grade 3-4 (OR=1.20 [95% CI: 0.79 to 1.81], P=0.40 ), as compared to chemotherapy alone. Importantly, the combination therapy was found to be well-tolerated and did not raise any new safety concerns. Furthermore, subgroup analysis revealed that the combination of neoadjuvant ICIs with platinum-doublet chemotherapy yielded superior clinical outcomes in terms of EFS based on PD-L1 expression level and EFS based on clinical stage. Specifically, patients with PD-L1 levels ≥ 1% exhibited better EFS compared to patients with PD-L1 levels < 1%. Moreover, patients in stage III experienced greater clinical benefits than those in stages IB-II.

Conclusions: The utilization of neoadjuvant ICIs alongside chemotherapy in resectable NSCLC patients demonstrated a greater proportion of individuals achieving a pCR and significantly prolonged EFS compared to chemotherapy alone. Importantly, the combination treatment was well tolerated and did not introduce any new safety concerns.