第三代酪胺酸激酶抑制劑合併全身治療與單用第三代酪胺酸激酶抑制劑在帶有表皮生長因子受體突變之第IV期非小細胞肺癌第一線治療中的比較：系統性回顧、網絡統合分析與臨床試驗計劃書

Abstract

一、背景 肺癌具有高發病率與高死亡率的特性，尤其早期肺癌通常缺乏明顯症狀，多數患者確診肺癌時已處於晚期。非小細胞肺癌（NSCLC）約占所有肺癌病例的85%[1]，其中約20%的西方患者與40-50%的亞洲患者具有表皮生長因子受體（EGFR）基因突變，尤以外顯子19缺失（Ex19del）與外顯子21 L858R點突變最為常見。第三代EGFR標靶藥物（如Osimertinib）因具有優異的療效與較佳的安全性，已成為EGFR突變非小細胞癌患者的第一線標準治療。然而，約四分之一患者在接受標靶治療後仍出現疾病進展，且以腦部轉移最為常見[5]。為延緩抗藥性的產生，臨床上常考慮合併系統性治療（如化學治療、抗血管新生藥物或雙特異性抗體Amivantamab），但合併治療亦可能增加毒性風險。本研究旨在探討第三代EGFR TKI單獨或合併系統性治療於EGFR突變晚期NSCLC患者中的療效與安全性。 二、方法 本研究進行系統性文獻回顧、統合分析及網絡統合分析，檢索PubMed、Embase及Cochrane資料庫，納入六項隨機對照試驗（RCTs），比較第三代EGFR TKI單獨或合併化學治療、抗血管新生藥物與雙特異性抗體的治療效果。主要評估指標包括無進展生存期（PFS）、總生存期（OS）、客觀反應率（ORR）、三級以上不良事件（AE）發生率與治療中斷率，並進行亞組分析，探討基因型態、年齡、種族、體能狀態（ECOG）及是否合併腦部轉移對治療反應之影響。 三、結果 這項研究納入了 1,991 名患有 EGFR 突變的晚期非小細胞肺癌 (NSCLC) 患者。分析結果顯示，第三代EGFR TKI合併鉑類化療在延長無惡化存活期（PFS）方面最有效益（HR=0.69，95%CI：0.53-0.89），其中合併治療對中樞神經系統（CNS）轉移患者更具有PFS效益（HR=0.47）。第三代EGFR TKI合併Amivantamab亦能顯著改善PFS（HR = 0.70，95% CI: 0.58–0.85），尤以65歲以下患者受益最大（HR = 0.62）。值得注意的是，65歲以上患者使用第三代EGFR TKI合併化學治療亦觀察到PFS改善的趨勢（HR = 0.68，95% CI: 0.47–0.98），顯示年齡本身不應成為限制合併治療使用的因素。相較之下，第三代EGFR TKI與抗血管新生藥物合併治療僅帶來有限的PFS改善（HR=0.81，95%CI：0.56-1.17），且對控制CNS轉移的效果較弱。亞組分析顯示，外顯子19缺失患者（HR=0.615）的治療反應優於L858R突變患者； ECOG 體能評分為 1 的患者從聯合治療中獲益較少（HR = 0.80），而 ECOG 評分為 0 的患者獲益較少。在總存活期（OS）方面，僅第三代EGFR TKI合併化療顯示出統計學上顯著的優勢（HR=0.77，95%CI：0.60-0.97）。但合併治療也伴隨較高的不良事件風險，包括3級或以上不良事件（第三代EGFR TKI合併化療：RR=2.34；合併Amivantamab：RR=1.76）及較高的治療中止率（合併Amivantamab：RR=2.54）。 四、結論 第三代EGFR TKI合併治療對於EGFR突變晚期非小細胞肺癌患者，特別是具有腦部轉移或年齡較輕者，能有效延長PFS。然而，合併治療同時伴隨較高的不良事件與治療中斷率，需在療效與安全性間取得平衡。第三代EGFR標靶藥物合併抗血管新生治療雖毒性較低，但其PFS與OS效益有限。治療決策應根據個別患者之基因型、年齡、ECOG表現與轉移部位進行個別化考量。本研究以第三代EGFR標靶藥物為共同基準間接比較，並未進行合併治療間的直接性比較，藥物間可能存在潛在異質性。未來仍需更多高品質、直接比較之隨機對照試驗以驗證本研究結果，進一步優化EGFR突變NSCLC之個別化治療策略。

1. Background Lung cancer is characterized by high incidence and mortality, especially as early-stage lung cancer often presents with no symptoms, and most patients are diagnosed at an advanced stage. Due to its aggressive nature and difficulty in early diagnosis, lung cancer remains the leading cause of cancer-related death globally, with non-small cell lung cancer (NSCLC) comprising 85% of all lung cancers [1]. Among NSCLC patients, EGFR mutations occur in approximately 20% of Western populations, while the prevalence is higher in East Asia, affecting 40-50% of NSCLC cases. The most common EGFR mutations are exon 19 deletions (Ex19del) and exon 21 L858R point mutations, which account for 44.8% and 39.8% of EGFR mutations, respectively. Third-generation EGFR tyrosine kinase inhibitors (TKIs), such as Osimertinib, have become the first-line treatment for EGFR-mutated NSCLC due to their excellent efficacy and lower toxicity. However, approximately 25% of patients with EGFR-mutated NSCLC experience disease progression after a period of targeted therapy, with brain metastasis being the most common form of progression [5]. After treatment failure, these patients generally rely on chemotherapy or other systemic medications. Common systemic therapies include chemotherapy, anti-angiogenic agents, and bispecific antibodies, which, when added during first-line targeted therapy, may delay resistance but could also increase toxicity. This study aims to explore the efficacy and safety of using third-generation EGFR TKIs alone or in combination with systemic treatments as first-line therapy for patients with EGFR-mutated NSCLC. 2. Methods This study conducted a systematic review, meta-analysis, and network meta-analysis to evaluate the efficacy and safety of third-generation EGFR TKIs combined with various systemic treatments, particularly in EGFR-mutated metastatic NSCLC. Relevant trials were identified through searches of PubMed, Embase, and Cochrane, and six randomized clinical trials were selected for analysis. The outcomes assessed included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), discontinuation rate, overall survival (OS), and correlations between these outcomes and subgroups, such as CNS metastasis, EGFR mutation subtypes, race, age, and ECOG performance status. 3. Results This study analyzed six randomized controlled trials (RCTs) involving 1,991 patients with EGFR-mutated metastatic NSCLC. To facilitate comparative evaluation, treatment strategies were categorized into three groups based on therapeutic mechanisms and clinical usage patterns: platinum-based chemotherapy combined with third-generation EGFR TKIs, anti-angiogenic (anti-VEGF) agents combined with third-generation EGFR TKIs, and third-generation EGFR TKI plus amivantamab combinations. Combination treatments significantly improved progression-free survival (PFS), with the most pronounced benefit observed in third-generation EGFR TKI plus chemotherapy (HR: 0.69, 95% CI: 0.53–0.89) and third-generation EGFR TKI plus amivantamab (HR: 0.70, 95% CI: 0.58–0.85). Younger patients (<65 years), patients with CNS metastases, and those harboring exon 19 deletions demonstrated the greatest benefit. Notably, older patients (≥65 years) also experienced favorable outcomes with chemotherapy-based combinations (HR: 0.68, 95% CI: 0.47–0.98), indicating that age alone should not preclude the use of combination therapies. In contrast, combinations with anti-VEGF therapy showed limited PFS improvement (HR: 0.81, 95% CI: 0.56–1.17) and no overall survival (OS) advantage. Combination therapies were associated with higher risks of grade ≥3 adverse events (RR: 2.34 for chemotherapy, RR: 1.76 for amivantamab) and increased treatment discontinuation rates (RR: 2.54 for amivantamab combinations). 4. Conclusion Third-generation EGFR TKI combination therapies, particularly with chemotherapy or amivantamab, provide meaningful clinical benefits in EGFR-mutated metastatic NSCLC, especially among younger patients, those with CNS metastases, and patients harboring exon 19 deletions. However, these combinations are associated with increased toxicity, emphasizing the need for careful patient selection based on age, ECOG performance status, and mutation subtype. Given the methodological limitations of network meta-analysis and potential biases from pharmacologic classification, further large-scale randomized trials are needed to confirm these findings and optimize individualized therapeutic strategies.