背景：CTONG1104 聯合吉非替尼切除 IIIA 期 NSCLC 平均總生存率為 59.4 個月，SAKK新輔助化療試驗平均生存率為 26.2 個月。對於表皮生長因子受體(EGFR)突變陽性期 IIIA（N2）非小細胞肺癌(NSCLC)患者（患者），新 CTONG1103 顯示新輔助/輔助厄洛替尼治療顯著改善，無進展生存期(PFS)。在這裏，實驗展示了該研究的最終總體生存率(OS)結果。

Background: Median Overall survival (mOS) of stage IIIA resected NSCLC was 59.4 months (m) in CTONG 1104 adj gefitinib and 26.2m in SAKK neoadjuvant chemo trial. EMERGING-CTONG1103 showed neo-adjuvant/adjuvant erlotinib treatment significantly improved progression-free survival (PFS) vs standard doublet chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive resectable stage IIIA (N2) non-small-cell lung cancer (NSCLC). Here, we present the final overall survival (OS) results from the study.

方法：多中心（中國 17 個中心）對 IIIA-N2NSCLC 患者與吉西他濱聯合順鉑(GC)作為19 或 21EGFR 突變的新輔助隨機對照試驗。2011 年 12 月至 2017 年 12 月，篩選了 386 例位點，72 例隨機分為新輔助/輔助埃羅替尼組（N=37）或 GC 組（N=35）。患者接受厄洛替尼150mg/d（新輔助治療，42 天；輔助治療，高達 12 個月）或吉西他濱 1250mg/m2 加順鉑 75mg/m2（新輔助治療，兩個周期；輔助治療，多達兩個周期）。術後每 6 周和每 3 個月進行一次評估。主要終點是實體腫瘤(RECIST)1.1 版的客觀響應率(ORR)；次要終點是病理完全反應、病理淋巴結下降率、進展生存期、總體生存率、安全性和耐受性。數據截止日期為 2021 年 1 月29 日。

Methods: This was a multicenter (17 centers in China) phase II randomized controlled trial of erlotinib（E）versus gemcitabine plus cisplatin (GC) as neoadjuvant/adjuvant therapy in pts with stage IIIA-N2 NSCLC with EGFR mutations in exon 19 or 21. From Dec 2011 to Dec. 2017, 386 pts sites were screened and 72 pts were randomly assigned to neoadjuvant/adjuvant E arm (N = 37) or GC arm(N = 35). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postoperative. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, downstaging rates of pathological lymph nodes, PFS, OS, safety, and tolerability. Data cut-off date was January, 29 2021.

結果：隨訪中值為 62.5 個月，ITT 人群 47 例（65.3%）事件的操作係統中值為 42.2 個月。輔助埃羅替尼組中的平均總生存率為 42.2 個月，氣相色譜中為 36.9 個月（風險率=0.83, 95% 置信區間為 0.47-1.47，P=0.513）。3 和 5 年的總體生存率分別為 58.6%，輔助埃羅替尼組為40.8%和 55.9%，27.6%（p3-y=0.819，p5-y=0.252）。所有預定義子群，包括年齡、性別、EGFR突變類型，在統計數據上無顯著差異。後續治療(ST)尤其是靶向治療對總體生存率的影響最大（風險率=0.35, 95%置信區間為 0.18-0.70）。接受後續治療的患者的平均總體生存率為 45.8 個月（n=38），其他治療為 34.6 個月（n=12），無後續治療為 24.6 個月（n=15）。輔助埃羅替尼組平均總生存率為 46.4 個月（n=15；目標治療），42.2 個月（n=8；其他）和 24.6 個月（n=9；無，P=0.021），吉西他濱聯合順鉑為 42.6 個月（n=23；目標治療），30.1 個月（n=4；其他）和 24.6 個月（n=6；無，P=0.130）。輔助埃羅替尼組組再次挑戰 EGFR 酪氨酸激酶抑製劑的患者的響應率為 53.3%，疾病控製率為 93.3%，mPFS 為 10.90 個月和 mPPS 為 21.90個月（n=15）。隨訪中未觀察到新的意外嚴重不良事件

Results: With a median follow-up of 62.5 months, the median OS was 42.2months based on 47 (65.3%) events in ITT whole population. The mOS was 42.2m in E and 36.9m in GC (HR 0.83, 95%CI 0.47-1.47, p = 0.513). The 3-,5-year OS rate were 58.6%, 40.8% in E and 55.9%, 27.6% in GC respectively (p3-y = 0.819, p5-y = 0.252). All predefined subgroups including age, gender, EGFR mutation type had no significant difference in statistics between two arms. Subsequent treatments (ST) especially targeted therapy contributed most to OS (HR = 0.35,95% CI 0.18- 0.70). Median OS of pts receiving ST was 45.8m (n = 38), 34.6m in other treatment (n = 12), 24.6m in without ST (n = 15). For E mOS were 46.4 (n = 15; target therapy), 42.2m (n = 8; other) and 24.6m (n = 9; without, p = 0.021), for GC 42.6 (n = 23; target therapy), 30.1m (n = 4;other) and 24.6m(n = 6; without, p = 0.130). The RR was 53.3%, DCR 93.3%, mPFS 10.9m and mPPS 21.9m for patients with rechallenged EGFR TKI in E arm (n = 15). No novel unexpected SAE was observed during follow up.

結論：厄洛替尼作為新輔助/輔助治療N2期非小細胞肺癌是可行的，具有良好的臨床應用前景。在新出現的試驗（NCT01407822）中，E的PFS生存優勢並未轉化為OS差異。

Conclusion: Erlotinib as neoadjuvant/adjuvant therapy for resected N2 NSCLC was feasibility and had a promising OS. The PFS survival advantage of E did not translate to OS difference in EMERGING trial (NCT01407822).