ALK阳性非小细胞肺癌术后辅助靶向治疗进展——QEELIN研究解读

doi:10.3877/cma.j.issn.2095-8773.2026.01.08

间变性淋巴瘤激酶（ALK）基因重排非小细胞肺癌（NSCLC）约占所有NSCLC的4%~5%，常见于年轻、不吸烟或轻度吸烟的肺腺癌患者。尽管手术切除为早期患者提供了治愈机会，但鉴于ALK阳性肿瘤生物学特性更具侵袭性，因此术后复发风险显著增加。近年来，随着ALK酪氨酸激酶抑制剂（TKIs）的不断发展，术后辅助靶向治疗已成为改善这一人群预后的重要策略。本文对近年来ALK阳性NSCLC术后辅助靶向治疗的临床研究进行综述，并对QEELIN研究进行重点解读，分析恩沙替尼、阿来替尼等药物在辅助治疗中的疗效与安全性证据，探讨当前临床实践面临的挑战，旨在为ALK阳性NSCLC患者的治疗提供临床指导意见。

关键词: 非小细胞肺癌, 间变性淋巴瘤激酶, 分子靶向治疗, QEELIN研究

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) constitutes 4%–5% of all NSCLC cases and is frequently identified in young, never- or light-smoking patients with lung adenocarcinoma. Although surgical resection offers a curative opportunity for early-stage patients, the risk of postoperative recurrence remains high, particularly in ALK-positive patients due to their more aggressive biological characteristics. In recent years, with the continuous development of ALK tyrosine kinase inhibitors (TKIs), postoperative adjuvant targeted therapy has become a crucial strategy for improving the prognosis of the patient population. This review summarizes recent clinical studies on postoperative adjuvant targeted therapy for ALK-positive NSCLC, with a focus on the QEELIN study. It analyzes the efficacy and safety profiles of drugs such as ensartinib and alectinib in adjuvant settings, addresses current challenges in clinical practice, and aims to provide clinical guidance for the management of ALK-positive NSCLC patients.

Key words: Non-small cell lung cancer, Anaplastic lymphoma kinase, Molecular targeted therapy, QEELIN study

表1 ALK阳性NSCLC辅助和新辅助靶向治疗研究特征对比

研究项目	治疗时机	研究类型	TNM分期	干预措施	主要终点	终点结局
ALINA^[6]	辅助	Ⅲ期RCT	ⅠB~ⅢA期	阿来替尼比化疗	DFS	2年DFS：93.60%比63.70%
ELEVATE^[16]	辅助	Ⅲ期RCT	ⅠB~ⅢB期	恩沙替尼比安慰剂（化疗后）	DFS	2年DFS：87.30%比57.20%
QEELIN^[19]	辅助	RWS	ⅠA1~ⅢB	恩沙替尼	DFS	2年DFS：92.1%
NAUTIKA1^[24]	新辅助	Ⅱ期单臂	ⅠB~Ⅲ期	阿来替尼	MPR	MPR：60.7%；pCR：25.0%
ALNEO^[25]	新辅助	Ⅱ期单臂	Ⅲ期	阿来替尼	MPR	MPR：46.0%；pCR：12.0%
Neo-INFINITY^[26]	新辅助	Ⅱ期单臂	ⅠB~ⅢB期	伊鲁阿克	MPR	MPR：50.0%；pCR：25.0%
WILDERNESS^[27]	新辅助	Ⅱ期单臂	Ⅰ~ⅢB期	布加替尼	MPR	MPR：58.3%；pCR：16.7%
ALTA 1L^[28]	新辅助	Ⅲ期RCT	ⅢB~Ⅳ期	布加替尼比克唑替尼	PFS	1年PFS：85.3%

表1 ALK阳性NSCLC辅助和新辅助靶向治疗研究特征对比

研究项目	治疗时机	研究类型	TNM分期	干预措施	主要终点	终点结局
ALINA^[6]	辅助	Ⅲ期RCT	ⅠB~ⅢA期	阿来替尼比化疗	DFS	2年DFS：93.60%比63.70%
ELEVATE^[16]	辅助	Ⅲ期RCT	ⅠB~ⅢB期	恩沙替尼比安慰剂（化疗后）	DFS	2年DFS：87.30%比57.20%
QEELIN^[19]	辅助	RWS	ⅠA1~ⅢB	恩沙替尼	DFS	2年DFS：92.1%
NAUTIKA1^[24]	新辅助	Ⅱ期单臂	ⅠB~Ⅲ期	阿来替尼	MPR	MPR：60.7%；pCR：25.0%
ALNEO^[25]	新辅助	Ⅱ期单臂	Ⅲ期	阿来替尼	MPR	MPR：46.0%；pCR：12.0%
Neo-INFINITY^[26]	新辅助	Ⅱ期单臂	ⅠB~ⅢB期	伊鲁阿克	MPR	MPR：50.0%；pCR：25.0%
WILDERNESS^[27]	新辅助	Ⅱ期单臂	Ⅰ~ⅢB期	布加替尼	MPR	MPR：58.3%；pCR：16.7%
ALTA 1L^[28]	新辅助	Ⅲ期RCT	ⅢB~Ⅳ期	布加替尼比克唑替尼	PFS	1年PFS：85.3%

1	Jeon H, Wang S, Song J, et al. Update 2025: Management of Non-Small-Cell Lung Cancer[J]. Lung, 2025, 203(1): 53.
2	Detterbeck FC, Boffa DJ, Kim AW, et al. The Eighth Edition Lung Cancer Stage Classification[J]. Chest, 2017, 151(1): 193-203.
3	中华医学会肿瘤学分会. 中华医学会肺癌临床诊疗指南（2025版）[J]. 中华医学杂志, 2025, 105(34): 2918-2959.
4	Reshetnyak AV, Rossi P, Myasnikov AG, et al. Mechanism for the activation of the anaplastic lymphoma kinase receptor[J]. Nature, 2021, 600(7887): 153-157.
5	Voena C, Ambrogio C, Iannelli F, et al. ALK in cancer: from function to therapeutic targeting[J]. Nat Rev Cancer, 2025, 25(5): 359-378.
6	Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer[J]. N Engl J Med, 2024, 390(14): 1265-1276.
7	Chaft JE, Dagogo-Jack I, Santini FC, et al. Clinical outcomes of patients with resected, early-stage ALK-positive lung cancer[J]. Lung Cancer, 2018, 122: 67-71.
8	Diaz-Jimenez A, Shuldiner EG, Somogyi K, et al. EML4-ALK Variant-Specific Genetic Interactions Shape Lung Tumorigenesis[J]. Cancer Discov, 2026, 16(1): 46-65.
9	Tao H, Shi L, Zhou A, et al. Distribution of EML4-ALK fusion variants and clinical outcomes in patients with resected non-small cell lung cancer[J]. Lung Cancer, 2020, 149: 154-161.
10	Elshatlawy M, Sampson J, Clarke K, et al. EML4-ALK biology and drug resistance in non-small cell lung cancer: a new phase of discoveries[J]. Mol Oncol, 2023, 17(6): 950-963.
11	Qian J, Xu J, Wang S, et al. Adjuvant Chemotherapy Candidates in Stage Ⅰ Lung Adenocarcinomas Following Complete Lobectomy[J]. Ann Surg Oncol, 2019, 26(8): 2392-2400.
12	Shin SH, Lee H, Jeong BH, et al. Anaplastic lymphoma kinase rearrangement in surgically resected stage ⅠA lung adenocarcinoma[J]. J Thorac Dis, 2018, 10(6): 3460-3467.
13	Fujibayashi Y, Tane S, Kitazume M, et al. Resected stage Ⅰ anaplastic lymphoma kinase-positive lung adenocarcinoma has a negative impact on recurrence-free survival[J]. Thorac Cancer, 2022, 13(8): 1109-1116.
14	潘锋, 张浩臣. 辅助治疗为早中期肺癌患者带来更多临床获益——《Ⅰ~ⅢB期非小细胞肺癌完全切除术后辅助治疗指南(2021版)》发布[J]. 中国医药导报, 2021, 18(16): 1-3.
15	Peters S, Camidge R, Dziadziuszko R, et al. Alectinib versus crizotinib in previously untreated ALK-positive advanced non-small cell lung cancer: final overall survival analysis of the phase Ⅲ ALEX study[J]. Ann Oncol, 2026, 37(1): 92-103.
16	Yue D, Huang M, Song P, et al. LBA66 Ensartinib as adjuvant therapy in patients (pts) with stage ⅠB–ⅢB ALK-positive (ALK+) non-small cell lung cancer (NSCLC) after complete tumor resection: The phase Ⅲ randomized ELEVATE trial[J]. Ann Oncol, 2025, 36(supplement 2): S1607.
17	Solomon BJ, Ahn JS, Dziadziuszko R, et al. LBA2 ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC)[J]. Ann Oncol, 2023, 34(supplement 2): S1295-S1296.
18	Dziadziuszko R, Solomon BJ, Wu Y, et al. 1787MO Updated results from the phase III ALINA study of adjuvant alectinib vs chemotherapy (chemo) in patients (pts) with early-stage ALK+ non-small cell lung cancer (NSCLC)[J]. Ann Oncol, 2025, 36(supplement 2): S971-S972.
19	Wang L, Zhang J, Wang S, et al. Ensartinib as postoperative adjuvant therapy in patients with ALK-positive non-small cell lung cancer (NSCLC): A registered, retrospective, real-world study[J]. J Clin Oncol 2025, 43(16_suppl): 8024.
20	Yang Y, Zhou J, Zhou J, et al. Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial[J]. Lancet Respir Med, 2020, 8(1): 45-53.
21	Horn L, Wang Z, Wu G, et al. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial[J]. JAMA Oncol, 2021, 7(11): 1617-1625.
22	Fuorivia V, Attili I, Corvaja C, et al. Management of Non-Metastatic Non-Small Cell Lung Cancer (NSCLC) with Driver Gene Alterations: An Evolving Scenario[J]. Curr Oncol, 2024, 31(9): 5121-5139.
23	Zhang C, Jiang BY, Yan LX, et al. Induction ALK-Tkis for Stage Ⅲ Non-Small Cell Lung Cancer Harboring ALK Fusion: A Single-Center Experience With 3-Year Follow-Up [C]. In: Proceedings of the 103rd Annual Meeting of the American Association for Thoracic Surgery. Los Angeles, CA, USA, 2023.
24	Lee JM, Negrao MV, Cummings A, et al. MA04.02 Nautika1: Clinical Outcomes and Pathologic Regression With Neoadjuvant Alectinib in Resectable Stage ⅠB–ⅢB ALK+ NSCLC[J]. J Thorac Oncol, 2025, 20(10, Supplement 1): S66.
25	Leonetti A, Boni L, Gnetti L, et al. Alectinib as neoadjuvant treatment in potentially resectable stage Ⅲ ALK-positive NSCLC: Final analysis of ALNEO phase Ⅱ trial (GOIRC-01-2020-ML42316)[J]. J Clin Oncol, 2025, 43(16_suppl): 8015.
26	Zhang G, Liu Y, Shen D, et al. Neoadjuvant and adjuvant iruplinalkib in resectable ALK or ROS1 fusion-positive, non-small cell lung cancer (NSCLC): The preliminary results of the single-arm, exploratory Neo-INFINITY study [J]. J Clin Oncol, 2025, 43(16_suppl): e20044.
27	Kim CG, Hong MH, Kim J, et al. A window of opportunity study for preoperative brigatinib in resectable anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC): WILDERNESS trial[J]. J Clin Oncol, 2025, 43(16_suppl): 8040.
28	Ćeriman KrstićV, Samardžić N, Stjepanović M, et al. Real World Data on the Efficacy of Brigatinib in ALK-Positive Non-Small Cell Lung Cancer: A Single-Center Experience[J]. Cancers (Basel), 2025, 17(18): 3084.
29	John A, McMahon DJ, Chauhan D, et al. Lorlatinib-associated weight gain and dyslipidaemia: A retrospective analysis and implications for future care[J]. Lung Cancer, 2024, 198: 108034.
30	Mimae T, Satouchi M, Okada M. Psychological states regarding adjuvant chemotherapy in patients with non-small cell lung cancer[J]. Cancer Treat Res Commun, 2022, 32: 100591.
31	Huang Y, Zhang H, Pan H, et al. P1.17.36 Perspectives on Health-Related Quality of Life Among Physicians and Patients With ALK-Positive NSCLC in China[J]. J Thorac Oncol, 2025, 20(10, Supplement 1): S227-S228.
32	Leal T, Sussell J, Ngiam C, et al. Are patients with early-stage non-small cell lung cancer receiving timely testing for the ALK rearrangement?[J]. J Clin Oncol, 2025, 43(16_suppl): e23276.
33	Poei D, Ali S, Ye S, et al. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies[J]. Cancer Drug Resist, 2024, 7: 20.
34	中国医师协会肿瘤医师分会, 中国医疗保健国际交流促进会肿瘤内科学分会. 间变性淋巴瘤激酶酪氨酸激酶抑制剂治疗非小细胞肺癌指南(2025版)[J]. 中华肿瘤杂志, 2025, 47(4): 283-297.
35	Wu L, Zou Z, Li Y, et al. Progression patterns, resistant mechanisms and subsequent therapy for ALK-positive NSCLC in the era of second-generation ALK-TKIs[J]. J Transl Med, 2024, 22(1): 585.
36	Bearz A, Bertoli E, Stanzione B, et al. EML4-ALK: Update on ALK Inhibitors[J]. Int J Mol Sci, 2025, 23(13): 7068.
37	Zhou C, Lu Y, Kim SW, et al. Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced ALK-Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study[J]. JTO Clin Res Rep, 2024, 5(9): 100700.
38	Solomon BJ, Liu G, Felip E, et al. Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase Ⅲ CROWN Study[J]. J Clin Oncol, 2024, 42(29): 3400-3409.
39	Kemper M, Elges S, Kies P, et al. What do we know about the role of neoadjuvant targeted therapy in early-stage EGFR-mutant and ALK-fused non-small cell lung cancer?—a narrative review of the current literature[J]. Transl Lung Cancer Res, 2024, 13(10): 2813-2827.
40	Lavaud P, Bortolot M, Zullo L, et al. Early-Stage Non-Small Cell Lung Cancer: New Challenges with Immune Checkpoint Blockers and Targeted Therapies[J]. Cancers (Basel), 2024, 16(16): 2779.
41	Urbanska EM, Koffeldt PR, Grauslund M, et al. Refining Criteria for Choosing the First-Line Treatment for Real-World Patients with Advanced ALK-Rearranged NSCLC[J]. Int J Mol Sci, 2025, 26(13): 5969.
42	Schneider JL, Lin JJ, Shaw AT. ALK-positive lung cancer: a moving target[J]. Nat Cancer, 2023, 4(3): 330-343.
43	Long M, Peng S, Wen Q, et al. New advances in understanding the mechanisms and treatment challenges of ALK-targeted therapy resistance in lung cancer[J]. Cancer Drug Resist, 2025, 8: 43.
44	Ashton JC. ALK inhibitors against resistance in non-small cell lung cancer: an 18 year medical arms race[J]. Biochem Pharmacol, 2025, 242(Pt 1): 117214.

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Advances of postoperative adjuvant targeted therapy for ALK-positive non-small cell lung cancer——insights from the QEELIN study

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Advances of postoperative adjuvant targeted therapy for ALK-positive non-small cell lung cancer——insights from the QEELIN study