Sun Yuanze, Yang Dan, Huang Zhe, Yan Huan, Zeng Liang, Xu Qinqin, Song Lianxi, Zhou Chunhua, Peng Ling, Xiao Jiwen, Lin Shaoding, Zhou Zhiqing, Xiang Siqi, Ruan Zhaohui, Yang Nong, Zhang Yongchang
Guizhou Medical University, Guiyang, Guizhou, China; Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Pathology, Immuno-Oncology Laboratory, School of Basic Medicine, Central South University, Changsha, Hunan, China.
Clin Lung Cancer. 2025 Jul 19. doi: 10.1016/j.cllc.2025.07.011.
DNA-based next-generation sequencing (NGS) has identified ALK rearrangements in lung squamous cell carcinoma (LUSC), a subset of nonsmall cell lung cancer traditionally lacking effective targeted therapies. While ALK tyrosine kinase inhibitors (TKIs) like crizotinib and alectinib are effective in ALK-rearranged lung adenocarcinoma, their efficacy in LUSC remains poorly defined due to limited subtype-specific data.
We presented a case of ALK-rearranged LUSC and established a patient-derived xenograft (PDX) model to validate the tumor-inhibitory effects of various ALK-TKIs on ALK-positive LUSC. Additionally, we conducted a retrospective study that included 28 patients diagnosed with stage IIIC-IV LUSC who received treatment at Hunan Cancer Hospital between June 2014 and May 2024 to evaluate the clinical characteristics and therapeutic outcomes of ALK-rearranged LUSC in a real-world cohort.
We report a patient with LUSC harboring a novel CSNK1G3-ALK fusion, who demonstrated treatment response and durable disease control with first-line alectinib for over 30 months. PDX-based in vivo studies demonstrated significant tumor shrinkage with crizotinib, alectinib, and lorlatinib compared to vehicle control. In the retrospective cohort (n = 28), first-line ALK-TKI treatment was associated with improved progression-free survival (median PFS: 16.0 months vs. 3.0 months, P < .01), overall survival (median OS: 30.0 months vs. 18.5 months, P = .039), and objective response rates (ORR: 75% vs. 25%, P = .021), compared to first-line chemotherapy.
This study provides real-world evidence supporting the therapeutic benefit of ALK-TKIs in ALK-rearranged LUSC, highlighting their potential as a viable therapeutic strategy for this rare nonsmall cell lung cancer subtype.
基于DNA的下一代测序（NGS）已在肺鳞状细胞癌（LUSC）中鉴定出ALK重排，肺鳞状细胞癌是非小细胞肺癌的一个子集，传统上缺乏有效的靶向治疗。虽然克唑替尼和阿来替尼等ALK酪氨酸激酶抑制剂（TKIs）在ALK重排的肺腺癌中有效，但由于亚型特异性数据有限，它们在LUSC中的疗效仍不明确。
我们报告了一例ALK重排的LUSC病例，并建立了患者来源的异种移植（PDX）模型，以验证各种ALK-TKIs对ALK阳性LUSC的肿瘤抑制作用。此外，我们进行了一项回顾性研究，纳入了2014年6月至2024年5月期间在湖南省肿瘤医院接受治疗的28例诊断为IIIC-IV期LUSC的患者，以评估ALK重排的LUSC在真实世界队列中的临床特征和治疗结果。
我们报告了一名患有LUSC的患者，其携带一种新的CSNK1G3-ALK融合基因，该患者一线使用阿来替尼治疗超过30个月，表现出治疗反应和持久的疾病控制。基于PDX的体内研究表明，与载体对照相比，克唑替尼、阿来替尼和洛拉替尼可使肿瘤显著缩小。在回顾性队列（n = 28）中，与一线化疗相比，一线ALK-TKI治疗与无进展生存期改善（中位PFS：16.0个月对3.0个月，P <.01）、总生存期改善（中位OS：30.0个月对18.5个月，P =.039）和客观缓解率提高（ORR：75%对25%，P =.021）相关。
本研究提供了真实世界的证据，支持ALK-TKIs在ALK重排的LUSC中的治疗益处，突出了它们作为这种罕见的非小细胞肺癌亚型可行治疗策略的潜力。
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