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Pathological Response and Tumor Immune Microenvironment Remodeling Upon Neoadjuvant ALK-TKI Treatment in ALK-Rearranged Non-Small Cell Lung Cancer

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Abstract

Background

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI; ALKi) have shown potent antitumor activity in metastatic non-small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+); however, their efficacy in neoadjuvant settings has been poorly explored.

Objective

This retrospective study aimed to examine the clinical activity and tumor immune microenvironment (TIME) changes of neoadjuvant ALKi therapy.

Methods

ALK+ NSCLC patients treated with neoadjuvant ALKi at three hospitals in China between February 2018 and January 2023 were assessed. Data on clinical features and radiographic and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pretreatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME.

Results

A total of 12 patients with stage IIA–IIIB NSCLC who received neoadjuvant ALKi therapy were analyzed. The objective response rate was 91.7% (11/12) and the major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed a significant increase in immune infiltration of CD8+ cells (histochemistry score [H-score]: median 10.51 vs. 24.01, p = 0.028; density: median 128.38 vs. 694.09 cells/mm2, p = 0.028; percentage: median 3.53% vs. 15.92%, p = 0.028) and CD4+ cells (density: median 275.56 vs. 651.82 cells/mm2, p = 0.028; percentage: median 5.98% vs. 10.46%, p = 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB- cells. However, macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy.

Conclusion

Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME changes by neoadjuvant ALKi therapy and merits further investigation.

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Author information

Author notes

  1. Nan Zheng, Yimin Zhang, Yue Zeng, and Qiang Ma contributed equally to this work.

Authors and Affiliations

  1. Department of Respiratory Medicine, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, China

    Nan Zheng, Yimin Zhang, Qian Zhao, Conghua Lu, Jie Tian, ZhiGuo Wang, Huan Tang, Nuo Luo, Yong He & Li Li

  2. Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China

    Yue Zeng & Fang Wu

  3. Department of Pathology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China

    Qiang Ma & Hualiang Xiao

  4. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ruiguang Zhang

  5. Department of Oncology, Hunan Key Laboratory of Tumor Models and Individualized Medicine, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Hunan Cancer Mega-Data Intelligent Application and Engineering Research Center, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China

    Fang Wu

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  1. Nan Zheng
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Corresponding authors

Correspondence to Yong He, Fang Wu or Li Li.

Ethics declarations

Funding

This work was supported by the National Natural Science Foundation of China (82272908); Natural Science Foundation of Chongqing Municipality (CSTB2022NSCQ-MSX1110); The Science Foundation for Outstanding Young People of the Army Medical University (40137-2780); The Science Foundation of Daping Hospital, Army Medical University (2019CXLCB011); Guangdong Association of Clinical Trials (GACT)/Chinese Thoracic Oncology Group (CTONG); Clinical medical technology innovation ability training program (2019CXLCA00); and Clinical Medical Research Talent Training Program of the Army Medical University (2018XLC1015).

Conflict of interest

Nan Zheng, Yimin Zhang, Yue Zeng, Qiang Ma, Ruiguang Zhang, Qian Zhao, Conghua Lu, Jie Tian, ZhiGuo Wang, Huan Tang, Nuo Luo, Hualiang Xiao, Yong He, Fang Wu, and Li Li declare they have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethics approval

This study was approved by the Ethics Committee of the Daping Hospital, Army Medical University (no. 2022173).

Consent to participate

Written informed consent was obtained from patients or their legal guardians, before their participation in the study.

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The authors confirm that this manuscript is original and will not be published elsewhere without the written consent of the publisher.

Data availability

All data included in this study are available upon request to the corresponding author.

Code availability

Not applicable.

Authors’ contributions

Conception and design: LL. Development of methodology: FW, YH. Acquisition of data (including acquired and managed patients, and provision of facilities, etc.): NZ, YZ, YZ, QM, RZ, QZ, Conghua Lu, Jie Tian, ZGW, HT, NL, HX. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): NZ, YZ, YZ, CL. Writing, review, and/or revision of the manuscript: NZ, YZ, YZ, QM. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): NZ, YZ, YZ, QM. Study supervision: LL, FW, YH.

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Zheng, N., Zhang, Y., Zeng, Y. et al. Pathological Response and Tumor Immune Microenvironment Remodeling Upon Neoadjuvant ALK-TKI Treatment in ALK-Rearranged Non-Small Cell Lung Cancer. Targ Oncol 18, 625–636 (2023). https://doi.org/10.1007/s11523-023-00981-7

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