Abstract
This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors (ICIs) by conducting systematic literature search in electronic databases up to May 31, 2021. The main outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and durable clinical benefit (DCB) were correlated with tumor genomic features. A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies. The Kirsten rat sarcoma viral oncogene homolog G12C (KRASG12C) mutation combined with tumor protein P53 (TP53) mutation revealed the promising efficacy of ICI therapy in these patients. Furthermore, patients with epidermal growth factor receptor (EGFR) classical activating mutations (including EGFRL858R and EGFRΔ19) exhibited worse outcomes to ICIs in OS (adjusted hazard ratio (HR), 1.40; 95% confidence interval (CI), 1.01–1.95; P=0.0411) and PFS (adjusted HR, 1.98; 95% CI, 1.49–2.63; P<0.0001), while classical activating mutations with EGFRT790M showed no difference compared to classical activating mutations without EGFRT790M in OS (adjusted HR, 0.96; 95% CI, 0.48–1.94; P=0.9157) or PFS (adjusted HR, 0.72; 95% CI, 0.39–1.35; P=0.3050). Of note, for patients harboring the Usher syndrome type-2A (USH2A) missense mutation, correspondingly better outcomes were observed in OS (adjusted HR, 0.52; 95% CI, 0.32–0.82; P=0.0077), PFS (adjusted HR, 0.51; 95% CI, 0.38–0.69; P<0.0001), DCB (adjusted odds ratio (OR), 4.74; 95% CI, 2.75–8.17; P<0.0001), and ORR (adjusted OR, 3.45; 95% CI, 1.88–6.33; P<0.0001). Our findings indicated that, USH2A missense mutations and the KRASG12C mutation combined with TP53 mutation were associated with better efficacy and survival outcomes, but EGFR classical mutations irrespective of combination with EGFRT790M showed the opposite role in the ICI therapy among lung cancer patients. Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.
概要
本研究以探索与免疫检查点抑制剂 (ICIs) 效果有关联的基因突变亚型为目标, 进行了系统文献检索 (电子数据库截至 2021 年 5 月 31 日). 与肿瘤基因特征相关联的主要结局事件包括: 总生存期、 无进展生存期、 客观反应率、 持久临床获益. 我们从 14 项研究中总计提取了 1546 个有基因突变数据的肺癌患者, 发现 ICIs 治疗在 KRASG12C联合 TP53 双突变的患者中有更好的疗效, 而在携带 EGFR 经典激活突变 (包括 EGFRL585R 和 EGFRΔ19) 的患者中的效果则截然相反: 总生存期 (调整后 HR, 1.40; 95% CI, 1.01–1.95; P=0.0411）, 无进展生存期 (调整后 HR, 1.98; 95% CI, 1.49–2.63; P<0.0001). 另外, ICIs 治疗在 EGFR 经典突变联合 EGFRT790M双突变患者与仅有 EGFR 经典突变的患者在总生存期 (调整后 HR, 0.96; 95% CI, 0.48–1.94; P=0.9157) 与无进展生存期 (调整后 HR, 0.72; 95% CI, 0.39–1.35; P=0.3050) 中均无明显差异. 更重要的是, 我们发现 ICIs 在携带 USH2A 错义突变的患者中可能有更好的疗效: 总生存期 (调整后 HR, 0.52; 95% CI, 0.32–0.82; P=0.0077), 无进展生存期 (调整后 HR, 0.51; 95% CI, 0.38–0.69; P<0.0001), 持久临床获益 (调整后 OR, 4.74; 95% CI, 2.75–8.17; P<0.0001) 与客观反应率 (调整后 OR, 3.45; 95% CI, 1.88–6.33; P<0.0001). 综上, 我们的研究发现在使用 ICIs 疗法的肺癌患者中, USH2A 错义突变、 KRASG12C 联合 TP53 双突变与更好的疗效和生存结局有关, 而 EGFR 经典突变无论是否合并 EGFRT790M 突变都预示着不良结局, 我们的结果可能会对在肿瘤 ICIs 的精准治疗方案提供新的依据和靶标.
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 21976155, 81802881, and 81773016), the Zhejiang Provincial Natural Science Foundation of China (No. LY18C060001), the Fundamental Research Funds for the Central Universities, and the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (No. 2019-I2M-5-044), China.
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Yihua WU and Dajing XIA contributed to the conception and design of the study. Yihua WU, Dexin YANG, and Yuqin FENG developed the workflow and methodology. Dexin YANG, Yuqin FENG, Haohua LU, Kelie CHEN, Jinming XU, Peiwei LI, and Tianru WANG contributed to data collection, data analysis, and interpretation. Yuqin FENG, Dexin YANG, Yihua WU, and Dajing XIA contributed to writing and review of the manuscript. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Dexin YANG, Yuqin FENG, Haohua LU, Kelie CHEN, Jinming XU, Peiwei LI, Tianru WANG, Dajing XIA, and Yihua WU declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects performed by any of the authors.
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Yang, D., Feng, Y., Lu, H. et al. USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer. J. Zhejiang Univ. Sci. B 24, 143–156 (2023). https://doi.org/10.1631/jzus.B2200292
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DOI: https://doi.org/10.1631/jzus.B2200292
Key words
- Immune checkpoint inhibitor (ICI)
- Lung cancer
- Usher syndrome type-2A (USH2A) missense mutation
- Kirsten rat sarcoma viral oncogene homolog G12C (KRAS 12C) mutation combined with tumor protein P53 (TP53) mutation
- Epidermal growth factor receptor (EGFR) mutation