Prognostic value of <i>ERBB2</i> Exon20 insertions in advanced NSCLC patients receiving first-line chemoimmunotherapy_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WANG Yuan ^1,2 , ZHANG Li ^1,2,3 ,  QIU Zhixin ^2,3

1. Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Respiratory and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. Department of Respiratory and Critical Care Medicine, Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

QIU Zhixin, Email: qiuseagull@foxmail.com

Keywords：

Non-small cell lung cancer; ERBB2; Exon20ins; progression-free survival; prognosis

DOI：

10.7507/1671-6205.202503068

Video：

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Objective To investigate the prognostic value of ERBB2 Exon20ins (Exon20ins) in advanced non-small cell lung cancer (NSCLC) patients receiving first-line chemotherapy combined with immunotherapy. Methods A retrospective analysis was conducted on clinical data from ERBB2-mutant stage IV NSCLC patients who received first-line chemotherapy combined with immunotherapy at West China Hospital of Sichuan University between 2020 and 2024. ERBB2 wild-type patients were matched using propensity score matching. Clinical pathological characteristics, distant metastatic sites, and treatment outcomes were compared among patients with different mutation statuses. The primary endpoint was progression-free survival (PFS), and Kaplan-Meier method was used to plot survival curves. Cox regression analysis was performed to adjust for confounding factors. Results This study included 41 ERBB2-mutant stage IV NSCLC patients, of whom 22 had Exon20ins mutations, and 19 had other ERBB2 mutations. Forty-one ERBB2 wild-type patients were matched for comparison. The mean age of all patients was 60.0±9.3 years, with 61 males (74.4%). A total of 67 patients (81.7%) received chemotherapy combined with immunotherapy, and 15 patients (18.3%) received chemotherapy combined with immunotherapy and anti-angiogenesis therapy. The Exon20ins group showed a higher incidence of lymph node metastasis compared with the ERBB2 other mutation group and the wild-type group (36.4% vs. 15.8% vs. 9.8%, P=0.045). The median PFS in the Exon20ins group was significantly shorter than in the other mutation group (5.8 months vs. 10.3 months, P=0.025) and the wild-type group (5.8 months vs. 8.3 months, P=0.023). Univariate Cox regression analysis indicated that the ERBB2 Exon20ins mutation was an adverse prognostic factor (Exon20ins vs. other ERBB2 mutations, HR=2.9, 95%CI 1.18 - 7.1, P=0.014; Exon20ins vs. wild-type, HR=2.6, 95%CI 1.25 - 5.6, P=0.014). The combination with anti-angiogenesis therapy did not significantly affect the prognosis of PFS (HR=0.66, 95%CI 0.28 - 1.6, P=0.363). Multivariate Cox regression analysis revealed that the ERBB2 Exon20ins mutation was an independent adverse prognostic factor for PFS (Exon20ins vs. other ERBB2 mutations, HR=3.3, 95%CI 1.27 - 8.3, P=0.015; Exon20ins vs. wild-type, HR=2.7, 95%CI 1.2 - 5.88, P=0.014). For the 67 patients receiving chemotherapy combined with immunotherapy, Cox regression analysis showed that the ERBB2 Exon20ins mutation was still associated with poor prognosis in advanced NSCLC (Exon20ins vs. other ERBB2 mutations, HR=3.2, 95%CI 1.12 - 9.1, P=0.030; Exon20ins vs. wild-type, HR=2.5, 95%CI 1 - 5.88, P=0.040). Conclusions Advanced NSCLC patients with ERBB2 Exon20ins mutation have a worse prognosis compared with those with other ERBB2 mutation subtypes or ERBB2 wild-type when treated with first-line chemotherapy combined with immunotherapy. This suggests that ERBB2 Exon20ins mutation, as a particularly refractory mutation, requires the exploration of new combination strategies based on molecular subtyping to improve survival outcomes.

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1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin, 2024, 74(1): 12-49.
2. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med, 2023, 389(21): 1935-1948.
3. Shaw AT, Bauer TM, De Marinis F, et al. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med, 2020, 383(21): 2018-2029.
4. Krishnamurti U, Silverman JF. HER2 in breast cancer: a review and update. Adv Anat Pathol, 2014, 21(2): 100-107.
5. Mano MS, Rosa DD, De Azambuja E, et al. The 17q12-q21 amplicon: Her2 and topoisomerase-IIalpha and their importance to the biology of solid tumours. Cancer Treat Rev, 2007, 33(1): 64-77.
6. Kato Y, Udagawa H, Matsumoto S, et al. Efficacy of immune checkpoint inhibitors plus platinum-based chemotherapy as 1st line treatment for patients with non-small cell lung cancer harboring HER2 mutations: Results from LC-SCRUM-Asia. Lung Cancer, 2024, 197(107992.
7. Sompallae RR, Dundar B, Guseva NV, et al. EGFR and ERBB2 exon 20 insertion/duplication in advanced non-small cell lung cancer: genomic profiling and clinicopathologic features. Front Oncol, 2023, 13: 1163485.
8. NATIONAL COMPREHENSIVE CANCER NETWORK. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer (Version 3.2025). NCCN; 2025. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450.
9. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med, 2022, 386(3): 241-251.
10. Li B T, Michelini F, Misale S, et al. HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers. Cancer Discov, 2020, 10(5): 674-687.
11. Ren S, Wang J, Ying J, et al. Consensus for HER2 alterations testing in non-small-cell lung cancer. ESMO open, 2022, 7(1): 100395.
12. Odintsov I, Makarem M, Nishino M, et al. Prevalence and therapeutic targeting of high-level ERBB2 amplification in NSCLC. J Thorac Oncol, 2024, 19(5): 732-748.
13. Cho B C, Kim DW, Spira A I, et al. Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Nat Med, 2023, 29(10): 2577-2585.
14. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 Trial. J Clin Oncol, 2023, 41(31): 4852-4863.
15. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med, 2018, 378(22): 2078-2092.
16. Chen K, Pan G, Cheng G, et al. Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer patients with EGFR or HER2 exon 20 insertions. Thorac Cancer, 2021, 12(2): 218-226.
17. Ho D, Imai K, King G, et al. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw, 2011, 42(8): 1-8.
18. Yang G, Tian L, Wang Y. Hyperprogressive disease induced by PD-1 inhibitor monotherapy in lung adenocarcinoma with HER2 exon 20 insertion: report of two cases and review of literature. Discov Oncol, 2025, 16(1): 12.
19. Miura A, Yamada D, Nakamura M, et al. Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. Int J Cancer, 2021, 149(8): 1593-1604.
20. Prelaj A, Bottiglieri A, Proto C, et al. Poziotinib for EGFR and HER2 exon 20 insertion mutation in advanced NSCLC: Results from the expanded access program. Eur J Cancer, 2021, 149: 235-248.
21. Liu Y, Yuan M, Wu C, et al. A comprehensive function analysis of LMO2 in different breast cancer subtypes. Oncotarget, 2018, 9(10): 8911-8926.
22. Xiang Z, Song S, Zhu Z, et al. LncRNAs GIHCG and SPINT1-AS1 are crucial factors for pan-cancer cells sensitivity to lapatinib. Front Genet, 2019, 10: 25.
23. Xia L, Yu Y, Lan F, et al. Case report: tumor microenvironment characteristics in a patient with HER2 mutant lung squamous cell carcinoma harboring high PD-L1 expression who presented hyperprogressive disease. Front Oncol, 2021, 11: 760703.
24. Yang M, Xu X, Cai J, et al. NSCLC harboring EGFR exon-20 insertions after the regulatory C-helix of kinase domain responds poorly to known EGFR inhibitors. Int J Cancer, 2016, 139(1): 171-176.
25. Song Z, Wang M, Ge Y, et al. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies. Acta Pharm Sin B, 2021, 11(1): 13-29.
26. Liu S Y, Erazo T, Jee J, et al. Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer. Eur J Cancer, 2024, 210: 114257.
27. Zhao S, Xian X, Tian P, et al. Efficacy of combination chemo-immunotherapy as a first-line treatment for advanced non-small-cell lung cancer patients with HER2 alterations: a case series. Front Oncol, 2021, 11: 633522.
28. Yamaguchi T, Shimizu J, Matsuzawa R, et al. Efficacy of chemotherapy plus immune checkpoint inhibitors in patients with non-small cell lung cancer who have rare oncogenic driver mutations: a retrospective analysis. BMC Cancer, 2024, 24(1): 842.

Chinese Journal of Respiratory and Critical Care Medicine

Latest ArticlesPrognostic value of ERBB2 Exon20 insertions in advanced NSCLC patients receiving first-line chemoimmunotherapy

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