New advances in the targeted therapy of EGFR exon20ins mutant advanced NSCLC

doi:10.3760/cma.j.cn371439-20250217-00065

Abstract

Abstract:

The epidermal growth factor receptor （EGFR） exon 20 insertion （ex20ins） mutation is a rare subtype of mutations in non-small cell lung cancer （NSCLC）. Patients with advanced NSCLC carrying the EGFR ex20ins mutation tend to have poor responses to traditional EGFR tyrosine kinase inhibitors （TKIs）， chemotherapy， and immunotherapy， leading to a poor clinical prognosis. Significant progress has been made in the development of new drugs targeting the EGFR ex20ins mutation. The research on new drugs targeting EGFR ex20ins mutations has made significant progress. The main ones include new EGFR-TKIs （such as sunvozertinib， mobocertinib， and furmetinib， etc.）， bispecific antibodies （such as amivantamab， JMT101， and GB263T， etc.）， and emerging drugs such as AUY922. These agents have demonstrated promising efficacy in clinical trials， improving the objective response rate and progression-free survival of patients， and are expected to improve overall survival. An in-depth analysis of the mechanism of action and clinical trial progress of these novel targeted drugs for EGFR ex20ins-mutated NSCLC can offer new therapeutic strategies for patients with EGFR ex20ins-mutated NSCLC.

Key words: Carcinoma， non-small-cell lung, Genes， erbB-1, Molecular targeted therapy

Yuan Chun, Yu Xuesong, Wang Mengchao, Zhang Shao, Huang Yanbo, Wang Chaoran, Kong Fanming, Chen Liwei. New advances in the targeted therapy of EGFR exon20ins mutant advanced NSCLC[J]. Journal of International Oncology, 2025, 52(6): 382-387.

References 48

[1]	Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73(1): 17-48. DOI: 10.3322/caac.21763.
[2]	杨雪, 赵军. EGFR外显子20插入突变阳性NSCLC治疗的临床研究进展[J]. 中国肺癌杂志, 2022, 25(5): 337-350. DOI: 10.3779/j.issn.1009-3419.2022.103.01.
[3]	Burnett H, Emich H, Carroll C, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review[J]. PLoS One, 2021, 16(3): e0247620. DOI: 10.1371/journal.pone.0247620.
[4]	Bazhenova L, Minchom A, Viteri S, et al. Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations[J]. Lung Cancer, 2021, 162: 154-161. DOI: 10.1016/j.lungcan.2021.10.020. pmid: 34818606
[5]	Passaro A, Leighl N, Blackhall F, et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer[J]. Ann Oncol, 2022, 33(5): 466-487. DOI: 10.1016/j.annonc.2022.02.003. pmid: 35176458
[6]	袁胜芳, 任婕, 林卫佳, 等. EGFR共突变状态对晚期肺腺癌患者预后的价值研究[J]. 国际肿瘤学杂志, 2024, 51(9): 556-562. DOI: 10.3760/cma.j.cn371439-20240621-00093.
[7]	Zhu H, Zhang H, Xu Y, et al. PCR past, present and future[J]. Biotechniques, 2020, 69(4): 317-325. DOI: 10.2144/btn-2020-0057.
[8]	He J, Pericone CD, Vanderpoel J. Real-world patient characteristics, treatment patterns, and mutation testing patterns among US patients with advanced non-small cell lung cancer harboring EGFR mutations[J]. Adv Ther, 2022, 39(7): 3347-3360. DOI: 10.1007/s12325-022-02189-z. pmid: 35674970
[9]	Suh JH, Schrock AB, Johnson A, et al. Hybrid capture-based comprehensive genomic profiling identifies lung cancer patients with well-characterized sensitizing epidermal growth factor receptor point mutations that were not detected by standard of care testing[J]. Oncologist, 2018, 23(7): 776-781. DOI: 10.1634/theoncologist.2017-0493.
[10]	Kwon CS, Lin HM, Crossland V, et al. Non-small cell lung cancer with EGFR exon 20 insertion mutation: a systematic literature review and meta-analysis of patient outcomes[J]. Curr Med Res Opin, 2022, 38(8): 1341-1350. DOI: 10.1080/03007995.2022.2083326.
[11]	Wang M, Yang JC, Mitchell PL, et al. Sunvozertinib, a selective EGFR inhibitor for previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations[J]. Cancer Discov, 2022, 12(7): 1676-1689. DOI: 10.1158/2159-8290.CD-21-1615. pmid: 35404393
[12]	Wang M, Fan Y, Sun M, et al. Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial[J]. Lancet Respir Med, 2024, 12(3): 217-224. DOI: 10.1016/S2213-2600(23)00379-X.
[13]	Yang JCH, Wang M, Chiu CH, et al. 1325P sunvozertinib as first-line treatment in NSCLC patients with EGFR exon20 insertion mutations[J]. Ann Oncol, 2023, 34: S765. DOI: 10.1016/j.annonc.2023.09.2358.
[14]	Dhillon S. Sunvozertinib: first approval[J]. Drugs, 2023, 83(17): 1629-1634. DOI: 10.1007/s40265-023-01959-5.
[15]	ClinicalTrials. Gov. A phase 3, open-label, randomized, multi-center study of DZD9008 versus platinum-based doublet chemotherapy as first-line treatment for patients with locally advanced or metastatic non-small cell lung cancer harboring epidermal growth factor receptor exon 20 insertion mutation[EB/OL]. [2025-02-25] [2025-04-28]. https://www.cancer.columbia.edu/cancer-types-care/clinical-trials/find-clinical-trial/phase-3-open-label-randomized-multi-center-study-ofdzd9008-versus-platinum-based-doublet-chemotherapy-first-line-treatment-patients-locally-advanced-or-metastatic-non-small-cell-lung-cancer-harboring.
[16]	Gonzalvez F, Vincent S, Baker TE, et al. Mobocertinib (TAK-788): a targeted inhibitor of EGFR exon 20 insertion mutants in non-small cell lung cancer[J]. Cancer Discov, 2021, 11(7): 1672-1687. DOI: 10.1158/2159-8290.CD-20-1683. pmid: 33632773
[17]	Hanley MJ, Camidge DR, Fram RJ, et al. Mobocertinib: mechanism of action, clinical, and translational science[J]. Clin Transl Sci, 2024, 17(3): e13766. DOI: 10.1111/cts.13766.
[18]	Janne PA, Wang BC, Cho BC, et al. EXCLAIM-2: phase Ⅲ trial of first-line (1L) mobocertinib versus platinum-based chemotherapy in patients (pts) with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins)+ locally advanced/metastatic NSCLC[J]. Ann Oncol, 2023, 34: S1663-S1664. DOI: 10. 1016/j.annonc. 2023.10.586.
[19]	Zalaquett Z, Catherine Rita Hachem M, Kassis Y, et al. Acquired resistance mechanisms to osimertinib: the constant battle[J]. Cancer Treat Rev, 2023, 116: 102557. DOI: 10.1016/j.ctrv.2023.102557.
[20]	Piotrowska Z, Wang YT, Lecia V, et al. ECOG-ACRIN 5162: a phase Ⅱ study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions[J]. J Clin Oncol, 2020, 38(15_suppl): 9513-9513. DOI: 10.1200/JCO.2020.38.15_suppl.9513.
[21]	Zwierenga F, van Veggel B, Hendriks LEL, et al. High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: results from the phase 2 multicenter POSITION20 trial[J]. Lung Cancer, 2022, 170: 133-140. DOI: 10.1016/j.lungcan.2022.06.012. pmid: 35777160
[22]	Meng J, Zhang H, Bao JJ, et al. Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans[J]. Acta Pharmacol Sin, 2022, 43(2): 494-503. DOI: 10.1038/s41401-021-00667-8.
[23]	Han B, Zhou C, Zheng W, et al. A phase 1b study of furmonertinib, an oral, brain penetrant, selective EGFR inhibitor, in patients with advanced NSCLC with EGFR exon 20 insertions[J]. J Thorac Oncol, 2023, 18(11): S49. DOI: 10.1016/j.jtho.2023.09. 033.
[24]	Hu S, Ming H, He Q, et al. A study of high dose furmonertinib in EGFR exon 20 insertion mutation-positive advanced non-small cell lung cancer[J]. Front Oncol, 2024, 14: 1314301. DOI: 10.3389/fonc.2024.1314301.
[25]	Spira A, Cho BC, Felip E, et al. FURVENT: phase 3 trial of furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon20 insertion mutations (FURMO-004)[J]. Lung Cancer, 2025, 42(16): 108066. DOI: 10.1016/j.lungcan. 2024.108066.
[26]	Udagawa H, Hasako S, Ohashi A, et al. TAS6417/CLN-081 is a pan-mutation-selective EGFR tyrosine kinase inhibitor with a broad spectrum of preclinical sctivity against clinically relevant EGFR mutations[J]. Mol Cancer Res, 2019, 17(11): 2233-2243. DOI: 10.1158/1541-7786.MCR-19-0419. pmid: 31467113
[27]	Aggarwal C, Liu SV. Zipalertinib in EGFR exon 20-mutant non-small-cell lung cancer: drug development in a rare but crowded setting[J]. J Clin Oncol, 2023, 41(26): 4200-4203. DOI: 10.1200/JCO.23.00958.
[28]	Piotrowska Z, Tan DS, Smit EF, et al. Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor exon 20 insertions[J]. J Clin Oncol, 2023, 41(26): 4218-4225. DOI: 10.1200/JCO.23.00152.
[29]	Heymach JV, Yu HA, Besse B, et al. REZILIENT3: randomized phase Ⅲ study of first-line zipalertinib plus chemotherapy in patients with EGFR exon 20 insertion-mutated NSCLC[J]. Future Oncol, 2025, 21(5): 549-556. DOI: 10.1080/14796694.2025.2457294. pmid: 39957151
[30]	Seo D, Lim JH. Targeted therapies for EGFR exon 20 insertion mutation in non-small-cell lung cancer[J]. Int J Mol Sci, 2024, 25(11): 5917. DOI: 10.3390/ijms25115917.
[31]	Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20-mutant NSCLC: clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity[J]. Cancer Cell, 2022, 40(7): 754-767.e6. DOI: 10.1016/j.ccell.2022.06.006. pmid: 35820397
[32]	Cornelissen R, Prelaj A, Sun S, et al. Poziotinib in treatment-naive NSCLC harboring HER2 exon 20 mutations: ZENITH20-4, a multicenter, multicohort, open-label, phase 2 trial (cohort 4)[J]. J Thorac Oncol, 2023, 18(8): 1031-1041. DOI: 10.1016/j.jtho.2023.03.016. pmid: 36958688
[33]	Borm FJ, Smit EF. Poziotinib for HER2 exon 20-mutated NSCLC: addition or burden to the therapeutic arsenal?[J]. J Thorac Oncol, 2023, 18(8): 964-966. DOI: 10.1016/j.jtho.2023.05.002. pmid: 37479324
[34]	Liu B, Gao F, Zhao H, et al. Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC[J]. Eur J Med Chem, 2023, 258: 115590. DOI: 10.1016/j.ejmech.2023.115590.
[35]	Duan J, Wu L, Yang K, et al. Safety, tolerability, pharmacokinetics, and preliminary efficacy of YK-029A in treatment-naive patients with advanced NSCLC harboring EGFR exon 20 insertion mutations: a phase 1 trial[J]. J Thorac Oncol, 2024, 19(2): 314-324. DOI: 10.1016/j.jtho.2023.09.1449.
[36]	Christopoulos P. A new era for EGFR exon20 targeting in non-small cell lung cancer[J]. Chin Clin Oncol, 2025, 14(1): 14. DOI: 10.21037/cco-24-102.
[37]	Neijssen J, Cardoso RMF, Chevalier KM, et al. Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET[J]. J Biol Chem, 2021, 296: 100641. DOI: 10.1016/j.jbc.2021.100641.
[38]	秦雪倩, 杨宏宇, 王真, 等. 双特异性抗体在非小细胞肺癌治疗中的进展[J]. 国际肿瘤学杂志, 2023, 50(9): 558-563. DOI: 10.3760/cma.j.cn371439-20230612-00107.
[39]	Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions[J]. N Engl J Med, 2023, 389(22): 2039-2051. DOI: 10.1056/NEJMoa2306441.
[40]	Zhao S, Zhuang W, Han B, et al. Phase 1b trial of anti-EGFR antibody JMT101 and osimertinib in EGFR exon 20 insertion-positive non-small-cell lung cancer[J]. Nat Commun, 2023, 14(1): 3468. DOI: 10.1038/s41467-023-39139-4.
[41]	Zhang L, Fang W, Zhao S, et al. 137MO phase Ⅱ study of becotarug (JMT101) combined with osimertinib in patients (pts) with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations (BECOME study)[J]. ESMO Open, 2024, 9(Sulp3): 102724. DOI: 10.1016/j.esmoop.2024.102724.
[42]	O'Malley DM, Myers TKN, Zamagni C, et al. A randomized, open-label, parallel-controlled phase 3 study of combination JMT101 and osimertinib compared with cisplatin-pemetrexed in patients with EGFR exon 20ins mutated locally advanced or metastatic non-small cell lung cancer[J]. J Clin Oncol, 2023, 41(16): TPS5622. DOI: 10.1200/JCO.2023.41.16_suppl.TPS562.
[43]	Du Q, Zeng W, Yang X, et al. Abstract LB538: characterization of GB263T,a tri-specific antibody against EGFR/cMET/cMET for NSCLC[J]. Cancer Res, 2022, 82(12_Supplement): LB538. DOI: 10.1158/1538-7445.AM2022-LB538.
[44]	Yang JJ, Pavlakis N, Xie F, et al. Preliminary dose escalation results from a first-in-human, phase Ⅰ/Ⅱ study of GB263T, a novel EGFR/cMET/cMET trispecific antibody, in patients with advanced EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2023, 41(16_suppl): e21085. DOI: 10.1200/JCO.2023.41.16_suppl.e21085.
[45]	De Gortet DJ, O'Connor MN, Deshiere A, et al. Abstract 336: mechanism of action of MCLA-129, a bispecific antibody that targets EGFR and c-MET and impairs growth of EGFR exon 20 insertion mutant non-small cell lung cancer[J]. Cancer Res, 2022, 82(12_Supplement): 336. DOI: 10.1158/1538-7445.AM2022-336.
[46]	Wang J, Zhong J, Wu L, et al. Efficacy and safety of MCLA-129, an EGFR/c-MET bispecific antibody, in advanced non-small cell lung cancer(NSCLC)[J]. J Clin Oncol, 2024, 42(16_suppl): 8604. DOI: 10.1200/JCO.2024.42.16_suppl.8604.
[47]	He CX, Lv Y, Guo M, et al. Complex crystal structure determination of hsp90N-NVP-AUY922 and in vitro anti-NSCLC activity of NVP-AUY922[J]. Front Oncol, 2022, 12: 847556. DOI: 10.3389/fonc.2022.847556.
[48]	Shen CH, Hsieh CC, Jiang KY, et al. AUY922 induces retinal toxicity through attenuating TRPM1[J]. J Biomed Sci, 2021, 28(1): 55. DOI: 10.1186/s12929-021-00751-5.