The development and progression of non-small cell lung cancer (NSCLC) are closely associated with core driving alterations, such as epidermal growth factor receptor (EGFR) mutations. With advances in targeted therapy, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have become the preferred treatment for patients with advanced NSCLC harboring EGFR mutations. However, the efficacy of EGFR-TKIs in patients with rare or compound mutations remains poorly understood. Here, we report a case of a patient with an EGFR L858R and R776C compound mutation who achieved a progression-free survival (PFS) of approximately twenty months after receiving the third-generation EGFR-TKIs osimertinib as first-line therapy. After this period, the disease progressed, and the patient is currently continuing targeted therapy (osimertinib plus amivantamab). These findings indicate that osimertinib provided substantial clinical benefit for this patient with the EGFR L858R and R776C compound mutation, suggesting that this strategy may represent a potential treatment option for NSCLC patients harboring such rare compound mutations.

1. BrayF, FerlayJ, SoerjomataramI, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492.

2. MaC, ZhangJ, TangD, et al. Tyrosine kinase inhibitors could be effective against non-small cell lung cancer brain metastases harboring uncommon EGFR mutations[J]. Front Oncol, 2020, 10: 224. DOI: 10.3389/fonc.2020.00224.

3. YangJC, WuYL, SchulerM, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-lung 3 and LUX-lung 6): analysis of overall survival data from two randomised, phase 3 trials[J]. Lancet Oncol, 2015, 16(2): 141-151. DOI: 10.1016/S1470-2045(14)71173-8.

4. HarrisonPT, VyseS, HuangPH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer[J]. Semin Cancer Biol, 2020, 61: 167-179. DOI: 10.1016/j.semcancer.2019.09.015.

5. ZengL, XiaoL, JiangW, et al. Investigation of efficacy and acquired resistance for EGFR-TKI plus bevacizumab as first-line treatment in patients with EGFR sensitive mutant non-small cell lung cancer in a real world population[J]. Lung Cancer, 2020, 141: 82-88. DOI: 10.1016/j.lungcan.2020.01.009.

6. KobayashiY, AzumaK, NagaiH, et al. Characterization of EGFR T790M, L792F, and C797S mutations as mechanisms of acquired resistance to afatinib in lung cancer[J]. Mol Cancer Ther, 2017, 16(2): 357-364. DOI: 10.1158/1535-7163.MCT-16-0407.

7. SchwartzLH, LitièreS, de VriesE, et al. RECIST 1.1—update and clarification: from the RECIST committee[J]. Eur J Cancer, 2016, 62: 132-137. DOI: 10.1016/j.ejca.2016.03.081.

8. SuPL, FuruyaN, AsrarA, et al. Recent advances in therapeutic strategies for non-small cell lung cancer[J]. J Hematol Oncol, 2025, 18(1): 35. DOI: 10.1186/s13045-025-01679-1.

9. 中国临床肿瘤学会非小细胞肺癌专家委员会, PACC专家共识编写小组. EGFR PACC突变晚期非小细胞肺癌诊疗专家共识(2025版)[J]. 中华肿瘤杂志, 2025, 47(9): 811-829.Chinese Society of Clinical Oncology, Committee of Experts on Non-Small Cell Lung Cancer, PACCExpert Consensus Writing Group. Expert consensus on the diagnosis and treatment of advanced non-small cell lung cancer with EGFR PACC mutations (2025 edition)[J]. Chinese Journal of Oncology, 2025, 47(9): 811-829.  DOI: 10.3760/cma.j.cn112152-20250529-00247.

10. MaffezzoliM, LauJ, JustinS, et al. Who truly benefits from first-line intensification in EGFR-mutant NSCLC?[J]. Curr Oncol Rep, 2025, 27(12): 1409-1415. DOI: 10.1007/s11912-025-01723-w.

11. WuJY, YuCJ, ChangYC, et al. Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer[J]. Clin Cancer Res, 2011, 17(11): 3812-3821. DOI: 10.1158/1078-0432.CCR-10-3408.

12. KlughammerB, BruggerW, CappuzzoF, et al. Examining treatment outcomes with erlotinib in patients with advanced non-small cell lung cancer whose tumors harbor uncommon EGFR mutations[J]. J Thorac Oncol, 2016, 11(4): 545-555. DOI: 10.1016/j.jtho.2015.12.107.

13. OkumaY, KubotaK, ShimokawaM, et al. First-line osimertinib for previously untreated patients with NSCLC and uncommon EGFR mutations: the UNICORN phase 2 nonrandomized clinical trial[J]. JAMA Oncol, 2024, 10(1): 43-51. DOI: 10.1001/jamaoncol.2023.5013.

14. BarJ, PeledN, SchokrpurS, et al. UNcommon EGFR mutations: international case series on efficacy of osimertinib in real-life practice in first-LiNe setting (UNICORN)[J]. J Thorac Oncol, 2023, 18(2): 169-180. DOI: 10.1016/j.jtho.2022.10.004.

15. ChoJH, LimSH, AnHJ, et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase Ⅱ trial (KCSG-LU15-09)[J]. J Clin Oncol, 2020, 38(5): 488-495. DOI: 10.1200/JCO.19.00931.

16. ZehirA, BenayedR, ShahRH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients[J]. Nat Med, 2017, 23(6): 703-713. DOI: 10.1038/nm.4333.

17. TuHY, KeEE, YangJJ, et al. A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer[J]. Lung Cancer, 2017, 114: 96-102. DOI: 10.1016/j.lungcan.2017.11.005.

18. HanC, DingX, LiM, et al. Afatinib, an effective treatment for patient with lung squamous cell carcinoma harboring uncommon EGFR G719A and R776C co-mutations[J]. J Cancer Res Clin Oncol, 2022, 148(5): 1265-1268. DOI: 10.1007/s00432-021-03864-4.

19. ZhaoY, ZhaiL, DengL, et al. Efficacy of osimertinib in afatinib-resistant lung cancer harboring uncommon EGFR mutations: case report and literature review[J]. Clin Lung Cancer, 2021, 22(3): e466-e469. DOI: 10.1016/j.cllc.2020.06.017.

20. RuanZ, KannanN. Mechanistic insights into R776H mediated activation of epidermal growth factor receptor kinase[J]. Biochemistry, 2015, 54(27): 4216-4225. DOI: 10.1021/acs.biochem.5b00444.

21. ShanY, EastwoodMP, ZhangX, et al. Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization[J]. Cell, 2012, 149(4): 860-870. DOI: 10.1016/j.cell.2012.02.063.

22. CrossDA, AshtonSE, GhiorghiuS, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer[J]. Cancer Discov, 2014, 4(9): 1046-1061. DOI: 10.1158/2159-8290.CD-14-0337.

23. National Comprehensive Cancer Network. Home[EB/OL]. [2026-06-02]. https://www.nccn.org.

24. MoikF, RiedlJM, AyC. Correspondence to: amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase Ⅲ MARIPOSA-2 study[J]. Ann Oncol, 2024, 35(3): 327. DOI: 10.1016/j.annonc.2023.11.007.

25. ChoBC, KimDW, SpiraAI, et al. Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial[J]. Nat Med, 2023, 29(10): 2577-2585. DOI: 10.1038/s41591-023-02554-7.

26. MET免疫组织化学标准化判读专家委员会, 中国抗癌协会肿瘤病理专业委员会分子病理协作组. 非小细胞肺癌MET免疫组织化学检测和判读标准中国专家共识(2023版)[J]. 中华病理学杂志, 2023, 52(11): 1090-1097.Chinese expert consensus on MET immunohistochemistry detection and interpretation standards for non-small cell lung cancer (2023 version) of Tumor Pathology Committee of Chinese Anti-Cancer Association. Chinese expert consensus on MET immunohistochemistry detection and interpretation standards for non-small cell lung cancer (2023 version)[J]. Chinese Journal of Pathology, 2023, 52(11): 1090-1097.  DOI: 10.3760/cma.j.cn112151-20230626-00423.