Efficacy of targeted therapy in advanced NSCLC patients with rare EGFR mutations and combinations of mutations

The efficacy of targeted therapy in rare epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer is debatable. However, due to introduction of NGS technology into clinical practice, patients with non-small cell lung cancer (NSCLC) harbouring rare EGFR mutations are being identified more often. We report here the case demonstrating the absence of EGFR mutations at the initial stage of diagnosis of metastatic lung adenocarcinoma in November 2024. The chemotherapy consisting of pemetrexed, carboplatin, and bevacizumab was initiated in December 2024. During treatment, a comprehensive genomic profiling test (Foundation One Liquid CDx Roche) was performed to evaluate a patient’s blood for circulating tumour DNA (ctDNA). A rare EGFR E114K extracellular domain mutation and mutations in the cell cycle checkpoint kinase 2 (CHEK2) – V335fs*14, PTPN11 – G503V, and TP53 splice site 375G > T were identified. Osimertinib at a dose of 80 mg daily has been administered since April 2025. After the sixth course of polychemotherapy and targeted therapy (PCT+TT) in May 2025 and with due account for stabilization based on 18F-FDG PET-CT findings, the patient continued to receive the maintenance chemotargeted therapy with pemetrexed and osimertinib, showing disease stability. Most studies that led to the introduction of tyrosine kinase inhibitors excluded patients with rare EGFR mutations. Moreover, for many mutations, it is still unclear whether they are disease activating or merely incidental findings. Nevertheless, the available separate data suggest that osimertinib, EGFR tyrosine kinase inhibitor (EGFR-TKI), has clinical efficacy in rare EGFR mutations.

1. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underly-ing responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–2139. https://doi.org/10.1056/NEJMoa040938.

2. Passaro A, Mok T, Peters S, Popat S, Ahn MJ, Marinis FD. Recent advances on the role of EGFR tyrosine kinase inhibitors in the management of NSCLC with uncommon, non exon 20 insertions, EGFR mutations. J Thorac Oncol. 2021;16(5):764–773. https://doi.org/10.1016/j.jtho.2020.12.002.

3. Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2013;8(1):45–51. https://doi.org/10.1097/JTO.0b013e3182781e35.

4. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumu S, Isobe H et al. North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–2388. https://doi.org/10.1056/NEJMoa0909530.

5. Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with meta-static lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327–3334. https://doi.org/10.1200/JCO.2012.44.2806.

6. Yang JC, Sequist LV, Geater SL, Tsai C, Mok TSK, Schuler M et al. Clinical activity of afatinib in patients with advanced non–small-cell lung cancer harboring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830–838. https://doi.org/10.1016/S1470-2045(15)00026-1.

7. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH et al.; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–125. https://doi.org/10.1056/NEJMoa1713137.

8. Cho JH, Lim SH, An HJ, Kim KH, Park KU, Kang EJ 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 Clin Oncol. 2020;38(5):488–495. https://doi.org/10.1200/JCO.19.00931.

9. Bar J, Peled N, Schokrpur S, Wolner M, Rotem O, Girard N et al. Uncommon EGFR mutations: international case series on efficacy of osimertinib in real-life practice in first-line setting (UNICORN). J Thorac Oncol. 2023;18(2):169–180. https://doi.org/10.1016/j.jtho.2022.10.004.

10. Okuma Y, Kubota K, Shimokawa M, Hashimoto K, Kawashima Y, Sakamoto T et al. First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations: The UNICORN Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2024;10(1):43–51. https://doi.org/10.1001/jamaoncol.2023.5013.

11. Chiu CH, Yang CT, Shih JY, Huang MS, Su WC, Lai RS et al. Epidermal growth factor receptor tyrosine kinase inhibitor treatment response in advanced lung adenocarcinomas with G719X/L861Q/S768I mutations. J Thorac Oncol. 2015;10(5):793–799. https://doi.org/10.1097/JTO.0000000000000504.

12. Yang JC, Schuler M, Popat S, Miura S, Park K, Passaro A et al. Afatinib for the treatment of non–small cell lung cancer harboring uncommon EGFR mutations: an updated database of 1023 cases brief report. Front Oncol. 2022;12:834704. https://doi.org/10.3389/fonc.2022.834704.

13. Robichaux JP, Le X, Vijayan RSK, Hicks JK, Heeke S, Elamin YY et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature. 2021;597(7878):732–737. https://doi.org/10.1038/s41586-021-03898-1.

14. Cho J, Chen L, Sangji N, Okabe T, Yonesaka K, Francis JM et al. Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res. 2013;73(22):6770–6779. https://doi.org/10.1158/0008-5472.CAN-13-1145.

15. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103(2):211–225. https://doi.org/10.1016/S0092-8674(00)00114-8.

16. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS et al; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–640. https://doi.org/10.1056/NEJMoa1612674.

17. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response evaluation criteria in solid tumours: revised RECIST guide-line (version 1.1). Eur J Cancer. 2009;45(2):228–247. https://doi.org/10.1016/j.ejca.2008.10.026.

18. Solomon SR, McDougall CR, Tsai JR, Myers SW, Dada HI, Drusbosky LM et al. EP16.03-019 Landscape of EGFR Extracellular Domain Mutations in Advanced Non Small Cell Lung Carcinoma. J Thor Oncol. 2022;17(9):596. Available at: https://www.jto.org/article/S1556-0864(22)01421-6/fulltext.

19. Mikheev DV, Chernyakova AP, Mitiushkina NV, Tyurin VI, Nikitina AS, Asadulaeva KA et al. The Spectrum of Uncommon EGFR Mutations in Non-Small Cell Lung Cancer. Voprosy Onkologii. 2024;70(6):1115–1121. (In Russ.) https://doi.org/10.37469/0507-3758-2024-70-6-1115-1121.

20. Wei L, Lao Y, Fu T, Xie Z, Wang Y, Yang T et al. Distinct Role of TP53 Co-mutations in Different EGFR Subtypes Mediating the Response to EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Clin Lung Cancer. 2025;26(6):478–491.e7. https://doi.org/10.1016/j.cllc.2025.04.007.

21. Planchard D, Jänne PA, Cheng Y, Yang JCH, Yanagitani N, Kim SW et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023;389:1935–1948. https://doi.org/10.1056/NEJMoa2306434.

22. Cekay M, Arndt PF, Dumitrascu R, Savai R, Braeuninger A, Gattenloehner S et al. Case Report: Durable therapy response to Osimertinib in rare EGFR Exon 18 mutated NSCLC. Front Oncol. 2023;13:1182391. https://doi.org/10.3389/fonc.2023.1182391.

23. Popuria N, Nagalapuramb V, Zamanb U, Aljumaily R. Osimertinib for Uncommon Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Carcinoma: A Case Report. Case Rep Oncol. 2024;17:1329–1334. https://doi.org/10.1159/000543459.

24. Barsouk A, Elghawy O, Watts A, Reed-Guy L, Tompkins W, Chandrasekhara K et al. Osimertinib vs. Afatinib in 1L therapy of atypical EGFR-mutated met-astatic non-small cell lung cancer (mNSCLC): A multi-institution, real-world survival analysis. Lung Cancer. 2025;203:108551. https://doi.org/10.1016/j.lungcan.2025.108551.