Treatment of Non-Small Cell Lung Cancer with Atypical EGFR Mutations

Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(14):2787–99.

Article  CAS  Google Scholar 

Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;2005(1):0010.

Google Scholar 

Nie W, Tang L, Zhang H, Shao J, Wang Y, Chen L, et al. Structural analysis of the EGFR TK domain and potential implications for EGFR targeted therapy. Int J Oncol. 2012;40(6):1763–9.

CAS  PubMed  Google Scholar 

Pines G, Köstler WJ, Yarden Y. Oncogenic mutant forms of EGFR: lessons in signal transduction and targets for cancer therapy. FEBS Lett. 2010;584(12):2699–706.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci. 2016;107(9):1179–86.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu L, Liu J, Shao D, Deng Q, Tang H, Liu Z, et al. Comprehensive genomic profiling of lung cancer using a validated panel to explore therapeutic targets in East Asian patients. Cancer Sci. 2017;108(12):2487–94.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985–93.

Article  PubMed  PubMed Central  Google Scholar 

John T, Taylor A, Wang H, Eichinger C, Freeman C, Ahn MJ. Uncommon EGFR mutations in non-small-cell lung cancer: a systematic literature review of prevalence and clinical outcomes. Cancer Epidemiol. 2022;76: 102080.

Article  PubMed  Google Scholar 

•• 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):732–7. This manuscript provides a new way of grouping atypical EGFR mutations, into “structure-function” categories which are predictive of response to therapy.

Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.

Article  CAS  PubMed  Google Scholar 

Harrison PT, Vyse S, Huang PH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer. Semin Cancer Biol. 2020;61:167–79.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ge M, Zhuang Y, Zhou X, Huang R, Liang X, Zhan Q. High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases. J Neurooncol. 2017;135(2):413–8.

Article  CAS  PubMed  Google Scholar 

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380–8.

Article  CAS  PubMed  Google Scholar 

Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8.

Article  CAS  PubMed  Google Scholar 

Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42.

Article  CAS  PubMed  Google Scholar 

Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.

Article  CAS  PubMed  Google Scholar 

Sequist LV, Yang JCH, Yamamoto N, O’Byrne K, Hirsh V, Mok T, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(27):3327–34.

Article  CAS  Google Scholar 

Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014;110(1):55–62.

Article  CAS  PubMed  Google Scholar 

Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15(2):213–22.

Article  CAS  PubMed  Google Scholar 

Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol Off J Eur Soc Med Oncol. 2015;26(9):1877–83.

Article  CAS  Google Scholar 

Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(11):1454–66.

Article  CAS  PubMed  Google Scholar 

Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113–25.

Article  CAS  PubMed  Google Scholar 

Yang JCH, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SHI, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012;13(5):539–48.

Article  CAS  PubMed  Google Scholar 

• Yang JCH, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, 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. Lancet Oncol. 2015;16(2):141–51. This manuscript provides the most robust clinical trial data available for outcomes on afatinib in patients with atypical EGFR mutations. Data indicates that afatinib is active in patients with atypical EGFR mutations and may be particularly efficacious in patients with mutations G719X and S768I (PACC mutations).

Watanabe S, Minegishi Y, Yoshizawa H, Maemondo M, Inoue A, Sugawara S, et al. Effectiveness of gefitinib against non-small-cell lung cancer with the uncommon EGFR mutations G719X and L861Q. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2014;9(2):189–94.

CAS  Google Scholar 

Yang JCH, 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.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhao Y, Cheng B, Chen Z, Li J, Liang H, Chen Y, et al. Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors for patients with lung cancer: a systematic review and network meta-analysis. Crit Rev Oncol Hematol. 2021;160: 103305.

Article  PubMed  Google Scholar 

Kang L, Mai J, Liang W, Zou Q, Huang C, Lin Y, et al. CNS efficacy of afatinib as first-line treatment in advanced non-small cell lung cancer patients with EGFR mutations. Front Oncol. 2023;13:1094195.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Updated overall survival in a randomized study comparing dacomitinib with gefitinib as first-line treatment in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. Drugs. 2021;81(2):257–66.

Article  CAS  PubMed  Google Scholar 

• Li HS, Yang GJ, Cai Y, Li JL, Xu HY, Zhang T, et al. Dacomitinib for advanced non-small cell lung cancer patients harboring major uncommon EGFR alterations: a dual-center, single-arm, ambispective cohort study in China. Front Pharmacol. 2022;13: 919652. This is the only clinical trial available that evaluates the use of dacomitinib in patients with atypical EGFR mutations. The data supports that dacomitinib can provide benefit in these patients.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang J, Wang Y, Liu Z, Wang L, Yao Y, Liu Y, et al. Efficacy of dacomitinib in patients with EGFR-mutated NSCLC and brain metastases. Thorac Cancer. 2021;12(24):3407–15.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629–40.

Article  CAS  PubMed  Google Scholar 

Yang JCH, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(12):1288–96.

Article  CAS  Google Scholar 

Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41–50.

Article  CAS  PubMed  Google Scholar 

Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2018;JCO2018783118.

• Okuma Y, Kubota K, Shimokawa M, Hashimoto K, Kawashima Y, Sakamoto T, et al. Uncommon EGFR mutations conducted with osimertinib in patients with NSCLC (UNICORN): A phase 2 study. J Clin Oncol. 2023;41(16_suppl):9045–9045. Though all data is not yet available from this trial, the preliminary results were recently presented at ASC0. This clinical trial provides evidence that osimertinib is efficacious in atypical EGFR mutations.

• 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 Off J Am Soc Clin Oncol. 2020;38(5):488–95. This manuscript describes the outcomes of patients with atypical EGFR mutations treated with osimertinib in a clinical trial. It provides support for the use of osimertinib in atypical EGFR mutations, particularly in classical-like mutations, like L861Q, which showed a robust response.

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 Off Publ Int Assoc Study Lung Cancer. 2023;18(2):169–80.

CAS  Google Scholar 

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